Csaba Vadasz, Ph.D.

mGluR7 Genetics and Alcohol: Intersection Yields Clues for Addiction
Gyetvai, Beatrix; Simonyi, Agnes; Oros, Melinda; Saito, Mariko; Smiley, John; Vadasz, Csaba
2011 Jun;36(6):1087-1100, Neurochemical research
Development of addiction to alcohol or other substances can be attributed in part to exposure-dependent modifications at synaptic efficacy leading to an organism which functions at an altered homeostatic setpoint. Genetic factors may also influence setpoints and the stability of the homeostatic system of an organism. Quantitative genetic analysis of voluntary alcohol drinking, and mapping of the involved genes in the quasi-congenic Recombinant QTL Introgression strain system, identified Eac2 as a Quantitative Trait Locus (QTL) on mouse chromosome 6 which explained 18% of the variance with an effect size of 2.09 g/kg/day alcohol consumption, and Grm7 as a quantitative trait gene underlying Eac2 [Vadasz et al. in Neurochem Res 32:1099-1112, 100, Genomics 90:690-702, 102]. In earlier studies, the product of Grm7 mGluR7, a G protein-coupled receptor, has been implicated in stress systems [Mitsukawa et al. in Proc Natl Acad Sci USA 102:18712-18717, 63], anxiety-like behaviors [Cryan et al. in Eur J Neurosci 17:2409-2417, 14], memory [Holscher et al. in Learn Mem 12:450-455, 26], and psychiatric disorders (e.g., [Mick et al. in Am J Med Genet B Neuropsychiatr Genet 147B:1412-1418, 61; Ohtsuki et al. in Schizophr Res 101:9-16, 72; Pergadia et al. in Paper presented at the 38th Annual Meeting of the Behavior Genetics Association, Louisville, Kentucky, USA, 76]. Here, in experiments with mice, we show that (1) Grm7 knockout mice express increased alcohol consumption, (2) sub-congenic, and congenic mice carrying a Grm7 variant characterized by higher Grm7 mRNA drink less alcohol, and show a tendency for higher circadian dark phase motor activity in a wheel running paradigm, respectively, and (3) there are significant genetic differences in Grm7 mRNA abundance in the mouse brain between congenic and background mice identifying brain areas whose function is implicated in addiction related processes. We hypothesize that metabotropic glutamate receptors may function as regulators of homeostasis, and Grm7 (mGluR7) is involved in multiple processes (including stress, circadian activity, reward control, memory, etc.) which interact with substance use and the development of addiction. In conclusion, we suggest that mGluR7 is a significant new therapeutic target in addiction and related neurobehavioral disorders
— id: 134257, year: 2011, vol: 36, page: 1087, stat: Journal Article,

Involvement of ceramide in ethanol-induced apoptotic neurodegeneration in the neonatal mouse brain
Saito, Mariko; Chakraborty, Goutam; Hegde, Medha; Ohsie, Jason; Paik, Sun-Mee; Vadasz, Csaba; Saito, Mitsuo
2010 Oct;115(1):168-77, Journal of neurochemistry
J. Neurochem. (2010) 115, 168-177. ABSTRACT: Acute administration of ethanol to 7-day-old mice is known to cause robust apoptotic neurodegeneration in the brain. Our previous studies have shown that such ethanol-induced neurodegeneration is accompanied by increases in lipids, including ceramide, triglyceride (TG), cholesterol ester (ChE), and N-acylphosphatidylethanolamine (NAPE) in the brain. In this study, the effects of ethanol on lipid profiles as well as caspase 3 activation were examined in the cortex, hippocampus, cerebellum, and inferior colliculus of the postnatal day 7 mouse brain. We found that the cortex, hippocampus, and inferior colliculus, which showed substantial caspase 3 activation by ethanol, manifested significant elevations in ceramide, TG, and NAPE. In contrast, the cerebellum, with the least caspase 3 activation, failed to show significant changes in ceramide and TG, and exhibits much smaller increases in NAPE than other brain regions. Ethanol-induced increases in ChE were observed in all brain regions tested. Inhibitors of serine palmitoyltransferase effectively blocked ethanol-induced caspase 3 activation as well as elevations in ceramide, ChE, and NAPE. Immunohistochemical studies indicated that the expression of serine palmitoyltransferase was mainly localized in neurons and was enhanced in activated caspase 3-positive neurons generated by ethanol. These results indicate that de novo ceramide synthesis has a vital role in ethanol-induced apoptotic neurodegeneration in the developing brain
— id: 112428, year: 2010, vol: 115, page: 168, stat: Journal Article,

Tau phosphorylation and cleavage in ethanol-induced neurodegeneration in the developing mouse brain
Saito, Mariko; Chakraborty, Goutam; Mao, Rui-Fen; Paik, Sun-Mee; Vadasz, Csaba; Saito, Mitsuo
2010 Apr;35(4):651-659, Neurochemical research
Previous studies indicated that ethanol-induced neurodegeneration in postnatal day 7 (P7) mice, widely used as a model for the fetal alcohol spectrum disorders, was accompanied by glycogen synthase kinase-3beta (GSK-3beta) and caspase-3 activation. Presently, we examined whether tau, a microtubule associated protein, is modified by GSK-3beta and caspase-3 in ethanol-treated P7 mouse forebrains. We found that ethanol increased phosphorylated tau recognized by the paired helical filament (PHF)-1 antibody and by the antibody against tau phosphorylated at Ser199. Ethanol also generated tau fragments recognized by an antibody against caspase-cleaved tau (C-tau). C-tau was localized in neurons bearing activated caspase-3 and fragmented nuclei. Over time, cell debris and degenerated projections containing C-tau appeared to be engulfed by activated microglia. A caspase-3 inhibitor partially blocked C-tau formation. Lithium, a GSK-3beta inhibitor, blocked ethanol-induced caspase-3 activation, phosphorylated tau elevation, C-tau formation, and microglial activation. These results indicate that tau is phosphorylated by GSK-3beta and cleaved by caspase-3 during ethanol-induced neurodegeneration in the developing brain
— id: 140578, year: 2010, vol: 35, page: 651, stat: Journal Article,

Developmental profiles of lipogenic enzymes and their regulators in the neonatal mouse brain
Saito, Mariko; Chakraborty, Goutam; Mao, Rui-Fen; Vadasz, Csaba; Saito, Mitsuo
2009 Nov;34(11):1945-1954, Neurochemical research
It has been shown that lipogenic enzymes, such as fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), are highly expressed in the rodent brain during the early neonatal period and decline thereafter. However, cellular localization of these enzymes is unknown. Presently, we examined developmental changes in the levels and cellular localization of FAS and ACC, and their putative regulators, sterol-regulatory element-binding protein (SREBP)-1 and AMP-activated protein kinase (AMPK) in the mouse brain. Levels of these proteins including phosphorylated forms of ACC and AMPK decreased between postnatal day 4 (P4) and P19. Immunohistochemical studies indicated that FAS, ACC, AMPK, and SREBP-1 were expressed in neurons at P7, while FAS was found mostly in cells of oligodendrocyte lineage at P19. These studies suggest that neurons in the early neonatal brain are involved in do novo fatty acid synthesis
— id: 128991, year: 2009, vol: 34, page: 1945, stat: Journal Article,

Lithium blocks ethanol-induced modulation of protein kinases in the developing brain
Chakraborty, Goutam; Saito, Mitsuo; Mao, Rui-Fen; Wang, Ray; Vadasz, Csaba; Saito, Mariko
2008 Mar 14;367(3):597-602, Biochemical & biophysical research communications
Lithium has been shown to be neuroprotective against various insults including ethanol exposure. We previously reported that ethanol-induced apoptotic neurodegeneration in the postnatal day 7 (P7) mice is associated with decreases in phosphorylation levels of Akt, glycogen synthase kinase-3beta (GSK-3beta), and AMP-activated protein kinase (AMPK), and alteration in lipid profiles in the brain. Here, P7 mice were injected with ethanol and lithium, and the effects of lithium on ethanol-induced alterations in phosphorylation levels of protein kinases and lipid profiles in the brain were examined. Immunoblot and immunohistochemical analyses showed that lithium significantly blocked ethanol-induced caspase-3 activation and reduction in phosphorylation levels of Akt, GSK-3beta, and AMPK. Further, lithium inhibited accumulation of cholesterol ester (ChE) and N-acylphosphatidylethanolamine (NAPE) triggered by ethanol in the brain. These results suggest that Akt, GSK-3beta, and AMPK are involved in ethanol-induced neurodegeneration and the neuroprotective effects of lithium by modulating both apoptotic and survival pathways
— id: 93994, year: 2008, vol: 367, page: 597, stat: Journal Article,

Genetic and pharmacological manipulations of the CB(1) receptor alter ethanol preference and dependence in ethanol preferring and nonpreferring mice
Vinod, K Yaragudri; Yalamanchili, Ratnakumar; Thanos, Panayotis K; Vadasz, Csaba; Cooper, Thomas B; Volkow, Nora D; Hungund, Basalingappa L
2008 Aug;62(8):574-581, Synapse
Recent studies have indicated a role for the endocannabinoid system in ethanol-related behaviors. This study examined the effect of pharmacological activation, blockade, and genetic deletion of the CB(1) receptors on ethanol-drinking behavior in ethanol preferring C57BL/6J (B6) and ethanol nonpreferring DBA/2J (D2) mice. The deletion of CB(1) receptor significantly reduced the ethanol preference. Although the stimulation of the CB(1) receptor by CP-55,940 markedly increased the ethanol preference, this effect was found to be greater in B6 than in D2 mice. The antagonism of CB(1) receptor function by SR141716A led to a significant reduction in voluntary ethanol preference in B6 than D2 mice. A significant lower hypothermic and greater sedative response to acute ethanol administration was observed in both the strains of CB(1) -/- mice than wild-type mice. Interestingly, genetic deletion and pharmacological blockade of the CB(1) receptor produced a marked reduction in severity of handling-induced convulsion in both the strains. The radioligand binding studies revealed significantly higher levels of CB(1) receptor-stimulated G-protein activation in the striatum of B6 compared to D2 mice. Innate differences in the CB(1) receptor function might be one of the contributing factors for higher ethanol drinking behavior. The antagonists of the CB(1) receptor may have therapeutic potential in the treatment of ethanol dependence
— id: 93993, year: 2008, vol: 62, page: 574, stat: Journal Article,

Ethanol alters lipid profiles and phosphorylation status of AMP-activated protein kinase in the neonatal mouse brain
Saito, Mariko; Chakraborty, Goutam; Mao, Rui-Fen; Wang, Ray; Cooper, Thomas B; Vadasz, Csaba; Saito, Mitsuo
2007 Nov;103(3):1208-1218, Journal of neurochemistry
Previously, we have shown that ethanol-induced apoptosis in cultured neurons is accompanied by changes in cellular lipid profiles. In the present study, the effects of ethanol on brain lipid metabolism were studied using 7-day-old C57BL/6ByJ mice, which display apoptotic neurodegeneration upon exposure to ethanol. The brain lipids were extracted 4-24 h after the ethanol or saline treatment, and analyzed by TLC. We found that the levels of triglyceride, cholesterol ester, ceramide, and N-acylphosphatidylethanolamine increased significantly in the brains of ethanol-treated mice compared to those of saline-treated mice. Concomitantly, ethanol reduced Thr172 phosphorylation of AMP-activated protein kinase (AMPK) alpha subunits. Ethanol also reduced phosphorylation of acetyl-CoA carboxylase, a substrate of AMPK and a lipogenic enzyme known to be activated by dephosphorylation. In contrast, lipid profiles of 19-day-old mouse brains, which scarcely manifested neurodegeneration upon ethanol exposure, were not significantly affected by ethanol. Also, the basal levels of Thr172-phosphorylated AMPK alpha were lower in these brains than in 7-day-old mouse brains, and no detectable changes in the phosphorylation status were observed by ethanol treatment. Our findings indicate that the ethanol-induced apoptotic neurodegeneration observed in mice during restricted developmental periods is accompanied by alterations in both the lipid content and the activity of AMPK in the brain
— id: 93995, year: 2007, vol: 103, page: 1208, stat: Journal Article,

Effects of gangliosides on ethanol-induced neurodegeneration in the developing mouse brain
Saito, Mariko; Mao, Rui-Fen; Wang, Ray; Vadasz, Csaba; Saito, Mitsuo
2007 Apr;31(4):665-674, Alcoholism: clinical & experimental research
BACKGROUND: Ethanol exposure induces apoptotic neurodegeneration in the developing rodent brain during synaptogenesis. This process has been studied as a model for fetal alcohol syndrome. Previously, we have shown that gangliosides and LIGA20 (a semisynthetic derivative of GM1 ganglioside) attenuate ethanol-induced apoptosis in cultured neurons. In the present study, the effects of GM1 and LIGA20 on ethanol-induced apoptotic neurodegeneration were examined using an in vivo neonatal mouse model. METHODS: Seven-day-old C57BL/6By (B6By) mice were pretreated twice with intraperitoneal administration of GM1 (30 mg/kg), LIGA20 (2.5 mg/kg), or saline, followed by subcutaneous injection of either saline or ethanol (2.5 g/kg) twice with a 2 hours interval. Then the brains were: (1) perfusion-fixed 24 hours after the first ethanol injection, and the extent of neurodegeneration was assessed by cupric silver staining of the brain sections, or (2) perfusion-fixed 8 hours after the first ethanol injection, and the sections were immunostained with anti-cleaved (activated) caspase-3 antibody to evaluate caspase-3 activation. RESULTS: The comparison of cupric silver stained coronal sections indicates that ethanol-induced widespread neurodegeneration in the forebrains of B6By mice was reduced overall by GM1 and LIGA20 pretreatments. The extent of neurodegeneration detected by silver impregnation and activated caspase-3 immunostaining was quantified in the cingulate and retrosplenial cortices, which were the regions most severely affected by ethanol. The results indicate that GM1 and LIGA20 pretreatments induced statistically significant reductions-approximately 50% of the ethanol-treated samples-in silver impregnation and activated caspase-3 immunostaining. No significant differences were observed between saline controls and samples treated with GM1 or LIGA20 alone. CONCLUSIONS: These results indicate that GM1 and LIGA20, which have been shown to be neuroprotective against insults caused by various agents, partially attenuate ethanol-induced apoptotic neurodegeneration in the developing mouse brain
— id: 93996, year: 2007, vol: 31, page: 665, stat: Journal Article,

Mesencephalic dopamine neuron number and tyrosine hydroxylase content: Genetic control and candidate genes
Vadasz, C; Smiley, J F; Figarsky, K; Saito, M; Toth, R; Gyetvai, B M; Oros, M; Kovacs, K K; Mohan, P; Wang, R
2007 Nov 9;149(3):561-572, Neuroscience
The mesotelencephalic dopamine system shows substantial genetic variation which fundamentally affects normal and pathological behaviors related to motor function, motivation, and learning. Our earlier radioenzyme assay studies demonstrated significantly higher activity of tyrosine hydroxylase (TH), the first and rate limiting enzyme in the biosynthesis of catecholamine neurotransmitters, in the substantia nigra-ventral tegmental area of BALB/cJ mice in comparison with that of C57BL/6ByJ mice. Here, using quantitative immunoblotting and immunocytochemistry, we tested the hypothesis that mesencephalic TH protein content and number of nigral TH-positive neurons show strain-dependent differences in C57BL/6ByJ and BALB/cJ parallel to those observed in the TH activity studies. Immunoblotting experiments detected significantly higher mesencephalic TH protein content in BALB/cJ in comparison to C57BL/6ByJ (P<0.05). Immunocytochemical studies demonstrated that the number of TH-positive cells in substantia nigra was 31.3% higher in BALB/cJ than that in C57BL/6ByJ (P<0.01), while the average dopamine neuron volume was not significantly different. In a search for candidate genes that modulate TH content and the size of mesencephalic dopamine neuron populations we also studied near-isogenic mouse sublines derived from the C57BL/6ByJ and BALB/cJ progenitor strains. A whole-genome scan with 768 single nucleotide polymorphism markers indicated that two sublines, C4A6/N and C4A6/B, were genetically very similar (98.3%). We found significantly higher mesencephalic TH protein content in C4A6/B in comparison to C4A6/N (P=0.01), and a tendency for higher number of dopamine neurons in the substantia nigra in C4A6/B in comparison to C4A6/N, which, however, did not reach statistical significance. To identify the genetic source of the TH content difference we analyzed the single nucleotide polymorphism (SNP) genotype data of the whole-genome scan, and detected two small differential chromosome segments on chr. 13 and chr. 14. Microarray gene expression studies and bioinformatic analysis of the two differential regions implicated two cis-regulated genes (Spock1 and Cxcl14, chr. 13), and two growth factor genes [bone morphogenetic protein 6 (Bmp6) (chr. 13), and fibroblast growth factor 14 (Fgf14) (chr. 14)]. Taken together, the results suggest that (1) nigral dopamine neuron number and TH protein content may be genetically associated but further studies are needed to establish unequivocally this linkage, and (2) Spock1, Cxcl14, Bmp6, and Fgf14 are novel candidates for modulating the expression and maintenance of TH content in mesencephalic dopamine neurons in vivo
— id: 75475, year: 2007, vol: 149, page: 561, stat: Journal Article,

Mapping of QTLs for oral alcohol self-administration in B6.C and B6.I quasi-congenic RQI strains
Vadasz, Csaba; Saito, Mariko; Gyetvai, Beatrix M; Oros, Melinda; Szakall, Istvan; Kovacs, Krisztina M; Prasad, Vidudala V T S; Morahan, Grant; Toth, Reka
2007 Jul;32(7):1099-1112, Neurochemical research
One strategy to identify neurochemical pathways of addiction is to map the relevant genes. In the present study we used 43 B6.C and 35 B6.I inbred RQI mouse strains, carrying <3% donor genome on C57BL/6ByJ background, for gene mapping. The strains were phenotyped for consumption of alcohol (12% v/v) in a two-bottle-choice paradigm, and genotyped for 396 microsatellite markers. The current mapping study extends our earlier experiment scanning five mouse chromosomes (Vadasz et al. (2000) Scanning of five chromosomes for alcohol consumption loci. Alcohol 22:25-34) to a whole-genome study, and discusses the differences and limitations. Data were analyzed with composite interval (CIM) and multiple interval (MIM) QTL mapping methods. CIM of B6.C strains detected significant QTLs on chrs. 6 and 12. A suggestive, but not significant, locus was detected in the B6.I strains on chr. 12. The best MIM model for B6.C strains confirmed one QTL on chr. 6 and one QTL on chr. 12, while the MIM model for the B6.I strains confirmed the suggestive locus on chr. 12. Some of the QTLs for alcohol consumption are new, while others confirm previously reported QTLs for alcohol preference, and alcohol acceptance
— id: 93997, year: 2007, vol: 32, page: 1099, stat: Journal Article,

Glutamate receptor metabotropic 7 is cis-regulated in the mouse brain and modulates alcohol drinking
Vadasz, Csaba; Saito, Mariko; Gyetvai, Beatrix M; Oros, Melinda; Szakall, Istvan; Kovacs, Krisztina M; Prasad, Vidudala V T S; Toth, Reka
2007 Dec;90(6):690-702, Genomics
Alcoholism is a heritable disease that afflicts about 8% of the adult population. Its development and symptoms, such as craving, loss of control, physical dependence, and tolerance, have been linked to changes in mesolimbic, mesocortical neurotransmitter systems utilizing biogenic amines, GABA, and glutamate. Identification of genes predisposing to alcoholism, or to alcohol-related behaviors in animal models, has been elusive because of variable interactions of multiple genes with relatively small individual effect size and sensitivity of the predisposing genotype to lifestyle and environmental factors. Here, using near-isogenic advanced animal models with reduced genetic background interactions, we integrate gene mapping and gene mRNA expression data in segregating and congenic mice and identify glutamate receptor metabotropic 7 (Grm7) as a cis-regulated gene for alcohol consumption. Traditionally, the mesoaccumbal dopamine reward hypothesis of addiction and the role of the ionotropic glutamate receptors have been emphasized. Our results lend support to an emerging direction of research on the role of metabotropic glutamate receptors in alcoholism and drug addiction. These data suggest for the first time that Grm7 is a risk factor for alcohol drinking and a new target in addiction therapy
— id: 75843, year: 2007, vol: 90, page: 690, stat: Journal Article,

Ventral tegmental transcriptome response to intermittent nicotine treatment and withdrawal in BALB/cJ, C57BL/6ByJ, and quasi-congenic RQI mice
Vadasz, Csaba; Saito, Mariko; O'Brien, Danielle; Zavadil, Jiri; Morahan, Grant; Chakraborty, Goutam; Wang, Ray
2007 Mar;32(3):457-480, Neurochemical research
The aim of this study was to identify neurochemical pathways and candidate genes involved in adaptation to nicotine treatment and withdrawal. Locomotor sensitization was assessed in a nicotine challenge test after exposure to intermittent nicotine treatment and withdrawal. About 24 h after the challenge test the ventral tegmentum of the mesencephaion was dissected and processed using oligonucleotide microarrays with 22,690 probe sets (Affymetrix 430A 2.0). Quasi-congenic RQI, and donor BALB/cJ mice developed significant locomotor sensitization, while sensitization was not significant in the background partner, C57BL/6By. Comparing saline treated controls of C57BL/6ByJ and BALB/cJ by a rigorous statistical microarray analysis method we identified 238 differentially expressed transcripts. Quasi-congenic strains B6.Cb4i5-alpha4/Vad and B6.Ib5i7-beta25A/Vad significantly differed from the background strain in 11 and 11 transcripts, respectively. Identification of several cis- and trans-regulated genes indicates that further work with quasi-congenic strains can quickly lead to mapping of Quantitative Trait Loci for nicotine susceptibility because donor chromosome regions have been mapped in quasi-congenic strains. Nicotine treatment significantly altered the abundance of 41, 29, 54, and 14 ventral tegmental transcripts in strains C57BL/6ByJ, BALB/cJ, B6.Cb4i5-alpha4/Vad, and B6.Ib5i7-beta25A/Vad, respectively. Although transcript sets overlapped to some extent, each strain showed a distinct profile of nicotine sensitive genes, indicating genetic effects on nicotine-induced gene expression. Nicotine-responsive genes were related to processes including regulation of signal transduction, intracellular protein transport, proteasomal ubiquitin-dependent protein catabolism, and neuropeptide signaling pathway. Our results suggest that while there are common regulatory mechanisms across inbred strains, even relatively small differences in genetic constitution can significantly affect transcriptome response to nicotine
— id: 79224, year: 2007, vol: 32, page: 457, stat: Journal Article,

Decreased oral self-administration of alcohol in kappa-opioid receptor knock-out mice
Kovacs, Krisztina M; Szakall, Istvan; O'Brien, Danielle; Wang, Ray; Vinod, K Yaragudri; Saito, Mariko; Simonin, Frederic; Kieffer, Brigitte L; Vadasz, Csaba
2005 May;29(5):730-738, Alcoholism: clinical & experimental research
BACKGROUND: Although a large body of evidence suggests a role for the opioid system in alcoholism, the precise role of mu-, delta-, kappa-, and ORL1-opioid receptors and the physiological significance of their natural genetic variation have not been identified. The method of targeted gene disruption by homologous recombination has been used to knock out (KO) genes coding for opioid receptors, and study their effects on alcohol self-administration. Here we examined the effects of targeted disruption of kappa-opioid receptor (KOR) on oral alcohol self-administration and other behaviors. METHODS: Oral alcohol, saccharin and quinine self-administration was assessed in a two-bottle choice paradigm using escalating concentrations of alcohol, or tastant solutions. In preference tests 12% alcohol, 0.033% and 0.066% saccharin, and 0.03 mM and 0.1 mM quinine solutions were used. Open-field activity was determined in an arena equipped with a computer-controlled activity-detection system. Subjects were tested for three consecutive days. Locomotor activity was assessed on days 1 and 2 (after saline injection, i.p.) and on day 3 (after alcohol injection, i.p.). Alcohol-induced locomotor activity was determined as the difference in activity between day 3 and day 2. RESULTS: Male KOR KO mice in preference tests with 12% alcohol consumed about half as much alcohol as wild-type (WT) or heterozygous (HET) mice, showed lower preference for saccharin (0.033% and 0.066%) and higher preference to quinine (0.1 mM) than WT mice. Female KOR KO mice showed similar reduction in alcohol consumption in comparison to WT and HET mice. Partial deletion of KOR in HET mice did not change alcohol consumption in comparison to WT mice. In all genotype-groups females drank significantly more alcohol than males. MANOVA of locomotor activity among KO, WT, and HET mice indicated that strain and sex effects were not significant for alcohol-induced activation (p > 0.05), while strain x sex interaction effects on alcohol-induced activation could be detected (F(1,55) = 6.07, p < 0.05). CONCLUSION: Our results indicating decreased alcohol consumption, lower saccharin preference, and higher quinine preference in KOR KO mice are in line with previous observations of opioid involvement in maintenance of food intake and raise the possibility that the deficient dynorphin/KOR system affects orosensory reward through central mechanisms which reduce alcohol intake and disrupt tastant responses, either as direct effects of absence of kappa-opioid receptors, or as effects of indirect developmental compensatory changes
— id: 93999, year: 2005, vol: 29, page: 730, stat: Journal Article,

Nicotine-induced sensitization in mice: changes in locomotor activity and mesencephalic gene expression
Saito, Mariko; O'Brien, Danielle; Kovacs, Krisztina M; Wang, Ray; Zavadil, Jiri; Vadasz, Csaba
2005 Aug;30(8):1027-1035, Neurochemical research
It is believed that drug-induced behavioral sensitization is an important process in the development of substance dependence. In order to explore mechanisms of sensitization, a mouse model of nicotine-induced locomotor sensitization was established, and effects of the sensitization process on mesencepahlic gene expression were examined. A schedule, which included 3 weeks of intermittent nicotine exposure (0.5 mg/kg, s.c.) and 3 weeks of withdrawal, resulted in locomotor sensitization. Effects of sensitization on mesencephalic expression of approximately 14,000 genes were assessed using oligonucleotide microarrays. Signal intensity differences in samples obtained from repeated nicotine- and saline-exposed animals were analyzed with z-test after False Discovery Rate (FDR) multiple test correction. Genes related to GABA-A receptors and protein phosphatases were among 68 genes showing significantly different expression levels between the saline and the nicotine groups. We hypothesize that some of the gene expression changes in the mesencephalon are involved in pathways leading to nicotine-induced sensitization. Down-regulation of GABA-A receptors induced by repeated nicotine exposure may facilitate dopaminergic neuronal transmission and may contribute to increased locomotor activity
— id: 58733, year: 2005, vol: 30, page: 1027, stat: Journal Article,

Ethanol-induced changes in the content of triglycerides, ceramides, and glucosylceramides in cultured neurons
Saito, Mariko; Saito, Mitsuo; Cooper, Thomas B; Vadasz, Csaba
2005 Aug;29(8):1374-1383, Alcoholism: clinical & experimental research
BACKGROUND: Ethanol induces apoptosis in cultured neurons. To assess the involvement of sphingolipids and neutral lipids in the apoptotic process, ethanol-induced alterations in lipid content and metabolism were examined by using primary cultured rat cerebellar granule neurons (CGNs), human neuroblastoma SK-N-SH cells, and mouse neuroblastoma Neuro2a cells. Ethanol treatment conditions that induced apoptosis in CGNs and SK-N-SH cells but not in Neuro2a cells were used for these experiments. METHODS: Cultured neurons were treated with and without 100 mM ethanol for one to three days, and the amounts of cellular sphingolipids [ceramide, glucosylceramide (GlcCer), and sphingomyelin] and neutral lipids [cholesterol, triglyceride (TG), and cholesterol ester (ChE)] were analyzed by high-performance thin-layer chromatography, using a Coomassie brilliant blue staining method. The incorporation of [C] acetate into each lipid fraction was measured in CGNs treated with and without ethanol. Also, the effect of delipidated serum, sterols, myriocin (a serine-palmitoyltransferase inhibitor), and desipramine (an acid sphingomyelinase inhibitor) on ethanol-induced lipid changes was studied by using Neuro2a cells. RESULTS: The most prominent change common to CGN, SK-N-SH, and Neuro2a cells was ethanol-induced TG accumulation. Higher incorporation of radioactivity into TG was also observed in ethanol-treated cultures when cellular lipids were metabolically labeled with [C] acetate in CGNs. In addition, ethanol elevated ceramide levels in all these neurons. However, ethanol induced decreases in GlcCer along with the reduction of cell viability in SK-N-SH cells and CGNs, whereas it increased GlcCer in Neuro2a cells that remained viable. Myriocin, which reduced ceramide levels, attenuated ethanol-induced cell death in SK-N-SH cells. Ethanol-induced accumulation of TG was sterol-independent, whereas changes in ceramide and GlcCer were affected in Neuro2a cells by the presence of sterols in the medium. Staurosporine, which induced cell death in SK-N-SH cells, increased levels of TG, ChE, and ceramides and reduced the level of GlcCer. CONCLUSIONS: The results showing that ethanol induces accumulation of TG and ceramide in cultured neurons suggest that ethanol enhances lipogenesis and/or reduces fatty acid degradation in neurons, as previously observed in other cell types. Further, ethanol-induced changes in lipid metabolism, specifically those of ceramide and GlcCer, may be related to the ethanol-induced apoptotic pathway
— id: 93998, year: 2005, vol: 29, page: 1374, stat: Journal Article,

Striatal transcriptome analysis in quasi-congenic mouse strains: Effects of oral alcohol self-administration
Saito, M; Szakali, I; Toth, R; Kovacs, KM; Oros, M; Prasad, VVTS; Blumenberg, M; Vadasz, C
2004 MAY ;28(5):9A-9A, Alcoholism: clinical & experimental research
— id: 46570, year: 2004, vol: 28, page: 9A, stat: Journal Article,

Mouse striatal transcriptome analysis: effects of oral self-administration of alcohol
Saito, Mariko; Szakall, Istvan; Toth, Reka; Kovacs, Krisztina M; Oros, Melinda; Prasad, Vidudala V T S; Blumenberg, Miroslav; Vadasz, Csaba
2004 May;32(3):223-241, Alcohol
Results of recent studies support the notion that substance self-administration is partially a genetically controlled component of addiction tied to habit formation and cellular modification of the striatum. Aiming to define pathways among genomic, neural, and behavioral determinants of addiction, we investigated global striatal gene expression in a paradigm of oral self-administration of alcohol by using genomically very similar alcohol-nonpreferring B6.Cb(5)i(7)-alpha 3/Vad (C5A3) and alcohol-preferring B6.Ib(5)i(7)-beta 25A/Vad (I5B25A) quasi-congenic mouse strains and their progenitors, C57BL/6By (B6By) and BALB/cJ. Expression of 12,488 genes and expressed sequence tags (ESTs) was studied by using 24 high-density oligonucleotide microarrays. Transcript signal intensity differences were analyzed with z test after iterative median normalization across groups and Hochberg step-down Bonferroni procedure. As expected, striatal transcriptome differences were far more extensive between the independently derived progenitor strains than between the quasi-congenic strains and their background partner, B6By. However, the genes, which were differentially expressed between the quasi-congenic strains and their background partner, were not subsets of the progenitorial differences and were not located on the chromosome segments introgressed into the quasi-congenic strains from the donor BALB/cJ strain that have been so far defined. Although 25 transcripts showed significantly different expression between the progenitor strains, only two transcripts, phosphatidylserine decarboxylase and a hypothetical 21.2-kDa protein, and one transcript, molybdenum co-factor synthesis 2, showed significantly different expression between C5A3 and I5B25A, and between B6By and I5B25A, respectively. The latter three transcripts are not located on previously identified chromosome segments introgressed from the donor BALB/cJ strain, supporting the suggestion of trans-acting regulatory variations among strains. Exposure to alcohol did not induce statistically significant striatal gene expression changes in any of the mouse strains. In conclusion, the results support the hypothesis that in functional genomic studies the chance of detecting function-relevant genes can be increased by the comparative analysis of quasi-congenic and background strains because the number of functionally irrelevant, differentially expressed genes between genomically similar strains is reduced. Lack of statistically significant alcohol-induced changes in transcript abundance indicated that oral self-administration had subtle effects on striatal gene expression and directed attention to important implications for the experimental design of future microarray gene expression studies on complex behaviors
— id: 45939, year: 2004, vol: 32, page: 223, stat: Journal Article,

Alcohol reduces GM1 ganglioside content in the serum of inbred mouse strains
Saito, Mitsuo; Saito, Mariko; Cooper, Thomas B; Vadasz, Csaba
2004 Jul;28(7):1107-1113, Alcoholism: clinical & experimental research
BACKGROUND: Endogenous and exogenous gangliosides in the plasma affect physiologic and pathologic processes such as angiogenesis and atherogenesis. However, the genetic and environmental factors that regulate the expression of plasma gangliosides are not well known. As shown in the liver and the brain, profiles of gangliosides in the plasma may be strain-specific and can be altered by intake of alcohol. Therefore, we analyzed serum gangliosides derived from inbred mouse strains with and without alcohol treatment. METHODS: C57BL/6ByJ (B6By) and BALB/cJ mice (60-70 days old) were injected with 20% alcohol (1-6 g/kg) or saline intraperitoneally, and the ganglioside content of the serum, liver, and cerebellum was measured 4 hr after the injection. Also, the effect of oral alcohol self-administration for 18 days with escalating (3-12%) concentrations of alcohol on the serum GM1 content was studied in B6By mice. The quantification of GM1 was performed with a thin-layer chromatography-staining procedure using a cholera toxin B subunit, and the content of other gangliosides was measured after staining with resorcinol reagent. RESULTS: We found that basal GM1 (containing N-glycolylneuraminic acid) content in the serum of BALB/cJ mice (4.8 +/- 0.26 ng/microl) was 25 times higher than that of B6By mice (0.19 +/- 0.01 ng/microl); the major ganglioside in both strains was GM2. The ganglioside profile in the liver was similar to that of the serum, and the GM1 content in BALB/cJ was nine times higher than that of B6By. Both injection and oral self-administration of alcohol lowered GM1 levels in the serum. CONCLUSIONS: Endogenous ganglioside profiles in the serum are under genetic control among inbred mouse strains, and they can be altered by acute and chronic alcohol administration. These genetic and alcohol-induced differences in the plasma gangliosides, which appear to reflect ganglioside metabolism in the liver, may affect alcohol-related behaviors and pathologic processes
— id: 94000, year: 2004, vol: 28, page: 1107, stat: Journal Article,

The nature and identification of quantitative trait loci: a community's view
Abiola, Oduola; Angel, Joe M; Avner, Philip; Bachmanov, Alexander A; Belknap, John K; Bennett, Beth; Blankenhorn, Elizabeth P; Blizard, David A; Bolivar, Valerie; Brockmann, Gundrun A; Buck, Kari J; Bureau, Jean-Francoise; Casley, William L; Chesler, Elissa J; Cheverud, James M; Churchill, Gary A; Cook, Melloni; Crabbe, John C; Crusio, Wim E; Darvasi, Ariel; de Haan, Gerald; Dermant, Peter; Doerge, R W; Elliot, Rosemary W; Farber, Charles R; Flaherty, Lorraine; Flint, Jonathan; Gershenfeld, Howard; Gibson, John P; Gu, Jing; Gu, Weikuan; Himmelbauer, Heinz; Hitzemann, Robert; Hsu, Hui-Chen; Hunter, Kent; Iraqi, Fuad F; Jansen, Ritsert C; Johnson, Thomas E; Jones, Byron C; Kempermann, Gerd; Lammert, Frank; Lu, Lu; Manly, Kenneth F; Matthews, Douglas B; Medrano, Juan F; Mehrabian, Margarete; Mittlemann, Guy; Mock, Beverly A; Mogil, Jeffrey S; Montagutelli, Xavier; Morahan, Grant; Mountz, John D; Nagase, Hiroki; Nowakowski, Richard S; O'Hara, Bruce F; Osadchuk, Alexander V; Paigen, Beverly; Palmer, Abraham A; Peirce, Jeremy L; Pomp, Daniel; Rosemann, Michael; Rosen, Glenn D; Schalkwyk, Leonard C; Seltzer, Ze'ev; Settle, Stephen; Shimomura, Kazuhiro; Shou, Siming; Sikela, James M; Siracusa, Linda D; Spearow, Jimmy L; Teuscher, Cory; Threadgill, David W; Toth, Linda A; Toye, Ayo A; Vadasz, Csaba; Van Zant, Gary; Wakeland, Edward; Williams, Robert W; Zhang, Huang-Ge; Zou, Fei
2003 Nov;4(11):911-916, Nature reviews. Genetics
This white paper by eighty members of the Complex Trait Consortium presents a community's view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?
— id: 94001, year: 2003, vol: 4, page: 911, stat: Journal Article,

Cannabinoid CB1 receptor knockout mice exhibit markedly reduced voluntary alcohol consumption and lack alcohol-induced dopamine release in the nucleus accumbens
Hungund, Basalingappa L; Szakall, Istvan; Adam, Agota; Basavarajappa, Balapal S; Vadasz, Csaba
2003 Feb;84(4):698-704, Journal of neurochemistry
The mechanisms underlying predisposition to alcohol abuse and alcoholism are poorly understood. In this study, we evaluated the role of cannabinoid (CB1) receptors in (i) voluntary alcohol consumption, and (ii) acute alcohol-induced dopamine (DA) release in the nucleus accumbens, using mice that lack the CB1 receptor gene (CB1-/-). CB1-/- mice exhibited dramatically reduced voluntary alcohol consumption, and completely lacked alcohol-induced DA release in the nucleus accumbens, as compared to wild-type mice. The gender difference, with female mice consuming significantly more alcohol than wild-type male mice, was observed in wild-type mice, whereas this gender difference was nonexistent in CB1 mutant male and female mice. There was also a significant gender difference, with the wild-type, heterozygous, and mutant females consuming significantly more liquid and food than wild-type, heterozygous and mutant males. However, the total volume of fluid consumption and food intake did not differ between wild-type, heterozygous, and mutant mice. These results strongly suggest that the CB1 receptor system plays an important role in regulating the positive reinforcing properties of alcohol
— id: 94003, year: 2003, vol: 84, page: 698, stat: Journal Article,

Variants of kappa-opioid receptor gene and mRNA in alcohol-preferring and alcohol-avoiding mice
Saito, Mariko; Ehringer, Marissa A; Toth, Reka; Oros, Melinda; Szakall, Istvan; Sikela, James M; Vadasz, Csaba
2003 Jan;29(1):39-49, Alcohol
Results of recent studies have indicated an association between voluntary alcohol intake and activities of kappa-opioid receptor systems in animal models. We assessed the possibility that genetic differences observed in alcohol preference among mouse strains are related to possible polymorphisms of the kappa-opioid receptor gene (Oprk1). We compared DNA sequences of the coding region and the promoter/regulatory region of Oprk1 among C57BL/6ByJ (B6, alcohol-preferring), BALB/cJ (alcohol-avoiding), CXBI (alcohol-avoiding), and six B6.C and B6.I Recombinant QTL Introgression (RQI) strains, which carry approximately 3% of the donor BALB/cJ genome in the background B6 genome and showed various alcohol preferences. Although there were no sequence differences in the coding region, BALB/cJ had a single nucleotide polymorphism (SNP) in the promoter region, which was not detected in other strains. The results indicate that the difference in alcohol preference between B6 and BALB/cJ is not correlated with polymorphisms of Oprk1. However, results of further studies comparing Oprk1 mRNA expression between B6 and BALB/cJ showed that Oprk1 expression is regulated differently in these strains. Also, DBA/2J mice (alcohol-avoiding) showed expression of Oprk1 mRNA subtypes (alternatively spliced) different from B6 and BALB/cJ mice. Search of the Celera Genomics database indicated that DBA/2J had several SNP sites in the promoter/regulatory regions, which might explain the different expression of Oprk1 mRNA subtypes in this strain. The strain-dependent variation in the expression of alternatively spliced genes can be a significant source of phenotypic variation of complex traits such as alcohol preference
— id: 94002, year: 2003, vol: 29, page: 39, stat: Journal Article,

Ethanol, endocannabinoids, and the cannabinoidergic signaling system
Hungund, Basalingappa L; Basavarajappa, Balapal S; Vadasz, Csaba; Kunos, George; Rodriguez de Fonseca, Fernando; Colombo, Giancarlo; Serra, Salvatore; Parsons, Loren; Koob, George F
2002 Apr;26(4):565-574, Alcoholism: clinical & experimental research
This article represents the proceedings of a symposium at the 2001 annual meeting of the Research Society on Alcoholism in Montreal, Canada. The chairpersons were Appa Hungund and George Koob. The presentations were (1) Role of endocannabinoids in ethanol tolerance, by Appa Hungund; (2) Modulation of cannabinoid receptor and its signal transduction in chronic alcoholism, by B. S. Basavarajappa; (3) Endocannabinoid involvement in the control of appetitive behavior, by George Kunos; (4) Regulation of voluntary ethanol intake by cannabinoid receptor agonists and antagonists in alcohol-preferring sP rats, by Giancarlo Colombo; (5) Role of endogenous cannabinoid system in alcoholism, by Fernado Rodriguez de Fonseca; and (6) Endocannabinoids and dopamine interactions in vivo, by Loren Parsons and George Koob
— id: 32464, year: 2002, vol: 26, page: 565, stat: Journal Article,

Microarray analysis of gene expression in rat hippocampus after chronic ethanol treatment
Saito, Mariko; Smiley, John; Toth, Reka; Vadasz, Csaba
2002 Oct;27(10):1221-1229, Neurochemical research
It is thought that changes in gene expression in the brain mediate chronic ethanol-induced complex behaviors such as tolerance, dependence, and sensitization, and also relate to ethanol-induced brain toxicity. Using high-density filter-based cDNA microarrays (GeneFilters), we analyzed the expression of over 5000 genes in the dorsal hippocampus of rats treated with 12% ethanol or tap water for 15 months. Ethanol-induced changes in gene expression were particularly prominent in two groups of genes. One group consisted of oxidoreductases, including ceruloplasmin, uricase, branched-chain alpha-keto acid dehydrogenase, NADH ubiquinone oxidoreductase, P450, NAD+-isocitrate dehydrogenase, and cytochrome c oxidase, which may be related to ethanol-induced oxidative stress. The other group of genes included ADP-ribosylation factor, RAS related protein rab10, phosphatidylinositol 4-kinase, dynein-associated polypeptides, and dynamin-1, which seem to be involved in membrane trafficking. The results may reveal some of the pathways involved in ethanol-induced pathophysiological changes
— id: 94004, year: 2002, vol: 27, page: 1221, stat: Journal Article,

Strain and sex differences in repeated ethanol treatment-induced motor activity in quasi-congenic mice
Sershen, H; Hashim, A; Vadasz, C
2002 Aug;1(3):156-165, Genes, brain & behavior
The B6.C quasi-congenic Recombinant QTL Introgression (RQI) strains of the b4i5 series have similar genetic background, but differ in about 5% of their genome from the C57BL/6ByJ (B6) background strain because they carry short chromosome segments introgressed from the BALB/cJ (C) donor strain. These RQI strains were derived from mouse lines selectively bred for high activity of mesencephalic tyrosine hydroxylase (TH/MES), therefore genetic variation in dopamine system-related behaviours, such as ethanol-induced motor activity, can be expected. Males and females of 17 RQI and two progenitor strains were tested for initial motor activity for 15 min after a habituating injection of saline, which was followed by an i.p. injection of saline or ethanol (2 g/kg) and an additional test of motor activity for 30 min. This procedure was repeated during 4 subsequent days. In all strains, the first-day ethanol treatment showed an inhibitory effect. With repetition of the treatment the inhibitory effect decreased, and a stimulatory effect could be observed with significant strain- and sex-dependent variation. Females exhibited higher activity in the saline group than males, and reached an equilibrium of inhibition and stimulation sooner than males with repetition of the ethanol treatment. The highest (> 25-fold) difference in activity after repeated ethanol treatment was detected between females of the two strains B6.Cb4i5-Alpha4/Vad and B6.Cb4i5-Beta13/Vad. These results firstly suggest that females are more sensitive to repeated ethanol exposure than males, secondly they support the observations that ethanol has both inhibitory and stimulatory effects on motor activity, which are affected by sex, genotype, and repetition of treatment, and thirdly offer new quasi-congenic animal models with highly different responses to ethanol allowing one to more quickly move to gene detection
— id: 60265, year: 2002, vol: 1, page: 156, stat: Journal Article,

Volumetric structural magnetic resonance imaging (MRI) of the rat hippocampus following kainic acid (KA) treatment
Wolf, O T; Dyakin, V; Patel, A; Vadasz, C; de Leon, M J; McEwen, B S; Bulloch, K
2002 May 3;934(2):87-96, Brain research
An in vivo MRI study employing a high field (7T) magnet and a T1- and T2-weighted imaging sequence with subsequent histopathological evaluations was undertaken to develop and evaluate MRI-based volumetric measurements in the rat. The brain structures considered were the hippocampus, the cingulate cortex, the retrosplenial granular cortex and the ventricles. Control (n=3) and kainic acid (KA; n=4) treated rats were scanned 10 days following the manifestation of stage four seizures. The MRI images exhibited anatomical details (125 microm in-plane resolution) that enabled volumetric analysis with high intra-rater reliability. Volumetric analysis revealed that KA-treated rats had significantly smaller hippocampi, and a significant increase in ventricular size. The cingulate cortex and the retrosplenial granular cortex did not differ in volume between the two groups. The histological observations supported the MRI data showing neuronal loss and neuronal degeneration in CA1 and CA3 of the hippocampus, which was accompanied by strong microglia activation. These data demonstrate a reliable and valid method for the measurement of the rat hippocampus in vivo using MRI with a high field magnet, thereby providing a useful tool for future studies of rodent models of neuro-degenerative diseases
— id: 32478, year: 2002, vol: 934, page: 87, stat: Journal Article,

Volumetric measurement of the hippocampus, the anterior cingulate cortex, and the retrosplenial granular cortex of the rat using structural MRI
Wolf, O T; Dyakin, V; Vadasz, C; de Leon, M J; McEwen, B S; Bulloch, K
2002 Aug;10(1):41-46, Brain research protocols
MRI imaging of the rodent brain is a rapidly growing field in the neurosciences. Relatively limited information is available for regional volume determination. The present paper describes a reliable method for the assessment of the hippocampus, the anterior cingulate cortex, the retrosplenial granular cortex and the ventricles in rats. MRI scans were acquired using a 7 T magnet. The anatomical sampling method was found to be highly reliable with an intra-rater reliability of greater than 0.93. The current protocol should facilitate future in vivo neuroimaging research using animal models of neurodegenerative diseases
— id: 71974, year: 2002, vol: 10, page: 41, stat: Journal Article,

Strain and sex differences in repeated ethanol treatment-induced motor activity in quasi-congenic mice
Sershen, H.; Hashim, A.; Vadasz, C.
2001 ;27(1):1184-1184, Abstracts (Society for Neuroscience)
B6.C quasi-congenic Recombinant QTL Introgression (RQI) strains of the b4i5 series differ in about 5% of their genome from the C57BL/6ByJ (B6) background strain because they carry chromosome segments introgressed from the BALB/cJ (C) strain. These RQI strains were derived from mouse lines selectively bred for high activity of mesencephalic tyrosine hydroxylase, therefore genetic variation in dopamine system-related behaviors, such as ethanol-induced motor activity, can be expected. Males and females of 17 RQI and 2 progenitor strains were tested for motor activity for 15 min after a habituating injection of saline, which was followed by i.p. injection of saline or ethanol (2 g/kg) and an additional test of motor activity for 30 min. This procedure was repeated for 4 subsequent days. In all strains, the first-day ethanol treatment showed inhibitory effect. With repetition of the treatment the inhibitory effect decreased, and a stimulatory effect could be observed with significant strain- and sex-dependent variation. Females exhibited higher activity in the saline group than males, and reached an equilibrium of inhibition and stimulation sooner than males with repetition of the ethanol treatment. The highest (>50-fold) difference in activity after repeated ethanol treatment was detected between the B6.Cb4i5 Alpha4/Vad and B6.Cb4i5-Beta13/Vad strains. These results suggest that females are more sensitive to repeated ethanol exposure than males, and ethanol has both inhibitory and stimulatory effects on motor activity, which are affected by sex, genotype, and repetition of treatment
— id: 115692, year: 2001, vol: 27, page: 1184, stat: Journal Article,

99HRT Protection Against Excessive Alcohol Consumption by Opioid Receptor Kappa 1
Vadasz, Csaba; Saito, Mariko; Basavarajappa, Balapal
[Ft. Belvoir, VA] : Ft. Belvoir Defense Technical Information Center, 2001,
The purpose of this work is to test the hypothesis that oploid receptor kappa 1 (Oprk1) affects excessive alcohol drinking in a murine quasi-congenic animal model system. The studies involve comparative analyses of: (1) DNA sequences, (2) Oprk1 gene expression and receptor ligand binding, (3) ethanol-induced dopamine release in quasi-congenic RQI strains and their progenitors (C57BL/6ByJ and BALB/cJ), and (4) alcohol preference tests in Oprk1 knock-out animals. Our results suggest that in the tested model system sequence polymorphism in the coding regions of Oprk1 is independent from alcohol preference. Preliminary data indicate that control of transcription, splicing, and Oprk1 receptor density may show alcohol preference associated genetic variation. The first alcohol consumption experiments on Oprk1 knock-out animals suggest that dysfunctional kappa receptors predispose to lower alcohol consumption in free choice preference test. Taken together, in the studied model system it is more likely that downstream regulatory processes determine the role of Oprk1 in alcohol consumption than variation in its coding sequences
— id: 2216, year: 2001, vol: , page: , stat: ,

The midbrain dopaminergic system: anatomy and genetic variation in dopamine neuron number of inbred mouse strains
Zaborszky, L; Vadasz, C
2001 Jan;31(1):47-59, Behavior genetics
The mesotelencephalic dopamine system is genetically variable and affects motor behavior, motivation, and learning. Here we examine the genetic variation of mesencephalic DA neuron number in a quasi-congenic RQI mouse strain and its background partner and in a recombinant inbred strain with different levels of mesencephalic tyrosine hydroxylase activity (TH/MES). We used B6.Cb4i5-alpha6/Vad, C57BL/6By, and CXBI, which are known to express high, intermediate, and low levels of TH/MES, respectively. Unbiased stereological sampling with optical disector counting methods were employed to estimate the number of TH-positive neurons in the A8-A9-A10 cell groups. Morphometric studies on the mesencephalic dopamine cell groups indicated that male mice of the B6.Cb4i5-alpha6/Vad strain were endowed with a significantly lower number of TH-positive cells than CXBI mice. In all strains studied, the right retrorubral field (A8 area) had a higher number of dopamine neurons compared to the left A8 area. The results suggest an inverse relationship between TH/MES and number of dopamine neurons in the A9-A10 cell groups and significant lateral asymmetry in the A8 cell group. A detailed anatomical atlas of the mesencephalic A8-A9-A10 dopaminergic cell groups in the mouse is also presented to facilitate the assignment of TH-positive neurons to specific cell groups
— id: 140579, year: 2001, vol: 31, page: 47, stat: Journal Article,

Mapping of quantitative trait loci for ethanol preference in quasi-congenic strains
Vadasz C; Saito M; Balla A; Kiraly I; Vadasz C 2nd; Gyetvai B; Mikics E; Pierson D; Brown D; Nelson JC
2000 Feb;20(2):161-171, Alcohol
Ethanol preference, a component of alcoholism, has been known for four decades to differ greatly between C57BL/6 and BALB/c inbred mouse strains. For mapping quantitative trait loci (QTLs) that affect ethanol preference, we used a set of B6.C Recombinant QTL Introgression (RQI) strains, which carry about 5% of the donor BALB/cJ (C) genome on a C57BL/6ByJ (B6) background. After characterizing males of the progenitor and RQI strains for variations in ethanol preference, we scanned their genome for polymorphisms at 244 dinucleotide-repeat marker loci known to differ between B6 and C. Because of the introgression of BALB/c-type QTLs onto the B6 background, some strains showed ethanol preference significantly lower or higher than that of the background strain, suggesting that genetic interaction between ethanol preference QTLs and the background can be operative. The genomic region showing the strongest influence on ethanol preference was on mouse chromosome 15, and corresponds to human chr.12q11-q13
— id: 27879, year: 2000, vol: 20, page: 161, stat: Journal Article,

Analysis of complex traits: mutagenesis versus QTLs
Vadasz, C
2000 Dec;26(4):395-395, Nature genetics
— id: 140580, year: 2000, vol: 26, page: 395, stat: Journal Article,

Phenotype QTL introgression: Analysis of the midbrain dopamine system
Vadasz, C; Zaborszky, L
1999 SEP ;29(5):371-372, Behavior genetics
— id: 54711, year: 1999, vol: 29, page: 371, stat: Journal Article,

Analysis of the mesotelencephalic dopamine system by quantitative-trait locus introgression
Vadasz C; Sziraki I; Sasvari M; Kabai P; Murthy LR; Saito M; Laszlovszky I
1998 Nov;23(11):1337-1354, Neurochemical research
One of the significant factors that affect brain dopamine function is the activity of tyrosine hydroxylase (TH), the first and rate-limiting enzyme in catecholamine biosynthesis. For the analysis of the genetically determined role of dopamine function and TH in behavior and in the regulatory mechanisms of the mesotelencephalic dopamine system we devised a novel genetic strategy (Vadasz; Mouse Genome 88:16-18; 1990). We hypothesized that phenotypic introgression and recombinant fixation could ensure the transfer of Quantitative Trait Loci (QTL) from one strain onto the genetic background of another strain, and new, genetically very similar quasi-congenic strains could be created that would carry individual QTLs, or QTLs in various combinations. Here we summarize the construction of the first set of QTL Introgression strains, and present evidence that QTLs that are responsible for the continuous variation of mesencephalic tyrosine hydroxylase activity (TH/MES), have been transferred onto the C57BL/6By (B6) strain background from BALB/cJ (C) and CXBI (I) donor strains with high and low TH/MES, respectively. The QTL transfer was carried out in two directions by repeated backcross-intercross cycles with concomitant selection for the extreme high and low expressions of TH/MES in replicates, resulting in four QTL Introgression lines. Analysis of regional brain TH activities in the course of the QTL introgression indicated that (a) TH activity in B6.I lines showed quite limited heritability, (b) TH/MES was not highly correlated with striatal TH, and (c) the control of hypothalamic and olfactory tubercle TH activities was largely independent from that of TH/MES. Examination of the open-field (OF) behavior data demonstrated that TH activity did not correlate significantly with OF behavior. After 5 backcross-intercross cycles, TH/MES in each replicate line was still significantly different from that of the B6 background strain. A genomewide scanning of microsatellite markers in the QTL introgression lines demonstrated that about 96% of the markers were of background (B6) type. These results indicate the successful transfer of TH/MES QTLs. After the QTL transfer phase of the experiment altogether more than 100 new RQI strains were initiated in the QTL Introgression lines by strict brother x sister mating. After fixing the introgressed QTLs, ten of the inbred RQI strains were tested for TH/MES. The results showed that in one of the new RQI strains TH/MES was restored to a level that is characteristic to the C donor strain, while TH/MES values in some other strains were between those of the background and donor strains, confirming our hypothesis that phenotypic introgression and recombinant fixation can ensure a virtually complete transfer of QTLs. We conclude from this study that complex, continuously distributed neural traits can successfully be subjected to QTL introgression, and the results raise the possibility that the RQI method can be efficiently applied for gene mapping of complex neural and behavioral traits even if their phenotypic expression is sensitive to confounding developmental and environmental variations, genetic interactions, and genotype-environment interactions
— id: 7834, year: 1998, vol: 23, page: 1337, stat: Journal Article,

Ethanol preference in quasicongenic recombinant QTL introgression (RQI) mouse strains: Preliminary results
Vadasz, C; Mao, R; Lafrancois, J; Balla, A
1997 NOV ;27(6):609-609, Behavior genetics
— id: 53588, year: 1997, vol: 27, page: 609, stat: Journal Article,

Recombinant QTL-introgression animal models serve as a novel tool for mapping brain dopamine-system genes
Vadasz, C; Sziraki, I; Balla, A; Lafrancois, J; Mao, R
1997 NOV 21 ;74(6):584-585, American journal of medical genetics
— id: 53178, year: 1997, vol: 74, page: 584, stat: Journal Article,

Self-administration of ethanol: towards the location of predisposing polygenes in quasi-congenic animal models
Vadasz C; Fleischer A; LaFrancois J; Mao RF
1996 Nov-Dec;13(6):617-620, Alcohol
Alcohol consumption by C57BL/6By background and BALB/cJ donor strains, and by two recently developed quasi-congenic QTL-introgression strains, which share about 96% of their genes with the background strain, was studied in a limited access paradigm. Alcohol and water were offered for 60 min per day using modified pipettes on a drinking cage. Increasing concentration of alcohol solutions, 3, 6, and 12%, were given for days 1-7, 8-14, and 15-22, respectively. Consumption of the 12% alcohol solution was highest in C57BL/6By (0.72 g/kg/h), lowest in BALB/cJ (0.14 g/kg/h). The B6.Cb4i5 beta 13 quasi-congenic strain, in spite of its genetic similarity to the C57BL/6By background strain, consumed significantly less alcohol (0.41 g/kg/h) than the background strain. The results suggest that polygenes that reduce alcohol consumption were introgressed from the BALB/cJ donor strain into the C57BL/6By background strain, and that the b4i5 series of the B6.C quasi-congenic QTL-introgression strains may be useful in mapping genes that influence alcohol-related behaviors. Locations of the introgressed candidate polygenes were tentatively identified by analyzing microsatellite maps of two of the quasi-congenic strains
— id: 60297, year: 1996, vol: 13, page: 617, stat: Journal Article,

Genomic characterization of two introgression strains (B6.Cb4i5) for the analysis of QTLs
Vadasz C; Sziraki I; Sasvari M; Kabai P; Laszlovszky I; Juhasz B; Zahorchak R
1996 Jul;7(7):545-548, Mammalian genome
— id: 60298, year: 1996, vol: 7, page: 545, stat: Journal Article,

Spike-and-wave epilepsy in rats: sex differences and inheritance of physiological traits
Jando, G; Carpi, D; Kandel, A; Urioste, R; Horvath, Z; Pierre, E; Vadi, D; Vadasz, C; Buzsaki, G
1995 Jan;64(2):301-317, Neuroscience
Spontaneously occurring spike-and-wave patterns were examined in seven to eight-month-old rats of the inbred Fischer 344 and Brown Norway strains and their F1 and F2 hybrids. Neocortical activity and movement were monitored for 12 night h. Spike-and-wave episodes were identified by a three-layer back-propagation neural network. The incidence, average duration and total duration of spike-and-wave episodes were significantly higher in F1 males and F2 hybrids than in the parental strains. Male rats of the Brown Norway strain had significantly more and longer episodes than females, whereas no sex differences were present in Fischer rats. The average intraepisodic frequency of spike-and-wave patterns was significantly lower in Fischer rats than in the other groups and significantly higher in males than females. Tremor (myoclonic movements) associated with spike-and-wave episodes was absent or of very small amplitude in Fischer rats but frequent and of large amplitude in Brown Norway rats and their F1 and F2 descendants. Most of the interstrain differences were limited to male rats. Spike-and-wave episodes recurred at predictable short-term (10-30 s) and long-term (15-30 min) periods. The long-term oscillation corresponded to a similar fluctuation of motor activity. The maximum probability of spike-and-wave patterns occurred at a relatively narrow range of delta power (0-3.1 Hz) of the background EEG activity. Systemic administration of the adrenergic alpha-2 agonist, clonidine, increased the incidence of spike-and-wave episodes several-fold. The total duration of spike-and-wave episodes in the clonidine sessions (15 min) and night sessions (12 h test) correlated significantly. We suggest that several genes interact with maturational, environmental and endocrine factors, resulting in sex differences, and produce the variety of EEG and behavioral findings encountered. In addition, we submit that the clonidine test may be useful in genetic investigations of human absence epilepsies. The findings of this work demonstrate that genetic manipulation of rodents is a promising method for producing analogous models for the various forms of human absence epilepsies
— id: 140581, year: 1995, vol: 64, page: 301, stat: Journal Article,

Genetic threshold hypothesis of neocortical spike-and-wave discharges in the rat: an animal model of petit mal epilepsy
Vadasz C; Carpi D; Jando G; Kandel A; Urioste R; Horvath Z; Pierre E; Vadi D; Fleischer A; Buzsaki G
1995 Feb 27;60(1):55-63, American journal of medical genetics
Neocortical high-voltage spike-and-wave discharges (HVS) in the rat are an animal model of petit mal epilepsy. Genetic analysis of total duration of HVS (s/12 hr) in reciprocal F1 and F2 hybrids of F344 and BN rats indicated that the phenotypic variability of HVS cannot be explained by a simple, monogenic Mendelian model. Biometrical analysis suggested the presence of additive, dominance, and sex-linked-epistatic effects, buffering maternal influence, and heterosis. High correlation was observed between average duration (s/episode) and frequency of occurrence of spike-and-wave episodes (n/12 hr) in parental and segregating generations, indicating that common genes affect both duration and frequency of the spike-and-wave pattern. We propose that both genetic and developmental-environmental factors control an underlying quantitative variable, which, above a certain threshold level, precipitates HVS discharges. These findings, together with the recent availability of rat DNA markers for total genome mapping, pave the way to the identification of genes that control the susceptibility of the brain to spike-and-wave discharges
— id: 60303, year: 1995, vol: 60, page: 55, stat: Journal Article,

Transfer of brain dopamine system-specific quantitative trait loci onto a C57BL/6ByJ background
Vadasz, C; Sziraki, I; Murthy, L R; Sasvari-Szekely, M; Kabai, P; Laszlovszky, I; Fleischer, A; Juhasz, B; Zahorchak, R
1994 Nov;5(11):735-737, Mammalian genome
— id: 140582, year: 1994, vol: 5, page: 735, stat: Journal Article,

GENETIC DISSECTION OF COMPLEX NEUROCHEMICAL TRAITS - A NOVEL STRATEGY
VADASZ, C; SZIRAKI, I; KABAI, P; SASVARI, M; LASZLOVSZKY, I; FLEISCHER, A
1993 JUL 16 ;61(1):S37-S37, Journal of neurochemistry
— id: 52267, year: 1993, vol: 61, page: S37, stat: Journal Article,

Inheritance of neocortical high voltage spike-and-wave (HVS) patterns in rats
Carpi, D.; Jando, G.; Pierre, E.; Vadi, D.; Fleischer, A.; Lajtha, A.; Vadasz, C.; Buzsaki, G.
1992 ;18(1-2):555-555, Abstracts (Society for Neuroscience)
— id: 115505, year: 1992, vol: 18, page: 555, stat: Journal Article,

Motor activity and the mesotelencephalic dopamine function. I. High-resolution temporal and genetic analysis of open-field behavior
Vadasz C; Kobor G; Lajtha A
1992 May 8;48(1):29-39, Behavioural brain research
In a genetic selection experiment whose goal was to construct congenic neurological animal model lines with different mesotelencephalic dopamine systems, we produced foundation F2 generations derived from crosses (C57BL/6ByJXBALB/cJ and C57BL/6ByJXCXBI/ByJ) between highly inbred mouse lines with different dopamine systems. In this report, temporal distribution, latency, and genetic variability of open-field (OF) behavioral variables were investigated in order to establish a behavioral profile for the various generations and to provide behavioral data as a first step towards multivariate studies on correlations between OF behaviors and mesencephalic and striatal tyrosine hydroxylase activity. Analysis of the behavioral data provided evidence that measures of the open-field behaviors varied significantly across time segments of the test and that the temporal profiles of several behavioral variables were genotype-dependent. It is suggested that (1) OF behaviors have dynamic temporal profiles, and (2) temporal-genetic analysis can be a useful auxiliary method in the functional interpretation of behavior
— id: 60498, year: 1992, vol: 48, page: 29, stat: Journal Article,

Motor activity and the mesotelencephalic dopamine function. II. Multivariate analysis of genetically segregating generations
Vadasz C; Kobor G; Lajtha A
1992 May 8;48(1):41-47, Behavioural brain research
Previous experiments on genetically different inbred strains of mice demonstrated parallel variations between the activity of regional brain tyrosine hydroxylase (TH) and locomotor behavior. Based on these associations, it was hypothesized that genetic variations in mesotelencephalic TH activity, an index of dopamine neurotransmitter function, would correlate positively with exploratory and locomotor behavior. In order to test this hypothesis, open-field motor behaviors and mesencephalic and striatal TH activities were analyzed by multivariate statistical methods in genetically segregating (C57BL/6ByJ X BALB/cJ)F2 and (C57BL/6ByJ X CXBI/ByJ)F2 generations. Factor analysis, based on correlation matrices of variables with significant genetic dominance or additive effects, demonstrated that locomotor activity and frequency of occurrence of various motor patterns were not correlated with mesencephalic and striatal TH activity. These results indicate that the assumption of a positive phenotypic correlation between spontaneous motor activity and mesotelencephalic TH activity does not hold in genetically segregating populations. Strategies and problems in revealing the behavioral consequences of genetically based variations in the mesotelencephalic DA system are briefly discussed
— id: 60497, year: 1992, vol: 48, page: 41, stat: Journal Article,

Genetic aspects of dopamine receptor binding in the mouse and rat brain: an overview
Vadasz C; Laszlovszky I; De Simone PA; Fleischer A
1992 Sep;59(3):793-808, Journal of neurochemistry
— id: 62222, year: 1992, vol: 59, page: 793, stat: Journal Article,

L-Tyrosine-3-hydroxylase regulation in the brain: Genetic aspects
Vadasz, C.; Kobor, G.; Lajtha, A; Sziraki, I.; Fleischer, A.
1992 ;3(3):229-234, Amino acids
L-tyrosine-3-hydroxylase (TH) is the first and rate limiting enzyme in the biosynthetic pathway of catecholamine neurotransmitters (dopamine, noradrenaline, adrenaline). Implication of dopamine (DA) in various psychopathological phenomena, such as schizophrenia, has considerably contributed to the intensity of investigation of basic biochemical regulation of TH by activation and induction. Here we consider a third, constitutional (genotypic) aspect of regulation and present evidence that differences in mesencephalic (TH/SN), striatal (TH/CS), and hypothalamic (TH/HT) TH activity between virtually isogeneic strains of mice can be explained by segregating genetic factors. Biometrical genetic analysis of progenitor strains and their crosses indicated significant additive gene effects for TH/SN, TH/CS, and TH/HT, whereas dominance effects were statistically non-significant. A monogenic model of inheritance for TH/SN and TH/CS could not be rejected, while more than one gene was indicated for TH/HT. Significant positive phenotypic correlations were found in genetically segregating populations among mesencephalic, striatal and hypothalamic TH activities. This would suggest that some common genetic factors (or linked genes) are involved in the genetic variation of all three traits. A genetic selection experiment to elucidate the cellular and biochemical mechanisms underlying these variations is in progress
— id: 115510, year: 1992, vol: 3, page: 229, stat: Journal Article,

Spike-and-wave neocortical patterns in rats: genetic and aminergic control
Buzsaki G; Laszlovszky I; Lajtha A; Vadasz C
1990 ;38(2):323-333, Neuroscience
Spontaneously occurring and drug-induced high voltage spike-and-wave electroencephalogram patterns were examined in inbred rats of the Fischer 344 and Buffalo strains and of the random-bred Sprague-Dawley strain at different ages. In addition, tyrosine hydroxylase activity and dopamine D2 receptor density were determined in the substantia nigra, corpus striatum, olfactory tubercle and ponsmedulla areas of Fisher 344 and Buffalo animals. High voltage spike-and-wave episodes were present in 87.5% of the 3-month-old and in 100% of the older Fischer 344 rats. High voltage spike-and-wave episodes were completely absent in 3-month-old Buffalo and Sprague-Dawley animals but could be induced by systemic injection of pentylenetetrazol and at an older age they appeared in 58.3% (12-month) and 71.4% (greater than 26-month) of the subjects of these strains. The incidence and duration of high voltage spike-and-wave episodes were significantly higher/longer in Fischer 344 rats than in the age-matched Buffalo and Sprague-Dawley animals. The dopamine blocker acepromazine induced a several-fold increase of the incidence and duration of high voltage spike-and-wave episodes in 3-month-old Fischer 344 rats, but failed to induce high voltage spike-and-wave episodes in Buffalo animals at this age. However, acepromazine also triggered high voltage spike-and-wave episodes in Buffalo rats when they were pretreated with subthreshold doses of pentylenetetrazol. Tyrosine hydroxylase activity was significantly higher in the substantia nigra, corpus striatum and olfactory tubercle of the Fischer 344 strain than in Buffalo rats. The higher tyrosine hydroxylase activity was paralleled with significantly higher D2 binding values in the corpus striatum and olfactory tubercle of Fischer 344 rats. These findings suggest that the neocortical high voltage spike-and-wave phenotype is genetically mediated and that the inbred Fischer 344 and Buffalo rats with defined bilineal origin will facilitate future works aimed at the identification of genetic elements involved in the generation of neocortical high voltage spike-and-wave episodes. The significant genotype x age interaction supports the suggestion, however, that high voltage spike-and-wave episodes are likely to be influenced by more than one gene; some of them are probably related to the regulation of brain aminergic systems
— id: 60522, year: 1990, vol: 38, page: 323, stat: Journal Article,

GENETIC DIFFERENCES IN NEOCORTICAL HIGH VOLTAGE SPIKE AND WAVE SPINDLE HVS PATTERNS PARALLEL VARIATIONS IN BRAIN DOPAMINE DA SYSTEMS
LASZLOVSZKY I; BUZSAKI G; LAJTHA A; VADASZ C
1990 ;16(1):782-782, Abstracts (Society for Neuroscience)
— id: 115518, year: 1990, vol: 16, page: 782, stat: Journal Article,

Effects of social isolation and the time of day on testosterone levels in plasma of C57BL/6By and BALB/cBy mice
Sayegh JF; Kobor G; Lajtha A; Vadasz C
1990 Feb;55(2):79-82, Steroids
Adult male C57BL/6By and BALB/cBy mice were housed either in large groups (20 per cage) or individually, and levels of plasma testosterone were measured in samples taken in the morning (9 to 10 A.M.) and in the evening (9 to 10 P.M.). No significant strain differences were found in testosterone levels, but the mean testis weight was significantly higher in the BALB/cBy strain. Two-way analysis of variances of pooled plasma testosterone data showed that social isolation of males results in a significant increase in A.M. (but not P.M.) testosterone concentrations and increased testis weight in both strains. Our results suggest that differential housing of a social species can affect testicular function. Since testicular function can also be influenced by the time of day, the question is raised whether the expression of circadian variation in plasma testosterone level is dependent on population density
— id: 22653, year: 1990, vol: 55, page: 79, stat: Journal Article,

COMPLEX NEURAL SYSTEMS AND BEHAVIORS A NOVEL STRATEGY FOR THEIR GENETIC DISSECTION
VADASZ C; LASZLOVSZKY I; KABAI P; SASVARI M; SZIRAKI I; VADASZ I; LAJTHA A
1990 ;16(2):1139-1139, Abstracts (Society for Neuroscience)
— id: 115520, year: 1990, vol: 16, page: 1139, stat: Journal Article,

NEONATAL GONADECTOMY HAS GENOTYPE DEPENDENT EFFECT ON BRAIN DOPAMINE SYSTEMS AND BEHAVIOR
KABAI P; SZIRAKI I; LAJTHA A; VADASZ C
1989 ;15(2):1015-1015, Abstracts (Society for Neuroscience)
— id: 115531, year: 1989, vol: 15, page: 1015, stat: Journal Article,

STRAIN-DEPENDENT VARIATIONS IN KINETIC-PROPERTIES OF MESENCEPHALIC TYROSINE-HYDROXYLASE
SZIRAKI, I; SASVARISZEKELY, M; KABAI, P; KOBOR, G; VADASZ, I; LAJTHA, A; VADASZ, C
1989 ;6(2):177-185, Biogenic amines
— id: 115535, year: 1989, vol: 6, page: 177, stat: Journal Article,

ETHOLOGICAL STUDY OF OPEN-FIELD BEHAVIOR
KABAI P; LAJTHA A; KOBOR G; VADASZ C
1988 ;14(2):1105-1105, Abstracts (Society for Neuroscience)
— id: 115540, year: 1988, vol: 14, page: 1105, stat: Journal Article,

Effects of estradiol and dexamethasone on choline acetyltransferase activity in various rat brain regions
Kaufman H; Vadasz C; Lajtha A
1988 Jun 21;453(1-2):389-392, Brain research
Estradiol, administered to ovariectomized rats, increased choline acetyltransferase (ChAT) activity in the caudate nucleus, cortex, hippocampus, and hypothalamus, suggesting possibly widespread central cholinergic involvement in estrus-related behavior. Dexamethasone also, except in hypothalamus, increased ChAT activity, notably (50%) in hippocampus. ChAT activity changes did not correlate with reported regional hormone receptor density. Estradiol's effect in the caudate suggests that hormone receptor and affected enzyme may not necessarily coexist intraneuronally
— id: 60554, year: 1988, vol: 453, page: 389, stat: Journal Article,

Perinatal anti-androgen treatment and genotype affect the mesotelencephalic dopamine system and behavior in mice
Vadasz C; Kobor G; Kabai P; Sziraki I; Vadasz I; Lajtha A
1988 Dec;22(4):528-539, Hormones & behavior
Sex and strain differences in tyrosine hydroxylase activity (TH) of brain dopamine systems have been reported for mice. To investigate if there might be a causal relationship between perinatal androgen secretion and regional mesotelencephalic TH activity, BALB/cJ and C57BL/6ByJ male mice were treated perinatally with cyproterone, a steroidal anti-androgen (or vehicle), and orchiectomized at 1 month of age. Two-way analysis of variance indicated significant treatment and strain effects in the mesencephalon and tuber olfactorium: perinatal cyproterone treatment lowered TH activity, and BALB/cJ had higher regional TH activities than those of C57BL/6ByJ. The most prominent behavioral effects of cyproterone treatment were found in the expression of scratching, which was considerably increased in both strains. Possible implications of these results are discussed
— id: 60548, year: 1988, vol: 22, page: 528, stat: Journal Article,

Autoradiographic distribution of binding sites of [3H]SKF 38393, a selective dopamine D1 receptor agonist, in the mouse forebrain
Juhasz M; Kobor G; Lajtha A; Vadasz C
1987 Oct 13;423(1-2):305-308, Brain research
Distribution of binding sites of [3H]SKF 38393, a selective dopamine D1 receptor agonist, was studied on forebrain coronal sections of CXBI/ByJ mice by radioligand binding and digital subtraction autoradiography. Highest levels of [3H]SKF 38393 binding were detected in olfactory tubercle and caudate nucleus/putamen. Intermediate to low concentrations of receptors were indicated in cortex, amygdala, hypothalamus, claustrum, and septal area, whereas the lowest binding was found in white matter tracts (commissura anterior, corpus callosum). Analysis of data on caudate nucleus/putamen indicates a striosomal pattern of binding with a gradient of binding sites from medial to lateral caudate/putamen. The distribution of [3H]SKF 38393 binding sites corresponds to that of dopaminergic projection fields in the studied areas
— id: 60563, year: 1987, vol: 423, page: 305, stat: Journal Article,

EFFECT OF MPTP AND MPP-+ ON TYROSINE HYDROXYLATION IN STRIATAL HOMOGENATE OF MICE
SZIRAKI I; LAJTHA A; VADASZ C
1987 ;22(SUPPL):S603-S603, Neuroscience
— id: 115561, year: 1987, vol: 22, page: S603, stat: Journal Article,

Genetic determination of hypothalamic tyrosine hydroxylase activity in mice
Sziraki I; Murthy LR; Lajtha A; Vadasz C
1987 Jan;18(1):13-18, Brain research bulletin
Tyrosine hydroxylase (TH) activity data obtained from hypothalamic tissue samples of highly inbred mouse strains with known differences in their mesencephalic TH activity (BALB/cJ, C57BL/6ByJ, CXBI/ByJ), F1 hybrids and F2 generations were subjected to quantitative genetic analysis. No differences were observed between C57BL/6ByJ and CXBI/ByJ strains, but highly significant differences were found in hypothalamic TH activity between BALB/cJ and C57BL/6ByJ strains. Segregating genetic factors could not be detected in the replicate (C57BL/6ByJ X CXBI/ByJ) F2 generations, while the presence of segregating genetic units was indicated in the (C57BL/6ByJ X BALB/cJ)F2 population. Estimation of minimum number of genes and Elston's non-parametric one-locus test reveal that more genes are responsible for strain differences of TH activity in the hypothalamus compared to the dopaminergic areas of the mesotelencephalon. The results indicate that the heterogeneity of the catecholamine neuronal populations and terminal fields in the hypothalamus is reflected by the complex nature of the genetic control of TH activity in this brain region
— id: 60577, year: 1987, vol: 18, page: 13, stat: Journal Article,

Genetic determination of mesencephalic tyrosine hydroxylase activity in the mouse
Vadasz C; Sziraki I; Murthy LR; Vadasz I; Badalamenti AF; Kobor G; Lajtha A
1987 Aug;4(5):241-252, Journal of neurogenetics
The hereditary factors that affect mesencephalic tyrosine hydroxylase (TH) activity were investigated in highly inbred mouse strains (CXBI/ByJ, C57BL/6ByJ, and BALB/cJ). The progenitor strains and their F1 hybrids, were compared for mesencephalic TH activity with each other and with replicated F2 generations. Quantitative and non-parametric genetic analysis of the data raise the possibility that there is a major gene with robust additive effect that is primarily responsible for the difference between the progenitor strains with intermediate and high mesencephalic TH activity. Strain differences in mesencephalic TH activity have been linked to differences in number of dopamine (DA) neurons in that area. If genetic variation of mesencephalic TH activity is entirely attributable to variation in number of mesencephalic dopamine (DA) neurons, identification of the genetic sources of variation of mesencephalic TH activity may take us a step closer to animal models and preparations that are needed in the study of the physiological and constitutional mechanisms of human disorders in which DA neurotransmission is involved
— id: 60567, year: 1987, vol: 4, page: 241, stat: Journal Article,

REGIONAL DIFFERENCES IN THE EFFECT OF METHYLPHENYL-6-TETRAHYDROPYRIDINE ON TYROSINE HYDROXYLASE ACTIVITY IN MICE
SZIRAKI I; JUHASZ M; KOBOR G; LAJTHA A; VADASZ C
1986 ;12(1):609-609, Abstracts (Society for Neuroscience)
— id: 115570, year: 1986, vol: 12, page: 609, stat: Journal Article,

HEREDITARY EFFECTS ON MESOTELENCEPHALIC TYROSINE HYDROXYLASE ACTIVITY AND COMPONENTS OF OPEN-FIELD BEHAVIOR
VADASZ C; KOBOR G; SZIRAKI I; LAJTHA A
1986 ;12(2):1225-1225, Abstracts (Society for Neuroscience)
— id: 115573, year: 1986, vol: 12, page: 1225, stat: Journal Article,

GENETICS OF MESENCEPHALIC TYROSINE HYDROXYLASE ACTIVITY
VADASZ C; SZIRAKI I; MURTHY L R; VADASZ I K; BADALAMENTI A F; KOBOR G; LAJTHA A
1986 ;12(26):S110-S110, Neuroscience letters. Supplement
— id: 115574, year: 1986, vol: 12, page: S110, stat: Journal Article,

Genetic determination of striatal tyrosine hydroxylase activity in mice
Vadasz C; Sziraki I; Murthy LR; Lajtha A
1986 Aug;11(8):1139-1149, Neurochemical research
An additive major gene effect is described for tyrosine hydroxylase activity in mouse corpus striatum (CS). Quantitative genetic analysis indicated the presence of a segregating Mendelian factor with robust additive effect in F2 generations derived from crossing two highly inbred mouse strains, C57BL/6ByJ and BALB/cJ, with intermediate (INT) and high (HI) TH activity in CS. Significant positive correlation was found between striatal and mesencephalic TH activity in the segregating generations, raising the possibility that a common single gene may express its effect through pleiotropy or linkage. Genetic preparations taking advantage of the major gene effect should serve well as animal models of DA-mediated neuropsychiatric disorders
— id: 60583, year: 1986, vol: 11, page: 1139, stat: Journal Article,

ETHOLOGICAL ANALYSIS OF OPEN-FIELD BEHAVIOR IN HIGHLY INBRED MOUSE STRAINS, THEIR F1 HYBRIDS, AND REPLICATED F2 GENERATIONS
VADASZ, C; KOBOR, G; LAJTHA, A
1986 ;16(6):638-638, Behavior genetics
— id: 115572, year: 1986, vol: 16, page: 638, stat: Journal Article,

GENETIC CORRELATION ANALYSIS OF HYPOTHALAMIC AND MIDBRAIN TYROSINE HYDROXYLASE ACTIVITY
MURTHY L R; SZIRAKI I; LAJTHA A; VADASZ C
1985 ;11(2):1203-1203, Abstracts (Society for Neuroscience)
— id: 115579, year: 1985, vol: 11, page: 1203, stat: Journal Article,

GENETIC CORRELATION ANALYSIS OF THE NIGROSTRIATAL DOPAMINE SYSTEM
SZIRAKI I; MURTHY L R; LAJTHA A; VADASZ C
1985 ;11(2):1204-1204, Abstracts (Society for Neuroscience)
— id: 115582, year: 1985, vol: 11, page: 1204, stat: Journal Article,

GENETIC APPROACHES TO STUDY RELATIONSHIPS BETWEEN BRAIN AND BEHAVIOR
VADASZ C; SZIRAKI I; MURTHY L R; LAJTHA A
1985 ;11(1):721-721, Abstracts (Society for Neuroscience)
— id: 115584, year: 1985, vol: 11, page: 721, stat: Journal Article,

GENETIC DISSECTION OF A MAMMALIAN BEHAVIOR PATTERN
VADASZ, C; KOBOR, G; LAJTHA, A
1983 ;31(NOV):1029-1036, Animal behaviour
— id: 115592, year: 1983, vol: 31, page: 1029, stat: Journal Article,

The inheritance and genetic correlation of tyrosine hydroxylase activities in the substantia nigra and corpus striatum in the C x B recombinant inbred mouse strains
Vadasz C; Baker H; Joh TH; Lajtha A; Reis DJ
1982 Feb 18;234(1):1-9, Brain research
In mouse, strain differences in the activity of tyrosine hydroxylase (TH) in ventral midbrain dopamine systems of substantia nigra-A10 (SN) region of mouse brain and in a terminal field, the striatum (CS), can be entirely attributed to variations in the number of dopaminergic neurons2. To obtain further information about the complexity of the genetic systems influencing phenotypes for regional TH activity, we examined TH activity in the SN and CS of 7 recombinant inbred (RI) mouse strains, their progenitor strains (BALB/cBy and C57BL/6By), their reciprocal F1 hybrids and a CB6F2 segregating generation. Genetic analysis indicated that TH activity in both brain regions seems unlikely to be controlled by single gene effects. However, the mode of inheritance is presumably not very complex. Estimates of the degree of genetic determination for TH activity in SN and CS were relatively high with significant and positive correlations with respect to either the RI lines (r = 0.82) or the CB6F2 generation (r = 0.53). These positive correlations suggest that some of the genes of two gene sets influencing TH activities in the SN and CS are the same. However, additional non-shared genes may also be present. Assuming that our two measures reflect the number of dopaminergic neurons in SN-A10 area and density of their processes in corpus striatum, our results lead us to the hypothesis that the number of dopaminergic neurons and the axonal arborization of these neurons in the nigrostriatal system are in part under a common genetic control but that other genes may contribute to branching of SN neurons
— id: 60637, year: 1982, vol: 234, page: 1, stat: Journal Article,

Strain differences in opiate receptors in mouse brain
Reith ME; Sershen H; Vadasz C; Lajtha A
1981 Sep 24;74(4):377-380, European journal of pharmacology
Various opiate ligands were bound to brain membranes of mice of the Recombinant Inbred System. The specific binding of low levels of [3H]naloxone, [3H]dihydromorphine and [3H]ethylketocyclazocine was disturbed in a similar fashion among the inbred strains, and in a pattern different from that observed for [3H](D-Ala2,D-Leu5)-enkephalin. The results indicate that the inbred strains differ in mu- and delta-type binding and support the concept of multiple opiate receptors in mouse brain
— id: 60641, year: 1981, vol: 74, page: 377, stat: Journal Article,

STRAIN-DEPENDENT DIFFERENCES IN OPEN-FIELD BEHAVIOR AND CEREBRAL CHOLINE-ACETYLTRANSFERASE ACTIVITY IN ESTROUS AND DIESTRUS MICE
VADASZ, C; LAJTHA, A
1981 ;6(1):63-68, Research communications in psychology, psychiatry & behavior
— id: 115600, year: 1981, vol: 6, page: 63, stat: Journal Article,

INHERITANCE OF GROOMING BEHAVIOR IN CXB RECOMBINANT-INBRED MICE
VADASZ, C; LAJTHA, A
1979 ;9(5):482-483, Behavior genetics
— id: 115604, year: 1979, vol: 9, page: 482, stat: Journal Article,