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| Mechanisms Involved in Psychotropic Drug Action in the Brain
Jeannette C. Miller Ph.D.
Associate Professor
Department of Psychiatry (Millhauser Labs) | | |
| Research Summary |
| Our research concerns the molecular neurobiological effects of antipsychotic drugs (APDs), which are compounds of a diverse chemical nature used to treat schizophrenia and other psychoses. Primarily, they reduce dopaminergic neurotransmission. Some APD classes, typical ones such as haloperidol, produce a spectrum of extrapyramidal side effects (EPS). Newer atypical agents, such as clozapine, appear to have reduced EPS liability. The development of more effective therapeutic agents with fewer EPS requires a better understanding of the neurochemical mechanisms involved in the expression of schizophrenia and the pharmacological effects of APDs. We focus on identifying changes that APDs produce in the brain that coincide, temporally, with expected EPS and therapeutic effects in humans. Our studies and those of others show that APDs trigger acute biological responses involving induction of immediate early genes (IEGs) within the neural dopaminergic motor system (striatum) that can be differentiated from those produced in systems that subserve the therapeutic actions of APDs, i.e., the mesolimbic (nucleus accumbens) and prefrontal cortical dopaminergic areas. The IEGs, c-fos, c-jun, and junB are induced after haloperidol treatment in the striatum of the rat, while the atypical drug has no effect on these IEGs. Typical and atypical APDs appear to induce c-fos and junB in the nucleus accumbens and, to some extent, the prefrontal cortex, strongly implicating the mesolimbic system in the therapeutic action of APDs and the c-fos response in striatum as a good predictor of EPS liability. These differential effects may guide the development of newer therapeutic agents with fundamentally different mechanisms of action for the treatment of psychosis. Current research involves: 1) the chronic effects of these and other psychotropic drug treatments on IEG expression, on the later expression of other Fos-related antigens, and on altered expression of specific target genes regulated by these transcription factors; 2) studies of differences in gene expression in monozygotic twins discordant for schizophrenia; 3) the usefulness of human lymphocytes to study gene expression relevant to the brain; and 4) the effects of perturbation of endogenous maternal biochemistry on brain neurochemistry and behavior of the progeny.
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| Research Information |
Research Interests | Mechanisms Involved in Psychotropic Drug Action in the Brain | Research Keywords | antipsychotic drugs, dopamine, Fos, gene expression, schizophrenia |
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