For many years, Dr. Brodie has maintained a close collaboration with Dr. Stephen Dewey and the PET group of Brookhaven National Laboratory. This effort has focused on the investigation of neurotransmitter interactions and their application to clinical issues. We use PET neuroimaging methods with pharmacological perturbations as probes and changes in binding of radioligands to specific neuroreceptors as outcome measures. We pair these human and non-human primate studies with microdialysis studies and behavioral observations as independent measures. With this strategy, we have established that the hallmark of any functioning psychoactive drug is chemical plasticity, expressed as neurotransmitter interactions, i.e. the ability to transmit and transduce a chemical signal to brain regions that may be distinguished in space and/or time. We are actively investigating the complexity of this accommodation with pharmacologic probes in non-human primates, normal controls and patient populations. Measurement of these interactions with PET is now an accepted method for examining pharmacological activity in vivo. Initially, we developed probes to investigate the ability of one neurotransmitter to modulate or be modulated by another functionally linked neurotransmitter system by using multiple radiotracers and pharmacologically specific challenges in the study of schizophrenia. These early studies have since evolved to encompass such areas as neuroleptic response and neurotransmitter stability. More recently our studies of GABAergic modulation of dopamine have led to the exciting findings that the suicide inhibitor of GABA transaminase, GVG, is an extraordinarily effective drug in blocking the use of virtually all drugs of abuse, including cocaine, nicotine, heroin, alcohol, methamphetamine and others. We are actively involved in the extension of these studies to human patients.