Psychostimulant abuse has been characterized by persistent changes in brain dopamine (DA) activity. Recently, we developed a novel pharmacologic strategy predicated on the understanding that GABA inhibits DA and other neurotransmitter systems. Specifically, gamma-vinyl GABA (GVG, vigabatrin), inhibits drug self-administration, the expression and acquisition of conditioned place preference and sensitization, the lowering of drug-induced brain stimulation reward thresholds and drug induced increases in synaptic and extracellular DA. Through irreversible inhibition of GABA-transaminase (GABA-T), the enzyme responsible for GABA catabolism, GVG provides a non-receptor mediated mechanism with a duration of effect on GABA-T that parallels the time required to synthesize new enzyme. However, the duration of GVG's effect on GABA levels does not parallel this time course. Further, when properly scheduled, GVG possesses a use-dependent mechanism such that increases in brain GABA are utilized only in the presence of abnormal stimulation. GVG pharmacotherapy represents the possibility of an approach unparalleled in duration and specificity. Under the premise that useful medications for cocaine or nicotine dependence also require a therapy that can treat withdrawal symptoms and block the euphoria associated with drug self-administration, we propose that the dosing intensity and duration of GVG's pharmacologic activity can be optimized to help maintain an extended, drug-free lifestyle. We intend to use in vivo microdialysis in rodents to measure the effects of several subchronic, low-dose GVG treatment schedules on the DA response to a cocaine or nicotine challenge following extended washout durations. Further, using the conditioned place preference (CPP) paradigm as an index of craving, we propose to explore the effects of similar treatment schedules and washout durations on drug seeking behavior. This development represents an identified therapeutic strategy for the treatment of psychostimulant abuse symptoms associated with their toxic effects.
Showing the most recent 10 out of 20 publications
