Upon withdrawal of chronic drugs of dependence, rats detect an unpleasant subjective effect similar to that of the stimulant drug pentylenetetrazol (PTZ). This PTZ-like withdrawal stimulus is produced by withdrawal of drugs representing several pharmacological classes, including ethanol, nicotine, cocaine and benzodiazepines. The long-term objective of the proposed research is to characterize neurochemical correlates of these withdrawal-related subjective events. Although the initial action of PTZ is blockade of chloride channels in the GABA/benzodiazepine receptor chloride ionophore complex, the neurochemical sequelae that then give rise to the """"""""withdrawal-like"""""""" subjective effect of PTZ are not known. Because dopaminergic mechanisms in the reward system have been postulated to mediate subjective effects of drug-withdrawal, the proposed study will focus upon dopaminergic responses to withdrawal and to PTZ. The purpose of the proposed study is to determine PTZ- and ethanol-withdrawal-induced changes in concentrations of dopamine and its metabolites in the extracellular fluid in the brain. Areas sampled will include several that may be important for drug addiction (n. accumbens, lateral hypothalamus, medial hypothalamus, prefrontal cortex, amygdala) and one (caudate) noted for high dopamine content and for its greater specificity for neuromuscular than for subjective phenomena. Rats will first be surgically implanted with chronic indwelling cannulae. Later, during active behavior, microdialysis probes will be inserted through these cannulae into target areas for collection of extracellular fluid samples. The samples will be assayed by High Performance Liquid Chromatography for dopamine, HVA and DOPAC.
Specific aims are to 1) identify changes in dopamine release produced by PTZ, 2) determine whether similar changes accompany ethanol withdrawal, and 3) determine the effect of PTZ discrimination training upon dopaminergic response to. PTZ.
