The long term goal of the current proposal is to employ psychopharmacological methods to identify the brain substrates responsible for the self-administration of opiate and stimulant drugs of abuse. Toward this end, we have employed a relatively unique model of drug-self-administration in which rats traverse a long straight alley once a day to receive drug reinforcement upon entry into the goal box. In this model, running speed represents a reliable index of the nondrugged animals' motivation to obtain the drug reinforcer on each new/trial/day. In addition, since running speed on a given trial is reliably altered by the magnitude of the reinforcer on the previous trial, putative reward manipulations (such as DA antagonist challenge) can be conducted on one day/trail and the effects observed 24 hrs later on the next (when the direct pharmacological effects of the antagonist probe have subsided). To date our work has identified both positive (response-reinstating) and negative (angiogenic) properties of drug reinforcers. In the Response Reinstatement Test, a single reinforced trial in the midst of extinction is sufficient to reinstate previously extinguished operant running 24 hrs later on the very next trial. This permits us to model the human condition where relapse probability after abstinence is high if the individual is reexpose to the drug. Thus far, the response-reinstating effects of food, water, heroin, and amphetamine have all been attenuated by pretreatment with DA antagonist drugs. Additional studies are proposed to a) extend our analysis to other self- administered drugs (e.g. nicotine, caffeine and ethanol); b) identify the drugs' central site(s) of action using localized intracerebral infusions of DA antagonists, and c) investigate the relative roles of dopamine receptor subtypes in the response-reinstating properties of the drug reinforcers. In a separate series of iv cocaine experiments we identified a putative """"""""conflict"""""""" state characterized by stop-and-retreat behaviors that grow more frequent as trials progress and occur in close proximity to the goalbox entryway. Such behaviors may stem from concurrent cocaine- induced positive (rewarding) and negative (anxiogenic) associations with the goal box. Studies are therefore proposed to assess a) whether other drug reinforcers share this dual (positive/negative) action; b) what pharmacological """"""""treatments"""""""" alter the putative antigenic properties of cocaine (e.g. heroin, ethanol, 5-HT3 antagonists...); and c) what brain sites might be responsible for these angiogenic properties. In summary, the proposed research should enhance our understanding of both the positive and negative factors that together determine the nature and extent of drug self-administration behaviors.
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