A primary hypothesis about the brain mechanisms through which drugs of abuse producing their reinforcing effects, is that such agents act on endogenous brain reward substrates whose """"""""natural"""""""" function is to ensure the incentive value of biologically essential stimuli such as food and water. Thus, understanding the brain mechanisms through which natural reinforcers act, should be relevant to our understanding of how drugs of abuse act in their role as positive reinforcers. In this regard, our laboratory has been involved in studies of the behavioral function of central dopaminergic pathways for several years. More specifically, the present proposal is intended to build upon our recent findings with dopamine (DA) receptor antagonist drugs. The administration of such drugs has long been known to interfere with the performance of operant behaviors in laboratory animals. However, interest and controversy continue to exist regarding the precise mechanism(s) through which these drugs exert their behavioral effects. We have made considerable progress establishing both limbic (reward) and extrapyramidal (motoric) deficits in DA antagonist-treated animals using a series of novel carefully- controlled behavioral test procedures developed in our laboratory. The novelty of our reinforcement assays is that they permit the investigation of drug-induced reward deficits at a test-time when the drug under investigation is no longer active. this obviously increases the power of our data set since non-specific performance consequences of drug administration are not present on test day. In the proposed experiments we plan to employ our behavioral tests in three specific ways: 1) to assess the relative contributions of D1 and D2 dopamine receptor subtypes to the behavioral deficits observed during DA antagonist challenge; 2) to extend the investigation of DA antagonist effects to a variety of positive reinforcers; and 3) to identify the brain sites responsible for the behavioral actions of DA antagonist drugs. Together, the proposed experiments should provide important new information on a) the precise mechanisms through which such drugs exert their behavioral effects; and b) the nature of the role of central dopaminergic neurons in reward and motivational processes. It is our view that such information will prove valuable to investigations of the neural substrates through which drugs of abuse exert their reinforcing actions.
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