Cocaine produces a strong positive motivational state, a craving, which is an addictive process. Current empirical evidence, gleaned from studies of brain reward processes, maintains that cocaine acts primarily on dopaminergic mesolimbic terminals. Yet, neurochemical evidence, to date, cannot begin to account for its basic underlying mechanisms of the quality of reinforcement, or """"""""addictive liability."""""""" The neurochemical evidence for cocaine's ability to block dopamine reuptake in nigrostriatal and mesolimbic areas of rat brain is abundant, but it does not lend an explanatory note for either the psychotropic or addictive properties of cocaine. Tricyclic antidepressants also block dopamine reuptake and are generally assumed non-addicting, Therefore, the specific aim (1) of this proposal is to delineate the basic neurochemical action of cocaine administration, in brain dopaminergic systems, known to mediate brain reward, by studying release processes with in vivo electrochemistry. This is the first study of the acute and chronic release mechanisms of cocaine in vivo. The ability to measure dopamine release in vivo represents a significant improvement in biochemical methodology. We can now derive data which more closely approximates the dynamic state. The delineation of the neurochemical differences which might ensue due to short term cocaine use, vis-a-vis long term cocaine use, is an issue which should be addressed because cocaine is a short acting drug. There is a need to unmask adverse effects due to the chronicity of cocaine use. Another specific aim (2) of this proposal is to compare the effects of cocaine with the effects of opiates and opioid peptides to further investigate the neurochemical similarities of their neuronal release properties, to study release processes as a possible predictor of abuse liability. Moreover, this research proposal (3) seeks to address new treatment modalities for cocaine abuse by investigating neurochemical mechanisms for the antagonism of cocaine's effect on mesolimbic and nigrostriatal areas of brain because new and effective treatment modalities are needed. Long range plans include the extension of these studies to dopamine release from neuroanatomical substrates implicated in brain reward, including the medial forebrain bundle, in the freely moving rat, under conditions of saline, acute and chronic cocaine use and during brain reward processes. The studies provide a closer than ever causal relationship between neurochemistry and brain reward. This research seeks to provide a new awareness of the health related risks from cocaine use.
| Broderick, P A; Phelan, F T; Eng, F et al. (1994) Ibogaine modulates cocaine responses which are altered due to environmental habituation: in vivo microvoltammetric and behavioral studies. Pharmacol Biochem Behav 49:711-28 |
