PEPTIDE MODULATION OF MESOLIMBIC DOPAMINE: BEHAVIORAL A

中脑边缘多巴胺（DA）系统，起源于

The mesolimbic dopamine (DA) system, which originates in the ventral tegmental area (VTA) and projects to limbic forebrain regions, plays a crucial role in mediating several important aspects of behavior. Mesolimbic DA neurons have been shown to be involved in such diverse functions as facilitation of motor output, reinforcement (including mediation of the rewarding properties of drugs of abuse), sensory and attentional processes. Surrounding these DA neurons are multiple networks of neuropeptide-containing nerve fibers, such as those containing opioid peptides, tachykinins, and neurotensin. Biochemical and behavioral experiments have suggested that these peptides have an important modulatory influence on the activity of mesolimbic DA neurons. Given the multiplicity of functions ascribed to the DA neurons and the striking diversity of peptidergic innervation associated with them, it would seem likely that their differential peptidergic modulation may constitute the substrate of different behavioral processes. The major objective of this project is to determine what specific behavioral processes these peptide-DA interactions are mediating. To accomplish this goal, paradigms which are able to distinguish drug effects on reinforcement, motor and sensory processes will be integrated with central microinfusion of putative peptide neurotransmitters. This will enable anatomically and chemically specific manipulations of VTA neuronal subpopulations, and evaluation of the behavioral state induced by the peptides. This investigation has direct relevance to the problem of drug abuse, which is a major medical and social problem. Of particular concern at the present moment are stimulant drugs such as cocaine and amphetamine, as well as opiate substances. There is convincing evidence that these two classes of drugs act on the mesolimbic dopamine system to produce a highly reinforcing behavioral state. Thus further study of the basic mechanisms of endogenous peptides which modulate this system may contribute to our understanding of how psychostimulant and opiate drugs produce their psychological effects, and may also help the development of new therapeutic treatment of drug addiction. Moreover, the proposed experiments specifically examine how peptide-dopamine interactions contribute to brain mechanisms of reward and motivation, which may further increase our knowledge of the reinforcing properties of self-administered drugs.