The consequences of drug abuse range from disruptive to devastating, affecting the health and ell-being of individuals, families, communities and nation. Intervention at athe individual level, with better methods of prevention and treatment, offers what may be the best hope for amelioration. But effective treatments require a better understanding of the mechanisms underlying the reinforcing power of drugs. Recent years have seen substantial gains in understanding the molecular mechanisms through which abused drugs influence the CNS. A number of specific brain structures have been implicated. In particular, the dopaminergic neurons of the ventral tegmental area (VTA) and their projection regions, including the nucleus accumbens (NAc) have been strongly implicated in the reinforcing effects of cocaine, as well as opiates, benzodiazepines, barbiturates and ethanol. But relatively little is known about the function of the VTA in awake, behaving animals. In particular, few experiments have examined the activity of VTA neurons during motivated behavior, and to our knowledge, none have extended these observations to the influence of cocaine or other abused drugs. In preliminary experiments, we found that VTA neurons showed systematic variations in firing rate associated with ongoing reward-seeking and consumption. For some neurons, cocaine enhanced both the excitatory and inhibitory phases of behaviorally correlated activity in the VTA. It is possible that this enhancement reflects an increased sensitivity to rewarding in general in the presence of cocaine. However, not all neurons responded to cocaine in this fashion: indeed, a considerable variation in response was observed. The VTA is known to include several distinct neural subtypes, and it is possible that this variability reflect recordings from these different neurons. Alternatively, the observed variability could accurately reflect normal information processing in the VTA. In the proposed studies, the activity of multiple single neurons will be simultaneously recorded from chronically implanted microwire electrodes in the ventral tegmental area (VTA). Basic electrophysiological characteristics will be determined for neurons recorded in rats under anesthetic and awake, and given drugs whose actions on VTA have been well characterized, and which are known to differentiate subtypes of TA neurons. These will allow direct comparison of results using the current method to previous studies, and direct comparison of responses in the anesthetized and awake rat. In addition, a better estimate of the number and nature of VTA neuronal subtypes can be derived, as well as strategies for the identification of these neurons that can be used in future experiments utilizing chronically implanted microwire electrodes. In further experiments, selected rats will be successively tested in three behavioral paradigms; 1) Signalled non-contingent presentation of sucrose solution, 2) pressing a lever for access to sucrose solution, and 3) extinction of lever pressing. These experiments will allow assessment of the behavioral associations of neural firing rates, and provide insight to the functional significance of VTA neuronal subtypes.
