The treatment of heroin addiction is often facilitated by medications that can either block its rewarding (pleasurable) effects or ameliorate the drug craving that is characteristic of withdrawal. The availability of drugs that might have similar effects on cocaine addicts should also facilitate their treatment. A complete understanding of how cocaine produces brain reward and what kind of changes long-term cocaine use produces in the brain would further such a search. It now appears that both the acute pleasurable effects of cocaine and the longer-term changes resulting from chronic use may be at least in part due to alterations in how the brain uses the neurotransmitter dopamine. Cocaine produces euphoria by increasing the levels of dopamine in the brain reward system, a key part of which is located in. the ventral striatal region (VSR). The regulation of dopamine synthesis and of the expression of dopamine receptors in the VSR both appear to be altered by repeated exposure to cocaine. These alterations change the way the VSR integrates its pervasive dopamine input with the other information it receives from other limbic system structures. Our understanding of the neurobiology of this system has come almost exclusively from studies in the rat. Despite the clear value of this information, it has become apparent that there are significant differences in how primates and rodents respond to cocaine. It therefore becomes increasingly important to study nonhuman primate models of addiction in order to understand better how cocaine acts in humans, to be able to interpret the differences between the rodent and the primate, and to be able to validate those aspects of the rat model that are directly relevant to primates. The studies proposed here represent one step in developing a neurobiological model of cocaine actions in macaque monkeys. Studies in the rat have shown that the VSR is composed of a complex mixture of compartments with distinct neurochemical and connectional characteristics. In the monkey, rather less is known about the organization of this region. There are compartments with specific neurochemical signatures, like those in the rat, but the distribution of these compartments, their relations to dopamine systems, their connections, and indeed, the identification of the territory involved in the effects of abused drugs have yet to be fully described. The research plan presented here is designed to address these issues. It will use histochemistry, immunocytochemistry, in vitro receptor autoradiography, and modern pathway tracing techniques to systematically map the neurochemical organization and afferent inputs to the VSR, and to relate these to each other and the distribution of dopamine. By better describing the normal organization of the primate VSR, the results of this study will help us to understand how drugs alter neural activity in the VSR, and they will aid in forming a basis for more detailed studies of the neurobiological effects of long-term cocaine administration in the monkey.
| Moore, R J; Vinsant, S L; Nader, M A et al. (1998) Effect of cocaine self-administration on dopamine D2 receptors in rhesus monkeys. Synapse 30:88-96 |
| Moore, R J; Vinsant, S L; Nader, M A et al. (1998) Effect of cocaine self-administration on striatal dopamine D1 receptors in rhesus monkeys. Synapse 28:1-9 |
| Lyons, D; Friedman, D P; Nader, M A et al. (1996) Cocaine alters cerebral metabolism within the ventral striatum and limbic cortex of monkeys. J Neurosci 16:1230-8 |
