The study of cocaine self-administration and the reinstatement of cocaine seeking in rats has provided much knowledge regarding the mechanisms underlying cocaine addiction and relapse. Yet few studies have explored the neurobiology of the extinction of cocaine-seeking behavior in rats, despite the fact that extinctio provides a major potential therapeutic target in the effort to reduce relapse to cocaine use. Thus, the long-term objective of the proposed work is to investigate the neural circuitry in rats mediating the suppression of cocaine seeking that develops from extinction training after cocaine self-administration. Our previous work suggests that a circuit involving the infralimbic cortex and nucleus accumbens shell is involved in the suppression of cocaine-seeking behavior, findings that parallel those from human studies regarding the human homologue of the infralimbic cortex. Based on our work and others' findings, we have developed a neural circuit that enables activity in the infralimbic cortex to inhibit activity in the ventral tegmental area va the rostromedial tegmental nucleus and the lateral habenula and, thereby, suppress cocaine seeking. The proposed experiments will examine specific parts of the neural circuit to determine their role in the suppression of cocaine seeking. In the experiments, male Sprague-Dawley rats will undergo cocaine self-administration followed by extinction training and, in some experiments, cue-induced reinstatement testing.
Aim 1 will examine whether the lateral habenula suppresses cocaine-seeking behavior after extinction training and whether it interacts with the infralimbic cortex to do so. Rats will receive bilateral microinjections of either GABA agonists to inactivate the structure or the AMPA receptor potentiator PEPA to activate the structure. The microinjections will be given into the structures either before an extinction sessio or a cue-induced reinstatement session in order to assess how the neural structures interact to suppress cocaine-seeking.
Aim 2 will use a similar approach to Aim 1 in order to examine whether the rostromedial tegmental nucleus suppresses cocaine-seeking and how it interacts with the infralimbic cortex to do so.
Aim 2 will also determine whether the lateral habenula and the rostromedial tegmental area interact with each other to regulate cocaine seeking.
Aim 3 will use a complementary approach to examining the neural circuit underlying the suppression of cocaine-seeking. Specifically, Aim 3 will use optogenetic inhibition of axonal projections from the infralimbic cortex to determine which projection pathways from the structure are involved in the suppression of cocaine seeking. This approach is of particular importance because it can reveal the specific pathways, and not just the structures themselves, that are crucial to a particular behavior. Together, the proposed experiments will provide converging lines of evidence regarding this novel circuit and its role in suppressing cocaine seeking. Moreover, the results will furnish critical new knowledge on the neural mechanisms underlying the suppression of cocaine-seeking behavior that will enable the development of new treatments for cocaine addiction.
The relapse to cocaine-seeking behavior remains a major impediment to the successful treatment of cocaine addiction. The proposed research will investigate the neural circuitry of the extinction of cocaine self-administration in rats. This research will have a significant impact on public health as the extinction process is a potential pharmacotherapeutic target in the treatment of drug addiction.
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