The neuronal circuitry underlying the reinstatement of cocaine-seeking behavior in rats.

摘要

The anatomical and neurochemical bases underlying cocaine priming-induced reinstatement, an animal model of relapse, have been studied in order to elucidate the mechanisms underlying cocaine craving in human addicts. In order to determine which biogenic amine was responsible for cocaine reinstatement, selective dopamine (GBR 12909), serotonin (fluoxetine), or norepinephrine (nisoxetine) transporter inhibitors were administered systemically to assess their ability to induce cocaine seeking in rats. Administration of GBR 12909, but not nisoxetine or fluoxetine, dose-dependently reinstated cocaine seeking, suggesting that increased dopamine levels in the rodent brain are the primary neurochemical trigger for reinstatement of cocaine seeking.; Although increases in dopamine transmission in the brain are clearly involved in reinstatement, the role of nucleus accumbens dopamine in cocaine priming-induced reinstatement remains controversial. The goal of the next series of experiments was to evaluate the relative contributions of D1-like and D2-like dopamine receptors in the nucleus accumbens in the reinstatement of cocaine seeking. Dopamine receptor agonists were microinjected into the accumbens core or shell in order to assess their ability to induce cocaine seeking. Administration of the D1-like agonist SKF-81297 or the D2/3 agonist quinpirole into the shell, but not the core, reinstated cocaine seeking. Intra-accumbal shell administration of the D2-like antagonist sulpiride blocked the ability of SKF-81297 to induce reinstatement. Quinpirole-induced reinstatement was blocked by intra-accumbal shell administration of the D1-like antagonist SCH-23390. Moreover, subthreshold doses of quinpirole and SKF-81297 co-infused into the shell reinstated cocaine seeking. Collectively, these results indicate that cooperative activation of D1-like and D2-like dopamine receptors in the accumbens shell is necessary to reinstate cocaine-seeking behavior.; The contribution of the medial prefrontal cortex (mPFC), pedunculopontine tegmental nucleus (PPTg), and ventral tegmental area (VTA) in cocaine reinstatement was also assessed. Administration of SKF-81297 into the mPFC reinstated cocaine seeking. Microinfusion of the glutamate receptor antagonist CNQX into the PPTg attenuated cocaine priming-induced reinstatement. Moreover, intra-VTA administration of the nicotinic receptor antagonist mecamylamine, the muscarinic receptor antagonist scopolamine, or CNQX attenuated cocaine priming-induced reinstatement. Overall, these findings suggest that cocaine reinstatement is mediated in part by a polysynaptic circuit involving the mPFC, PPTg, VTA and nucleus accumbens.