Administration of the D2 Dopamine Receptor Antagonist Sulpiride into the Shell, but not the Core, of the Nucleus Accumbens Attenuates Cocaine Priming-Induced Reinstatement of Drug Seeking

Abstract

Enhanced dopamine transmission in the nucleus accumbens plays an important role in cocaine priming-induced reinstatement of drugseeking behavior. However, the contribution of each dopamine receptor subtype to this behavior remains unclear. The present experiments were designed to assess the role of D2-like dopamine receptors in the nucleus accumbens core and shell subregions in cocaine priming-induced reinstatement of drug seeking. Rats were trained to lever press for cocaine using a fixed ratio (FR) 5 schedule of reinforcement. After approximately 18 days of cocaine self-administration, the animals underwent an extinction phase during which cocaine was replaced with saline. Daily extinction sessions were conducted until responding was less than 10% of the response rate maintained by cocaine self-administration. Following the extinction phase, priming-induced reinstatement of cocaine-seeking behavior was assessed. A range of doses of antagonists selective for D2-(sulpiride, 0.2 or 2.0 mg), D3-(U99194A, 3.9 or 7.8 mg), or D4-(L-750,667, 5.5 or 11 mg) dopamine receptors were microinjected into either the nucleus accumbens core, shell or lateral septum prior to a priming injection of cocaine (10 mg/kg, i.p.). Following administration into the shell, but not core or lateral septum, sulpiride dose-dependently attenuated reinstatement induced by a cocaine priming injection. In contrast, U99194A and L-750,667 failed to influence cocaine seeking at any of the doses tested in either accumbal subregion. Collectively, these findings indicate that activation of D2 dopamine receptors mediates cocaine priming-induced reinstatement of cocaine seeking in a region-specific manner within the nucleus accumbens.

When administered into the nucleus accumbens core or shell, the NMDA receptor antagonist AP-5 reinstates cocaine-seeking behavior in the rat

“…Since the accumbens core and shell are relatively small and adjacent nuclei, it is possible that the effect of intra-core AP-5 was due to lateral diffusion into the shell. While this explanation cannot be ruled out, it is important to note that the procedures used here were similar or identical to previous studies that demonstrated clear and statistically significant functional differences between the core and shell subregions of the nucleus accumbens [2,3,15,23,28,37].…”

“…In contrast, the core is more involved in the compulsivity of drug addiction [16] and the effects of drug-associated cues [14,18,25]. In terms of cocaine priming-induced reinstatement of drug seeking, dopamine receptors play differential roles in the shell versus the core [2][3][4]. For example, infusion of dopamine receptor antagonists into the accumbens shell, but not the core, attenuates the reinstatement of cocaine-seeking behavior [2][3][4].…”

“…In terms of cocaine priming-induced reinstatement of drug seeking, dopamine receptors play differential roles in the shell versus the core [2][3][4]. For example, infusion of dopamine receptor antagonists into the accumbens shell, but not the core, attenuates the reinstatement of cocaine-seeking behavior [2][3][4]. Similarly, dopamine receptor agonists promote the reinstatement of cocaine seeking when microinjected into the shell, but not core [4,37].…”

“…Treatments were counterbalanced across sessions to avoid any rank-order effects. Similar microinjection procedures (specifically, the use of a 0.5 μl microinjection volume) have been used to identify functional differences between the nucleus accumbens core and shell [2,3,15,23,28,37]. DL-2-Amino-5-phosphonovaleric acid lithium salt (AP-5) was purchased from Sigma-Aldrich.…”

Cannabinoid CB1Receptor Antagonist AM251 Inhibits Cocaine-Primed Relapse in Rats: Role of Glutamate in the Nucleus Accumbens

“…Systemic administration or local NAc microinjection of DA agonists reinstate, whereas DA antagonists block, reinstatement of cocaine-seeking behavior (Shalev et al, 2002;Anderson et al, 2003Anderson et al, , 2006Bachtell et al, 2005). Endocannabinoids appear uninvolved in such DAdependent drug-primed relapse, because CB 1 receptor blockade by SR141716A fails to block cocaine-or heroin-induced increases in NAc DA in drug-naive rats (Tanda et al, 1997;Caillé and Parsons, 2006).…”