Effects of SCH-23390 Infused into the Amygdala or Adjacent Cortex and Basal Ganglia on Cocaine Seeking and Self-Administration in Rats

Abstract

Amygdala D1 receptors have been implicated in the motivating effects of cocaine-conditioned cues and cocaine itself, but the specific nucleus involved is unclear. Thus, we infused the D1 antagonist, SCH-23390, into the rostral basolateral amygdala (rBLA), caudal basolateral amygdala (cBLA), or central amygdala (CEA), and tested its effects on self-administration of cocaine, as well as reinstatement of extinguished cocaine-seeking behavior by cocaine-conditioned cues or cocaine itself. Two anatomical controls, the posterior regions of basal ganglia (BG) and somatosensory/insular cortices (CTX), were also examined. Cocaine self-administration was increased and cue and cocaine reinstatement were decreased by SCH-23390 infusion into every region when examined across the hour test session, with the exception that cBLA infusion did not alter cocaine reinstatement. In the first 20 min of the session, when SCH-23390 was more localized in the target sites, self-administration was increased by infusion into the CEA, cBLA, BG, and CTX, with lesser increases in the rBLA. Cocaine reinstatement was attenuated during the first 20 min only by infusion into the CEA, rBLA, and CTX. Cue reinstatement was not reliably observed in the first 20 min, but there was a trend for attenuation by infusion into the cBLA, and surprisingly, significant attenuations in the BG and CTX. The findings suggest that D1 receptors in subregions of the amygdala play differential roles in the reinforcing/motivational effects of cocaine, while the cue reinstatement effects are less clear. Further research is needed to examine the novel findings that neighboring regions of the BG and CTX may play a role in motivation for cocaine.

Role of dopamine D1 receptors in the prefrontal dorsal agranular insular cortex in mediating cocaine self-administration in rats

“…The disparity between our results and those of Bachtell et al (2005) for food self-administration likely reflect differences in the type of operant schedule used (FI5(FR5:S) versus FR1) and the brain region targeted. Moreover, it should be noted that the doses of SCH 23390 used in the current study are quite high and, as pointed out by others (Alleweireldt et al 2006), any changes in behavior may reflect interactions with additional receptors in the AId such as 5-HT 2C receptors (Millan et al 2001) and G proteincoupled, inwardly rectifying potassium channels (Kuzhikandathil and Oxford 2002) for which SCH-23390 has an affinity. Given that SCH 23390 is a potent agonist at 5-HT 2C receptors (Millan et al 2001) and that 5-HT 2C agonists have been shown to reduce food-maintained responding in squirrel monkeys (Brady and Barrett, 1985;McKearney, 1990), this may be why infusion of SCH 23390 but not SKF 81297 led to global disruptions in operant responding.…”

“…Others have shown that intra-cranial infusion of SCH 23390 within the medial PFC (0.3 μg/ side), NAc shell (1.0 μg/side), or BLA (2.0 μg/side) reduces drug-seeking behavior induced by cocaine-associated cues or a priming injection of cocaine (See et al 2001;Bachtell et al 2005;Sun and Rebec 2005;Berglind et al 2006), whereas infusion into the caudal BLA (2.0 μg/side) or NAc shell (1.0 μg/side) significantly increases the number of cocaine infusions earned during maintenance testing (Alleweireldt et al, 2006;Bachtell et al 2005). In the present study however, intra-AId infusions with similar doses of SCH 23390 (i.e., 1.0 and 2.0 mg/side) did not yield any significant findings.…”

“…For cocaine maintenance and food maintenance testing, a series of one-way ANOVAs with repeated measures were used to analyze each dependent variable, with each ANOVA comparing vehicle infusions with SCH 23390 and/or SKF 81297 infusions. In addition, given that the time course of the effects of D 1 receptor manipulation has been shown to be greatest at the onset of cocaine self-administration test sessions (Alleweireldt et al 2006), the number of active lever responses emitted and infusions earned during the first and last 30min of each cocaine session was calculated from these dependent measures and similarly analyzed using single factor ANOVAs with repeated measures. Tukey tests were used for all post-hoc comparisons.…”

“…For instance, D 1 receptor antagonism in the nucleus accumbens (NAc) shell with SCH 23390 (1.0 μg/side) attenuates cocaine-induced reinstatement (Anderson et al 2003), whereas administration of the D 1 -like receptor agonist SKF 81297 (1.0 μg/side) reinstates drug-seeking behavior (Bachtell et al, 2005;Schmidt et al 2006). Moreover, infusion of SCH 23390 (2.0 μg/side) into the caudal basolateral amygdala (BLA) has been shown to increase the number of infusions earned during cocaine self-administration sessions, whereas infusion into the rostral BLA (2.0 μg/side) fails to alter this behavior, but attenuates cue-and cocaine-induced reinstatement of drug-seeking behavior (Alleweireldt et al 2006). …”

Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

“…For instance, although dopaminergic input from the VTA to the OFC controls neuronal activity (Aou et al, 1983), back-projections from the OFC to the VTA may also regulate dopaminergic input to the OFC itself and to the BLA (Takahashi et al, 2009). In particular, input from the VTA to the BLA may be important for processing the motivational effects of cocaine-paired contextual stimuli, given that dopamine D1-like receptor antagonism in the BLA prevents explicit drug-paired cues from eliciting cocaineseeking behavior (Alleweireldt et al, 2005;Berglind et al, 2006;Mashhoon et al, 2009;See et al, 2001).…”