Influence of Cocaine History on the Behavioral Effects of Dopamine D3 Receptor-Selective Compounds in Monkeys

Abstract

While dopamine D3 receptors have been associated with cocaine abuse, little is known about the consequences of chronic cocaine on functional activity of D3 receptor-preferring compounds. The present study examined the behavioral effects of D3 receptor selective 4-phenylpiperazines with differing in vitro functional profiles in adult male rhesus monkeys with a history of cocaine self-administration and controls. In vitro assays found that PG 619 was a potent D3 antagonist in the mitogenesis assay but a fully efficacious agonist in the adenylyl cyclase assay, NGB 2904 was a selective D3 antagonist, whereas CJB090 exhibited a partial agonist profile in both in vitro assays. In behavioral studies, the D3 preferential agonist quinpirole (0.03–1.0 mg/kg, i.v.) dose-dependently elicited yawns in both groups of monkeys. PG 619 and CJB090 elicited yawns only in monkeys with an extensive history of cocaine, while NGB 2904 did not elicit yawns, but did antagonize quinpirole and PG 619-elicited yawning in cocaine-history monkeys. In another experiment, doses of PG 619 that elicited yawns did not alter response rates in monkeys self-administering cocaine (0.03–1.0 mg/kg/injection). Following saline extinction, cocaine (0.1 mg/kg) and quinpirole (0.1 mg/kg), but not PG 619 (0.1 mg/kg) reinstated cocaine-seeking behavior. When given prior to a cocaine prime, PG 619 decreased cocaine-elicited reinstatement. These findings suggest (1) an incongruence between in vitro and in vivo assays and (2) a history of cocaine self-administration can affect in vivo efficacy of D3 receptor-preferring compounds PG 619 and CJB 090, which appear to be dependent on the behavioral assay.

Further Characterization of Quinpirole-Elicited Yawning as a Model of Dopamine D3 Receptor Activation in Male and Female Monkeys

“…With a cumulative quinpirole dosing procedure, differences between MA-experienced monkeys and drug-naive monkeys were noted, with the MA group showing greater sensitivity to quinpirole. We also replicated an earlier study (Blaylock et al, 2011) showing no differences in quinpiroleelicited yawning between drug-naive and cocaine-experienced monkeys. Lastly, the comparison of drug-naive male and female monkeys revealed sex differences, with quinpirole showing greater efficacy and greater potency in eliciting yawning in males compared with females.…”

“…Second, we extended previous findings that a cocaine history does not influence sensitivity to quinpirole-elicited yawning (Blaylock et al, 2011;Collins et al, 2011) to monkeys with an extensive MA self-administration history. Finally, recent data investigating D2-like receptor availability in cocaine abuse suggested possible sex differences in the relationship between DA receptor function and cocaine abuse.…”

“…Despite the differences noted in D2-like and D3R availability after cocaine exposure, quinpirole-elicited yawning was not different in cocaine-naive versus cocaine-experienced monkeys (Blaylock et al, 2011). However, although D3R partial agonists do not elicit yawning when administered to cocaine-naive monkeys (Martelle et al, 2007), they do elicit yawning in monkeys with an extensive cocaine history (Blaylock et al, 2011). This finding suggests that drug-elicited yawning may be an effective baseline on which to assess functional consequences of chronic cocaine exposure.…”

“…Collins et al (2005Collins et al ( , 2007 concluded that the ascending limb of the quinpirole dose-response curve is mediated by D3R, whereas the descending limb is primarily D 2 receptor (D2R)-mediated and coincides with an onset of hypothermia. Despite the differences noted in D2-like and D3R availability after cocaine exposure, quinpirole-elicited yawning was not different in cocaine-naive versus cocaine-experienced monkeys (Blaylock et al, 2011). However, although D3R partial agonists do not elicit yawning when administered to cocaine-naive monkeys (Martelle et al, 2007), they do elicit yawning in monkeys with an extensive cocaine history (Blaylock et al, 2011).…”

“…A behavioral assay that has been frequently used to characterize D3R agonists is the unconditioned behavior of drug-elicited yawning using the D 3 /D 2 receptor agonist quinpirole in rodents (e.g., Collins et al, 2005Collins et al, , 2007Baladi and France, 2009) and nonhuman primates (Martelle et al, 2007;Hamilton et al, 2010;Blaylock et al, 2011). The quinpirole-induced yawning doseresponse curve is an inverted U-shaped function of dose.…”