Characterization of PG‐619, a dopamine D3 receptor partial agonist, on cocaine self‐administration and drug‐elicited yawning in rhesus monkeys

Abstract

The dopamine D3 receptor is a promising target for the development of novel treatment agents for addiction due to its restricted expression in limbic brain regions and involvement in reinforcement pathways (Newman et al., 2005). The present study examined the effects of PG‐619, a D3 receptor partial agonist, with 100‐fold selectivity for the D3 over D2 receptors (Grundt et al., 2007), on cocaine self‐administration (SA) and yawning in male rhesus monkeys with an extensive cocaine history (n=3). Monkeys self‐administered cocaine (0.003‐0.3 mg/kg) under a fixed‐ratio 30 schedule during daily 2‐hr sessions. Prior work found CJB 090, a D3 partial agonist with 60‐fold D3 selectivity, decreased cocaine‐maintained responding (Martelle et al., 2007). Acute doses of PG‐619 (0.1 ‐ 1.0 mg/kg, i.v., 10 min presession) did not significantly affect cocaine SA; higher doses of PG‐619 are currently being evaluated. In vivo potency of PG‐619 to elicit yawning was also examined. As with CJB 090, no doses of PG‐619 (0.1 ‐ 1.0 mg/kg) elicited yawning. The preliminary findings support prior work that D3 partial agonists do not have D3 agonist effects in vivo. Furthermore, the findings suggest greater selectivity of D3 over D2 receptors may result in substantial decreases in potency to affect cocaine SA, although bioavailability and pharmacokinetic factors may contribute to the behavioral profiles of these drugs. DA 12460 and NIDA‐IRP.