Dopamine D3 receptors have been implicated as potential pharmacotherapeutic targets for cocaine addiction because of their restricted localization to limbic brain regions and involvement in the behavioral effects of cocaine (Heidbreder and Newman, 2010). The rationale for developing D3 receptor-selective treatment candidates has been strengthened by evidence suggesting a history of cocaine use dynamically impacts D3 receptor expression and activity.

The recent development of high-affinity D3 receptor-selective compounds and the validation of agonist-elicited yawning as a D3-specific unconditioned behavior (Collins et al, 2007) have provided an experimental framework for the examination of the relationship between cocaine exposure and D3 receptor function. One strategy for drug development is the use of partial agonists—compounds with less functional activity than full agonists in vitro. However, a limitation of this approach has been an inability to identify agonist actions of partial agonists in vivo. We recently reported that the partial agonist CJB090 and D3 receptor-selective compound PG619 elicited yawns similar to that of the D3 agonist quinpirole in monkeys with an extensive history of cocaine self-administration, while displaying no agonist-like activity in drug-naïve controls (Blaylock et al, 2011). This finding suggests that D3 receptors may be functionally sensitized in response to chronic cocaine, thus differentially affecting the in vivo profile of low-efficacy D3 compounds. Although CJB090 and PG619 appeared to function as full agonists when measuring an unconditioned behavior (yawning), neither drug elicited reinstatement of cocaine seeking in these same monkeys, whereas quinpirole did. These findings suggest that D3 receptors contribute differentially to the multitude of behavioral effects associated with cocaine use.

Several key findings have suggested that cocaine-induced alterations to D3 receptors may persist and become more pronounced even after withdrawal from cocaine exposure. Using the behavioral sensitization paradigm, Collins et al (2011) reported progressive enhancements in agonist-elicited yawning in rats exposed to non-contingent cocaine injections for a 7-day period. These increases continued over the 42-day study and were associated with higher D3 receptor binding as determined with in vitro receptor autoradiography. Interestingly, exposure to cocaine in utero has also been shown to influence D3 receptor activity well into adulthood, as monkeys gestationally exposed to large amounts of cocaine displayed greater responses to quinpirole-elicited yawning than control monkeys up to 13 years after their prenatal cocaine exposure (Hamilton et al, 2010). Collectively, these findings suggest that cocaine exposure has long-lasting impacts on D3 receptor activity and expression.

As it relates to cocaine self-administration, we recently began studies using a food–drug choice self-administration paradigm and found that PG619 treatment reduced cocaine self-administration, which was enhanced with continued PG619 administration. Although there have not been clinical trials reported with partial D3 receptor agonists, D3 receptor antagonists are currently being examined in phase I and II clinical trials for treatment of addiction-related disorders, including tobacco dependence and obesity (NIDA, 2000). The evidence described above strongly demonstrates a relationship between cocaine exposure and D3 receptor alterations, and encourage clinical investigation of D3 partial agonists and antagonists for cocaine addiction treatments.