| Dopamine (DA) D3 receptors are found primarily in limbic regions of the brain that are involved in cognition, emotion, and endocrine functions. This neuroanatomical distribution suggests that DA D3 receptors may be an important target for the development of therapeutic treatments for drug abuse. With this in mind, the first series of experiments characterized dose-dependent effects of the DA D3-preferring agonists, 7-OH-PIPAT and PD-128,907, on motor behaviors and conditioned place preference (CPP) in rats. High doses produced an increase in sniffing and locomotion, and only the highest dose of PD-128,907 produced CPP. In contrast, low doses of 7-OH-PIPAT and PD-128,907 produced a decrease in sniffing and locomotion, an increase in yawning, and no CPP. Behaviors produced by low doses of DA D3-preferring agonists may be mediated by preferential stimulation of either D3 post-synaptic receptors or M/D3 autoreceptors. Furthermore, the lack of CPP suggests that low doses of D3-preferring agonists may be useful as treatments for psychomotor stimulant abuse. To address these issues, the effects of a low dose of the D3-preferring agonist 7-OH-DPAT on behaviors produced by cocaine and d-amphetamine were examined. In addition, the effects of 7-OH-DPAT on behaviors produced by the direct DA agonist apomorphine were examined to elucidate whether low doses of 7-OH-DPAT act at D2/D3 autoreceptors or post-synaptic D3 receptors. 7-OH-DPAT enhanced d-amphetamine-, cocaine-, and apomorphine-induced stereotypies following repeated administration. The enhancement of stereotypies may involve M/D3 autoreceptor subsensitivity and/or enhancement of post-synaptic D2 receptor stimulation in the nigrostriatal pathway. 7-OH-DPAT also attenuated both d-amphetamine-and cocaine-CPP, but potentiated apomorphine-CPP. The former likely involves stimulation of M/D3 autoreceptors in the mesolimbic pathway, whereas the latter likely involves stimulation of DVD3 post-synaptic receptors. Lastly, 7-OH-DPAT decreased locomotion produced by higher doses of apomorphine that are thought to stimulate post-synaptic DA receptors. Thus, it is suggested that inhibition of apomorphine-induced locomotion by 7-OH-DPAT likely involves stimulation of post-synaptic D3 receptors in the mesolimbic pathway. In conclusion, it is suggested that if post-synaptic D3 receptors mediate the effects of CPP and locomotion, then stimulation of D3 receptors facilitates reward but inhibits locomotion. Furthermore, if D3 receptors are involved in reward, then D3-preferring agonists may be useful as pharmacotherapies that partially substitute for psychomotor stimulants. |
