Objective: Intracerebroventricular administration of orphanin FQ/nociceptin (OFQ/N), the endogenous agonist ligand of the opioid receptor-like (ORL-1) receptor, decreases extracellular levels of dopamine and suppresses motor activity. The presence of the ORL-1 receptor on mesoaccumbal and nigrostriatal dopaminergic neurons raises the possibility that an action along these pathways may be one means by which OFQ/N produces motor suppression. Thus, the present study used local administration of OFQ/N into the ventral tegmental area (VTA), the substantia nigra, the nucleus accumbens and the striatum to determine the contribution of cell-body regions and terminal fields of the dopaminergic neurons to the motor-suppressant effect of OFQ/N. Methods: Rats were implanted bilaterally with guide cannulae into one of the brain regions and tested 4 days later. First, the effect of a single dose of OFQ/N (30 mug/0.5 muL per side) on motor activity was determined after direct injection into the VTA, substantia nigra, nucleus accumbens or striatum. Rats were habituated to activity chambers for 1 hour and then injected with either artificial cerebrospinal fluid or OFQ/N into one of the brain regions, and motor activity was recorded for a further 1 hour. Next, the dose-response effect of intra-VTA or intranigral OFQ/N (3 mug or 30 mug/0.5 muL per side) on motor activity was examined. Finally, the effect of intra-VTA OFQ/N (3 mug or 30 mug/0.5 muL per side) on motor activity was determined in the presence of J-113397, an ORL-1 receptor antagonist. Results: OFQ/N suppressed motor activity when injected into the VTA and to a lesser extent after direct injection into the nucleus accumbens. However, OFQ/N failed to attenuate motor activity significantly after injection into the substantia nigra or the striatum. Subsequent dose-response studies showed that OFQ/N suppressed motor activity even at a 10-fold-lower dose after intrategmental but not intranigral administration. The motor-suppressant action of intra-VTA OFQ/N was attenuated by J-113397 (1.5 mug/0.5 muL per side) administered into the VTA 10 minutes before administration of OFQ/N. Conclusion: Our results indicate that OFQ/N suppresses motor activity through activation of the ORL1 receptor primarily through an action in the VTA.
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