Apomorphine has been used as a pharmacological probe of dopaminergic receptors in a variety of central nervous system disorders. The utility of apomorphine as an agent for the treatment of erectile dysfunction has also been demonstrated clinically. Apomorphine is a nonselective dopaminergic receptor agonist with potent binding affinity (K i ) of 101, 32, 26, 2.6, and 10 nM for D 1 , D 2 , D 3 , D 4 , and D 5 , respectively. When administered either subcutaneously (s.c.) or intracerebroventricularly (i.c.v.), apomorphine fully evoked penile erections in conscious rats with maximum effect at 0.1 mol/kg s.c. and 3 nmol/rat i.c.v., respectively. Apomorphine was less efficacious when injected intrathecally (i.t.) to L4-L6 spinal levels (50% at 30 -100 nmol/rat i.t.). Penile erection facilitated by apomorphine was blocked by haloperidol and clozapine (i.p. and i.c.v.) but not by domperidone (a peripherally acting dopaminergic receptor antagonist). In this model using conscious rats, penile erection was significantly induced by quinpirole (D 2 -D 3 -D 4 receptor agonist), but not by R(ϩ)

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Background and purpose: Activation of cannabinoid CB 1 and/or CB 2 receptors mediates analgesic effects across a broad spectrum of preclinical pain models. Selective activation of CB 2 receptors may produce analgesia without the undesirable psychotropic side effects associated with modulation of CB 1 receptors. To address selectivity in vivo, we describe non-invasive, non-ionizing, functional data that distinguish CB 1 from CB 2 receptor neural activity using pharmacological MRI (phMRI) in awake rats. Experimental approach: Using a high field (7 T) MRI scanner, we examined and quantified the effects of non-selective CB 1 / CB 2 (A-834735) and selective CB 2 (AM1241) agonists on neural activity in awake rats. Pharmacological specificity was determined using selective CB 1 (rimonabant) or CB 2 (AM630) antagonists. Behavioural studies, plasma and brain exposures were used as benchmarks for activity in vivo. Key results: The non-selective CB 1 /CB 2 agonist produced a dose-related, region-specific activation of brain structures that agrees well with published autoradiographic CB 1 receptor density binding maps. Pretreatment with a CB 1 antagonist but not with a CB 2 antagonist, abolished these activation patterns, suggesting an effect mediated by CB 1 receptors alone. In contrast, no significant changes in brain activity were found with relevant doses of the CB 2 selective agonist. Conclusion and implications: These results provide the first clear evidence for quantifying in vivo functional selectivity between CB 1 and CB 2