A comparison of the locomotor stimulant effects of D1-like receptor agonists in mice

Efficacy in stimulating adenylyl cyclase (AC) has traditionally been used to distinguish dopamine D-1-like receptor agonists from dopamine D-2-like receptor agonists. However, there is a limited association between the effects of D-1-like agonists in behavioral assays and their effectiveness at stimulating AC. Other second messenger actions might contribute to the behavioral effects of D-1-like agonists, as there is evidence for a link to the hydrolysis of phosphomositide (PI). The present study compared the locomotor stimulant effects of five D-1-like receptor agonists having different efficacies in assays of AC and PI activity. All D-1-like agonists produced long-lasting biphasic effects on locomotor activity. SKF 38393, the prototypical partial agonist (based on AC activity), produced limited changes in locomotor activity, whereas the partial agonists SKF 75670 and SKF 77434 produced locomotor stimulant effects that were similar to or greater than those of the full efficacy agonists SKF 82958 and SKF 81297. However, there did not appear to be a relationship between maximal behavioral effects and AC stimulation or PI hydrolysis. The results suggest a complex relationship between the behavioral effects of D-1-like agonists and their intrinsic efficacies as measured by AC and /or PI stimulation. Although a limited number of compounds were examined, neither second messenaer system alone appears to account fully for these behavioral effects. The current classification of D-1-like agonists according to their intrinsic efficacies as defined by AC stimulation needs further scrutiny. Published by Elsevier Inc.