A comparison of the locomotor stimulant effects of D 1 -like receptor agonists in mice Rajeev I. Desai, Philip Terry 1 , Jonathan L. Katz * Psychobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, P.O. Box 5180, Baltimore MD 21224, USA Received 8 March 2005; received in revised form 2 June 2005; accepted 9 June 2005 Available online 5 July 2005 Abstract 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 phosphoinositide (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 messenger 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. Keywords: Dopamine D 1 -like receptors; Locomotor activity; Cocaine; Adenylyl cyclase; Inositol phosphate; D 1 -like agonists 1. Introduction Stimulation of adenylyl cyclase (AC) conventionally distinguishes dopamine D 1 -like receptor agonists from dopamine D 2 -like receptor agonists (e.g. Kebabian and Calne, 1979). However, despite the importance of this intracellular signalling system for the classification of dopaminergic compounds, questions have been raised con- cerning its significance to the behavioral effects of dopamine D 1 -like receptor agonists (Terry and Katz, 1992; Daly and Waddington, 1992; Gnanalingham et al., 1995a,b; Katz et al., 1999; Platt et al., 2001; Sinnott and Nader, 2001; Desai et al., 2003). For example, SKF 83959 is a potent in vitro antagonist of AC-linked dopamine D 1 -like receptors (Arnt et al., 1992; Gnanalingham et al., 1995c; Andringa et al., 1999), but its profile of behavioral effects–in particular, the induction of vacuous chewing and enhanced grooming–is similar to that produced by drugs classified as full agonists at D 1 -like receptors (Downes and Waddington, 1993). Further, in rats trained to discriminate the partial D 1 -like agonist, SKF 38393, from saline, the full agonist, SKF 82958, was less effective in substituting than was the partial agonist SKF 75670 (Desai et al., 2003). Moreover, the behavioral effects of both SKF 83959 and the full agonist A-68930 are retained in D 1 -like receptor knockout mice (Clifford et al., 1999), suggesting that at least some of their in vivo effects 0091-3057/$ - see front matter. Published by Elsevier Inc. doi:10.1016/j.pbb.2005.06.006 * Corresponding author. Medications Discovery Research Branch, Psy- chobiology Section, NIH/NIDA Building C-Room 327, 5500 Nathan Shock Drive, P.O.Box 5180, Baltimore, MD 21224, USA. Tel.: +1 410 550 1533; fax: +1 410 550 1648. E-mail address: jkatz@intra.nida.nih.gov (J.L. Katz). 1 Present Address: School of Psychology, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Pharmacology, Biochemistry and Behavior 81 (2005) 843 – 848 www.elsevier.com/locate/pharmbiochembeh