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BEHAVIORAL PHARMACOLOGY

Contribution of GABA_A Receptor Subtypes to the Anxiolytic-Like, Motor, and Discriminative Stimulus Effects of Benzodiazepines: Studies with the Functionally Selective Ligand SL651498 [6-Fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one]

Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts (S.C.L., D.M.P., J.K.R.); University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (J.M.C., P.V.V.S.S.); and Central Nervous System Research Department, Sanofi-Aventis, Bagneux, France (G.G.)

Benzodiazepines (BZs) are prescribed for a variety of disorders, including those involving anxiety and sleep, but have unwanted side effects that limit their use. Elucidating the GABA_A receptor mechanisms underlying the behavioral effects of BZs will help develop new drugs having both maximum clinical benefit and minimum adverse side effects. A recently developed compound is SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one], which is a full agonist at GABA_A receptors containing ₂and ₃ subunits and a partial agonist at GABA_A receptors containing ₁ and ₅ subunits. We assessed the ability of SL651498 to engender anxiolytic-like, motor, and subjective effects characteristic of BZ-type drugs in nonhuman primates. Anxiolytic-like activity was assessed with a conflict procedure in rhesus monkeys. Motor effects were evaluated in squirrel monkeys using observational techniques, and the subjective effects of SL651498 were assessed in squirrel monkeys trained to discriminate the nonselective BZ triazolam from saline. SL651498 engendered anxiolytic-like effects similar to conventional BZs. In addition, SL651498 fully induced muscle relaxation, but unlike conventional BZs, engendered minimal ataxia. In drug discrimination studies, SL651498 partially substituted for triazolam. This effect was blocked with the ₁ GABA_A subtype-preferring antagonist -CCT (-carboline-3-carboxylate-t-butyl ester), implicating ₁ GABA_A effects receptors in the subjective of SL651498. Together, these studies suggest that compounds such as SL651498 that have high intrinsic efficacy at ₂GABA_A and/or ₃GABA_A receptors may have clinical potential as anxiolytics and muscle relaxants. Moreover, a compound with reduced efficacy at ₁ GABA_A and/or ₅ GABA_A receptors may lack some of the motor and subjective effects associated with conventional BZs.

Address correspondence to: Dr. Stephanie C. Licata, One Pine Hill Drive, P.O. Box 9102, Southborough, MA 01772. E-mail: stephanie_licata{at}hms.harvard.edu

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