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Contribution of GABAA Receptor Subtypes to the Anxiolytic

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Contribution of GABAA Receptor Subtypes to the Anxiolytic 0022-3565/05/3133-1118–1125$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 313, No. 3 Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics 81612/1199531 JPET 313:1118–1125, 2005 Printed in U.S.A. Contribution of GABAA 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] Stephanie C. Licata, Donna M. Platt, James M. Cook, P. V. V. Srirama Sarma, Guy Griebel, and James K. Rowlett 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.) Received December 3, 2004; accepted January 31, 2005 ABSTRACT Benzodiazepines (BZs) are prescribed for a variety of disorders, effects of SL651498 were assessed in squirrel monkeys trained including those involving anxiety and sleep, but have unwanted to discriminate the nonselective BZ triazolam from saline. side effects that limit their use. Elucidating the GABAA receptor SL651498 engendered anxiolytic-like effects similar to conven- mechanisms underlying the behavioral effects of BZs will help tional BZs. In addition, SL651498 fully induced muscle relax- develop new drugs having both maximum clinical benefit ation, but unlike conventional BZs, engendered minimal ataxia. and minimum adverse side effects. A recently developed In drug discrimination studies, SL651498 partially substituted ␣ compound is SL651498 [6-fluoro-9-methyl-2-phenyl-4- for triazolam. This effect was blocked with the 1GABAA sub- (pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1- type-preferring antagonist ␤-CCT (␤-carboline-3-carboxylate- ␣ ␣ one], which is a full agonist at GABAA receptors containing 2 t-butyl ester), implicating 1GABAA receptors in the subjective ␣ and 3 subunits and a partial agonist at GABAA receptors effects of SL651498. Together, these studies suggest that ␣ ␣ containing 1 and 5 subunits. We assessed the ability of compounds such as SL651498 that have high intrinsic efficacy ␣ ␣ SL651498 to engender anxiolytic-like, motor, and subjective at 2GABAA and/or 3GABAA receptors may have clinical po- effects characteristic of BZ-type drugs in nonhuman primates. tential as anxiolytics and muscle relaxants. Moreover, a com- ␣ ␣ Anxiolytic-like activity was assessed with a conflict procedure pound with reduced efficacy at 1GABAA and/or 5GABAA in rhesus monkeys. Motor effects were evaluated in squirrel receptors may lack some of the motor and subjective effects monkeys using observational techniques, and the subjective associated with conventional BZs. Benzodiazepine (BZ) receptor agonists are commonly rently are aimed at developing novel BZ agonists that prescribed for the treatment of anxiety, sleep, and seizure retain therapeutically beneficial properties without the disorders. Their clinical utility is limited, however, due to unwanted side effects. undesirable side effects, which include sedation, motor BZ agonists produce their behavioral effects by positive incoordination, memory impairment, abuse, and depen- allosteric modulation of GABA binding at the GABAA dence (Griffiths and Wolf, 1990; Korpi et al., 1997; Belzung receptor complex. The GABAA receptor is a pentameric et al., 2000; Verster et al., 2002). Research efforts cur- ionophore formed by the assembly of subunits from at least five different families (Sanger et al., 1994; Lu¨ ddens et al., This work was supported by U.S. Public Health Services Grants DA11792, 1995; McKernan and Whiting, 1996). The presence of ␣, DA00499, and RR00168, as well as the National Institute of Mental Health ␤ ␥ Grant MH-46851. A preliminary report of these data was made at the 2004 , and subunits are necessary to confer sensitivity Annual Meeting of the College on Problems of Drug Dependence. to BZ ligands (Pritchett et al., 1989; McKernan and Whit- Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. ing, 1996; Rudolph et al., 2001), and conventional BZs doi:10.1124/jpet.104.081612. exert their pharmacological effects via binding nonselec- ABBREVIATIONS: BZ, benzodiazepine; SL651498, 6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1- one; FR, fixed ratio; ␤-CCT, ␤-carboline-3-carboxylate-t-butyl ester; MS, maximum score; MD, minimally effective dose. 1118 Behavioral Effects of SL651498 in Nonhuman Primates 1119 ␣ ␣ ␣ ␣ tively to GABAA receptors containing 1, 2, 3, and 5 drug discrimination study. Monkeys used in the conflict and discrim- subunits. ination studies were maintained at 90 to 95% of their free-feeding Recent research has been aimed at elucidating the receptor weight. Monkeys used in the observational study were maintained mechanisms underlying the specific behavioral effects of BZs, under free-feeding conditions. All monkeys were housed individually with the goal of developing BZ-type drugs having both max- and maintained under a 12-h light/dark cycle in a temperature- and humidity-controlled room. All procedures were conducted with the imum clinical benefit and minimum adverse side effects. One approval and under the supervision of the Harvard University In- such compound that has been developed recently is 6-fluoro- stitutional Animal Care and Use Committees. Animals in this study 9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro- were maintained in accordance with the guidelines of the Committee 1H-pyridol[3,4-b]indol-1-one (SL651498). SL651498 is a on Animals of the Harvard Medical School and the “Guide for Care novel pyridoindole derivative that has high affinity for rat and Use of Laboratory Animals” National Research Council, Depart- ␣ ␣ native GABAA receptors containing 1 and 2 subunits and ment of Health, Education and Welfare Publication No. (NIH 85-23), ␣ weaker affinity for 5GABAA receptors, although having in- revised 1996. Monkeys in the conflict and discrimination studies were prepared termediate affinity for recombinant rat GABAA receptors ␣ with chronic indwelling venous catheters using the general surgical containing the 3 subunit (Griebel et al., 2001). However, SL651498 is “functionally selective” in that it acts as a full procedures described by Carey and Spealman (1998). Under isoflu- ␣ ␣ rane anesthesia and aseptic conditions, one end of a polyvinyl chlo- agonist at 2GABAA and 3GABAA receptors and as a partial ϭ ␣ ␣ ride catheter (rhesus monkey i.d., 0.64 mm; o.d., 1.35 mm; squirrel agonist at 1GABAA and 5GABAA receptors, as determined ϭ Ϫ monkey i.d., 0.38 mm; o.d., 0.76 mm) was passed to the level of the in vitro by modulation of GABA-mediated Cl flux (Griebel et right atrium by way of a brachial, femoral, or jugular vein. The distal al., 2001). Behavioral studies in rodents demonstrated that end of the catheter was passed subcutaneously and exited in the SL651498 elicited anxiolytic-like activity similar to that of mid-scapular region. Rhesus monkey catheters were flushed daily diazepam (Griebel et al., 2001, 2003). SL651498 also induced with heparinized saline (150–200 U/ml), whereas squirrel monkey muscle weakness, ataxia, and sedation as measured by motor catheters were flushed daily with saline that did not contain heparin. activity; nevertheless, the doses that engendered these ef- All catheters were sealed with stainless steel obturators when not in fects were much higher than those producing anxiolytic-like use. Monkeys wore custom-made nylon mesh jackets (Lomir Biomed- activity. In addition, SL651498 produced neither tolerance to ical, Toronto, ON, Canada) at all times to protect the catheter. its anticonvulsant effects nor physical dependence after re- Conflict Study. Rhesus monkeys were trained to sit in a custom- designed restraint chair (Crist Instruments, Hagerstown, MD) lo- peated administration (Griebel et al., 2001, 2003). Taken cated in a sound-attenuating chamber. A response lever, stimulus together, these results suggest that the anxiolytic and anti- lights (Med Associates, Georgia, VT), and a receptacle into which convulsant activity of SL651498 may make this compound a food pellets (1 g of marshmallow-flavored pellets; BioServ, French- suitable alternative to currently prescribed drugs for those town, NJ) were delivered were positioned in front of the monkey. indications. Furthermore, the observed behavioral effects Monkeys were trained on a multiple schedule of food reinforcement may be a result of selective actions at specific GABAA recep- consisting of two components: 1) a schedule of food pellet delivery, tor subtypes. and 2) a schedule of food pellet delivery plus a schedule of foot shock delivery (0.25-s duration, 1–3 mA depending on the individual mon- Our current knowledge of the role of GABAA receptor sub- types in the behavioral effects of BZs is predominantly based key). Four components were available in a session, separated by on studies with transgenic and wild-type rodents. At present, 10-min timeout periods in which responding had no programmed consequences. Responding was maintained in each component under relatively little information is available regarding the roles of an 18 response, fixed-ratio (FR) schedule of food pellet delivery. Each particular GABAA receptor subtypes in the characteristic component
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