Benzodiazepines exert their effects by binding to multiple subtypes of the GABAA receptor, the predominant subtypes in the brain being those that contain ␣1-, ␣2-, ␣3-, and ␣5-subunits. To understand the potentially different roles of these subtypes in the therapeutic and side effects of benzodiazepines, we evaluated GABAA receptor subtype-preferring compounds in nonhuman primate models predictive of anxiolytic, sedative, motor, subjective, and reinforcing effects of benzodiazepine-type drugs. These compounds included zolpidem, which shows preferential binding to GABAA receptors containing ␣1-subunits (␣1GABAA receptors); L-838,417, which shows functional selectivity for ␣2GABAA, ␣3GABAA, and ␣5GABAA receptors; and nonselective conventional benzodiazepines. The results provide evidence in nonhuman primates that ␣1GABAA receptors do not play a key role in the anxiolytic and muscle-relaxant properties of benzodiazepine-type drugs; instead, these effects involve ␣2GABAA, ␣3GABAA, and͞or ␣5GABAA subtypes. Our results also suggest that the ␣1GABAA receptor subtype might be critically involved in the subjective, sedative, and motor effects of benzodiazepine-type drugs. In contrast, stimulation of ␣1GABAA receptors is sufficient, but not necessary, for mediation of the abuse potential of these drugs.addiction ͉ anxiety R eceptors for the neurotransmitter GABA, in particular the type A subtype (GABA A receptor), have received considerable attention as the site of action for drugs acting as anxiolytics, sedatives, anticonvulsants, and muscle relaxants. These clinically beneficial effects are exhibited by the benzodiazepines, which act by allosterically binding to GABA A receptors and enhancing the ability of GABA to increase chloride conductance. The therapeutic use of benzodiazepines is constrained, however, by other characteristic effects of these drugs, such as daytime drowsiness and impairment of motor coordination. Benzodiazepines additionally have subjective and reinforcing effects that might contribute to their widespread abuse (1). Recent studies have revealed the existence of multiple subtypes of the GABA A receptor (2, 3), and research with transgenic mice has postulated that the diverse behavioral effects of benzodiazepine-like drugs may reflect action at different subtypes of GABA A receptors (3-5). Although provocative, the extent to which these findings in transgenic mice are applicable to other species, especially primates, is not known. Moreover, virtually no information is available regarding the role of specific GABA A receptor subtypes in the addictive properties of benzodiazepines in any species.The GABA A receptors in the central nervous system are pentamers constituted from structurally distinct proteins, with each protein family consisting of different subunits (for review, see ref.3). The majority of GABA A receptors consist of ␣-, ␤-, and ␥-subunit families, and benzodiazepine action appears to be determined by the presence of particular ␣-subunits. Benzodiazepine-like drugs bind predominantly to...

These data suggest that the CRF(1) antagonist DMP696 might retain the therapeutic benefits of classical benzodiazepines but have fewer motoric side effects.

CRF(1) antagonists DMP696 and DMP904 were designed as drug development candidates for the treatment of anxiety and depression. Both compounds display nanomolar affinity for human CRF(1) receptors, and exhibit >1000-fold selectivity for CRF(1) over CRF(2) receptors and over a broad panel of other proteins. DMP696 and DMP904 block CRF-stimulated adenylyl cyclase activity in cortical homogenates and cell-lines expressing CRF(1) receptors. Both compounds inhibit CRF-stimulated ACTH release from rat pituitary corticotropes. Binding and functional studies indicate that DMP696 and DMP904 behave as noncompetitive full antagonists. DMP696 and DMP904 exhibit anxiolytic-like efficacy in several rat anxiety models. In the defensive withdrawal test, both compounds reduce exit latency with lowest effective doses of 3 and 1 mg/kg, respectively. The anxiolytic-like effect is maintained over 14 days of repeated dosing. In the context of a novel environment used in this test, DMP696 and DMP904 reverse mild stress-induced increases in plasma CORT secretion but at doses 3-4-fold greater than those required for anxiolyticlike efficacy. DMP696 and DMP904 are ineffective in three depression models including the learned helplessness paradigm at doses up to 30 mg/kg. At lowest anxiolytic-like doses, DMP696 and DMP904 occupy >50% CRF(1) receptors in the brain. The in vivo IC(50) values (plasma concentrations required for occupying 50% CRF(1) receptors) estimated based upon free, but not total, plasma concentrations are an excellent correlation with the in vitro IC(50) values. Neither compound produces sedation, ataxia, chlordiazepoxide-like subjective effects or adverse effects on cognition at doses 10-fold higher than anxiolytic-like doses. Neither compound produces physiologically significant changes in cardiovascular, respiratory, gastrointestinal or renal functions at anxiolytic-like doses. DMP696 and DMP904 have favorable pharmacokinetic profiles with good oral bioavailabilities. The overall pharmacological properties suggest that both compounds may be effective anxiolytics with low behavioral side effect liabilities.

A rhesus monkey conflict procedure was established with predictive validity for therapeutic doses in people and provided evidence that anxiolytic-like effects of BZs can occur with relatively low intrinsic efficacy at GABAA receptors and are reduced by alpha1GABAA receptor selectivity.