Different GABA _A receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates

Abstract

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...

Reinforcing Effects Of Compounds Lacking Intrinsic Efficacy At α1 Subunit-Containing GABAA Receptor Subtypes in Midazolam- But Not Cocaine-Experienced Rhesus Monkeys

“…Expanding on our previous findings with the a1-sparing compound L-838,417 (Rowlett et al, 2005), we show that a1-sparing compounds with varying pharmacodynamic and pharmacokinetic profiles can have reinforcing effects in rhesus monkeys. However, self-administration of a1-sparing compounds appears to depend critically on baseline conditions, as all compounds tested had reinforcing effects in monkeys experienced primarily with midazolam, but not in monkeys experienced primarily with cocaine.…”

“…Moreover, mice with point mutations rendering the a1GABA A receptor insensitive to benzodiazepines did not show a preference for oral midazolam vs sucrose solutions, in contrast to wild-type mice (Tan et al, 2010). We have shown, however, that the a1-sparing compound, L-838,417, was reliably self-administered by rhesus monkeys (Rowlett et al, 2005), a finding clearly inconsistent with the hypothesis that a1GABA A receptors mediate the reinforcing effects of benzodiazepines.…”

“…drug injection (Rowlett et al, 2005;Rowlett and Lelas, 2007). Previously, the monkeys in the midazolam baseline group had received single-day tests with other benzodiazepines (clonazepam, diazepam, alprazolam, triazolam) over an approximately 6-month period (unpublished).…”

“…A possibility is the differences in the pharmacological profiles of the two compounds: TPA023 has notably lower intrinsic efficacy in vitro (measured via Cl-conductance in cloned human receptor subtypes) than L-838,417, with the highest efficacy for TPA023 at a3GABA A receptors whereas L-838 417 is equi-effective at a2GABA A , a3 GABA A , and a5GABA A receptors, raising the possibility that differences in levels of intrinsic efficacy could be key factors mediating selfadministration (for reviews, see Licata and Rowlett, 2008;Atack, 2011). Moreover, TPA023 likely has a relatively long duration of action (Atack et al, 2006Ator et al, 2010) while that of L-838 417 is shorter (Rowlett et al, 2005;Licata et al, 2010;J.R. Atack, unpublished data).…”

“…Although there are several differences between the studies of Ator et al (2010) and Rowlett et al (2005), one potentially important difference is training/maintenance drug (cocaine vs methohexital). Drug history, including the type of drug used for self-administration training, has been shown to be a major determinant of the reinforcing effects of benzodiazepines (Nelson et al, 1983;Bergman and Johanson, 1985;Falk and Tang, 1989).…”