Role Of GABAA Receptor Subtypes Research Articles

Tolerance and dependence following chronic alprazolam treatment in rhesus monkeys: Role of GABAA receptor subtypes

BackgroundTo assess GABAA receptor subtypes involved in benzodiazepine tolerance and dependence, we evaluated the ability of subtype-selective and non-selective ligands to substitute for (i.e., produce “cross-tolerance”) or precipitate withdrawal during chronic alprazolam treatment. MethodsFour female rhesus monkeys (Macaca mulatta) were implanted with chronic intravenous catheters and administered alprazolam (1.0 mg/kg every 4 h). Following 14+ days of chronic alprazolam, acute administration of selected doses of non-selective and subtype-selective ligands were substituted for, or administered with, alprazolam, followed by quantitative behavioral observations. The ligands included alprazolam and midazolam (positive modulators, non-selective), zolpidem (positive modulator, preferential affinity for α1-containing GABAA receptors), HZ-166 (positive modulator, preferential efficacy at α2- and α3-containing GABAA receptors), and βCCT (antagonist, preferential affinity for α1-containing GABAA receptors). ResultsAcutely, alprazolam and midazolam both induced observable ataxia along with a mild form of sedation referred to as “rest/sleep posture” at a lower dose (0.1 mg/kg, i.v.), whereas at a higher dose (1.0 mg/kg, i.v.), induced deep sedation and observable ataxia. With chronic alprazolam treatment, observable ataxia and deep sedation were reduced significantly, whereas rest/sleep posture was unchanged or emerged. Zolpidem showed a similar pattern of effects, whereas no behaviors engendered by HZ-166 were changed by chronic alprazolam. Administration of βCCT, but not HZ-166, resulted in significant withdrawal signs. ConclusionsThese results are consistent with a role for α1-containing GABAA receptor subtypes in tolerance and dependence observed with chronic alprazolam, although other receptors may be involved in the withdrawal syndrome.

Role of GABAA receptor subtypes in the behavioural effects of intravenous general anaesthetics

Since the introduction of general anaesthetics into clinical practice, researchers have been mystified as to how these chemically disparate drugs act to produce their dramatic effects on central nervous system function and behaviour. Scientific advances, particularly during the last 25 years, have now begun to reveal the molecular mechanisms underpinning their behavioural effects. For certain i.v. general anaesthetics, such as etomidate and propofol, a persuasive case can now be made that the GABAA receptor, a major inhibitory receptor in the mammalian central nervous system, is an important target. Advances in molecular pharmacology and in genetic manipulation of rodent genes reveal that different subtypes of the GABAA receptor are responsible for mediating particular aspects of the anaesthetic behavioural repertoire. Such studies provide a better understanding of the neuronal circuitry involved in the various anaesthetic-induced behaviours and, in the future, may result in the development of novel therapeutics with a reduced propensity for side-effects.

Antagonism of triazolam self-administration in rhesus monkeys responding under a progressive-ratio schedule: In vivo apparent pA2 analysis

BackgroundConventional benzodiazepines bind non-selectively to GABAA receptors containing α1, α2, α3, and α5 subunits (α1GABAA, α2GABAA, α3GABAA, and α5GABAA receptors, respectively), and the role of these different GABAA receptor subtypes in the reinforcing effects of benzodiazepines has not been characterized fully. We used a pharmacological antagonist approach with available subtype-selective ligands to evaluate the role of GABAA receptor subtypes in the reinforcing effects of the non-selective conventional benzodiazepine, triazolam. MethodsRhesus monkeys (n=4) were trained under a progressive-ratio schedule of intravenous midazolam delivery and dose–response functions were determined for triazolam, in the absence and presence of flumazenil (non-selective antagonist), βCCT and 3-PBC (α1GABAA-preferring antagonists), and XLi-093 (α5GABAA-selective antagonist). ResultsFlumazenil, βCCT and 3-PBC shifted the dose–response functions for triazolam to the right in a surmountable fashion, whereas XLi-093 was ineffective. Schild analyses revealed rank orders of potencies of flumazenil=βCCT>3-PBC. Comparison of potencies between self-administration and previous binding studies with human cloned GABAA receptor subtypes suggested that the potencies for βCCT and 3-PBC were most consistent with binding at α2GABAA and α3GABAA receptors, but not α1GABAA or α5GABAA receptor subtypes. ConclusionsOur findings were not entirely consistent with blockade of α1GABAA receptors and are consistent with the possibility of α2GABAA and/or α3GABAA subtype involvement in antagonism of the reinforcing effects of triazolam. The α5GABAA receptor subtype likely does not play a substantial role in self-administration under these conditions.

Cognition-impairing effects of benzodiazepine-type drugs: Role of GABAA receptor subtypes in an executive function task in rhesus monkeys

The present studies evaluated the role of α1 and α5 subunit-containing GABAA receptors (α1GABAA and α5GABAA receptors, respectively) in the ability of benzodiazepine (BZ)-type drugs to alter performance in the cognitive domain of executive function. Five adult female rhesus monkeys (ages of 9–17years old) were trained on the object retrieval with detours (ORD) task of executive function. For the ORD task, the monkeys were required to retrieve food items from a clear box with one open end that was rotated to different positions along with varying placements of food. When the non-selective BZ triazolam and the α1GABAA-preferring agonists zolpidem and zaleplon were evaluated in the ORD task, deficits in performance occurred at doses that did not increase the latency of monkeys to initiate responding and/or increase the percentage of reaches that were incorrect (i.e., reaches in which food was not obtained). Cognition-impairing effects of triazolam and zolpidem in ORD were blocked by the α1GABAA-preferring antagonist, βCCT, whereas the α5GABAA-preferring antagonist XLi-093 blocked the effects of triazolam but not zolpidem. While these findings suggest a role for both α1GABAA and α5GABAA receptor mechanisms, α1GABAA receptor mechanisms appear to be sufficient for impairments in executive function induced by BZ-type drugs.

The role of GABA-A receptor subtypes as analgesic targets

Recent GABA(A) receptor drug discovery efforts have culminated in the development of transgenic mice and subtype-selective pharmacological tools, enhancing our understanding of the major inhibitory neural system in the central nervous system. Notably, subtype-selective tools have demonstrated in both preclinical studies and, to some extent, in man that it is possible to develop drugs that share the clinical benefits of benzodiazepines (e.g., anxiolysis) while obviating some adverse effects of these clinically important drugs. Here, we highlight chronic pain as another therapeutic area in which subtype-selective GABA(A) receptor drugs might have clinical utility. Specifically, based on research in animal models of inflammatory/neuropathic pain, we suggest that subtype-selective positive modulators of GABA(A) alpha(2/3) receptors might reverse a loss of postsynaptic GABA(A) receptor-mediated inhibitory function in spinal cord, leading to analgesia. However, alteration of presynaptic inhibitory neural transmission in chronic pain suggests that drugs that negatively modulate GABA(A) receptors might also be effective analgesics. For example, the non-selective negative allosteric modulator FG-7142 reverses allodynia in an animal model of neuropathic pain. Importantly, these two mechanisms are not mutually exclusive. Further clinical exploration in pain of available positive and negative subtype-selective modulators that have been administered to humans would considerably aid back translation, allowing for improved therapeutic development.

Enhanced sucrose pellet consumption induced by benzodiazepine-type drugs in squirrel monkeys: role of GABAA receptor subtypes

Benzodiazepine agonists characteristically increase food intake in humans and non-human subjects, and the underlying mechanisms of this effect are not understood completely. Compounds with selectivity for GABAA receptor subtypes were used to evaluate the role of GABAA receptors containing alpha1 and alpha5 subunits (alpha1GABAA and alpha5GABAA receptors, respectively) in benzodiazepine-induced increases in sucrose pellet consumption. Adult male squirrel monkeys (N=4-6), maintained under free-feeding conditions, were administered with intramuscular injections of the nonselective benzodiazepines diazepam and alprazolam, the alpha1GABAA-preferring compounds zolpidem and zaleplon, or the alpha5GABAA-preferring agonist QH-ii-066 before daily 10-min periods when sucrose pellets were available. In a separate experiment, observable behavioral effects (e.g., ataxia and procumbent posture) were quantified after administration of alprazolam, zaleplon, and QH-ii-066. To further assess the roles of GABAA receptor subtypes, zolpidem-induced increases in pellet consumption were re-evaluated after pretreatment with nonselective antagonist flumazenil, the alpha1GABAA-preferring antagonist beta-carboline-3-carboxylate-t-butyl ester (BCCT), or QH-ii-066. Alprazolam, diazepam, zolpidem, and zaleplon but not QH-ii-066 significantly increased sucrose pellet consumption. In addition, all agonists decreased locomotion and environment-directed behavior as well as engendered ataxia and procumbent posture. For all compounds except QH-ii-066, these behaviors occurred at doses similar to those that increased pellet consumption. Flumazenil and BCCT, but not QH-ii-066, antagonized zolpidem-induced increases in pellet consumption in a surmountable fashion. These results suggest that the alpha1GABAA receptor subtype plays a key role in benzodiazepine-induced increases in consumption of palatable food, whereas the alpha5GABAA receptor subtype may not be involved in this effect.