Comparing the discriminative stimulus effects of modulators of GABAA receptors containing α4-δ subunits with those of gaboxadol in rats

Abstract

Rationale Gaboxadol is a selective agonist at GABAA receptors that contain α4-δ subunits, and it produces anxiolytic and sedative effects. Although adverse effects preclude its clinical use, its mechanism of action suggests that those receptors might provide novel therapeutic targets, particularly for modulators of those GABAA-receptor subtypes, by retaining therapeutic effects of gaboxadol and not adverse effects. Objectives The current study compared discriminative stimulus effects of gaboxadol with those of modulators acting at GABAA receptors containing α4-δ subunits. Materials Eight rats discriminated 5.6 mg/kg gaboxadol from vehicle while responding under a fixed-ratio 10 schedule for food. Modulators acting at GABAA receptors containing α4-δ subunits (pregnanolone, ethanol, flumazenil) and receptors that do not contain those subunits (midazolam) were studied alone; pregnanolone and ethanol were also combined with gaboxadol. In addition, gaboxadol was studied in separate groups discriminating 0.32 mg/kg midazolam, 3.2 mg/kg pregnanolone, or 0.75 g/kg ethanol from vehicle. Results Gaboxadol produced ≥80% gaboxadol-lever responding and did not alter rates. No other drug produced, on average, ≥80% drug-lever responding up to doses that decreased rates, although 1.78 mg/kg midazolam produced 32% gaboxadol-lever responding. Ethanol and pregnanolone did not enhance the effects of gaboxadol. Rats discriminating midazolam, pregnanolone or ethanol from vehicle responded predominantly on the vehicle lever after receiving gaboxadol. Conclusions Drugs that modulate GABAA receptors containing α4-δ subunits neither mimicked nor enhanced the discriminative stimulus effects of gaboxadol, indicating that at least some effects of gaboxadol are not shared with modulators of that GABAA-receptor subtype.

Advances in Therapeutics to Alleviate Cognitive Decline and Neuropsychiatric Symptoms of Alzheimer’s Disease

“…Currently, other than Gaboxadol, such subunit-specific therapies have not been identified. However, there are neurosteroid modulators such as Brexanolone (SAGE-547), Zuranolone (SAGE-217), and Ganaxolone that can target both synaptic and extrasynaptic GABA A Rs [133][134][135][136].…”

Benzodiazepine-induced anterograde amnesia: detrimental side effect to novel study tool

“…These compounds range in their affinity and selectivity for varying isoforms of GABAa receptors, with some acting as full agonists to receptors containing DS binding sites while others act as partial agonists on receptors with DS and DI binding sites ( Figure 2 ) ( Mehta and Shank, 1995 ; Lippa et al, 2005 ; Pym et al, 2005 ; Sieghart and Savic, 2018 ). Understanding how these anxioselective drugs affect GABAa receptors differently compared to classical BZDs, newer BZD compounds like remimazolam, and other GABAa agonists like gaboxadol could point to new directions regarding how BZDs induce amnesia through different isoforms ( Zanettini et al, 2016 ; Noor et al, 2021 ; Sente et al, 2022 ). Evidence strongly suggests that the α1 and α5 subunits of GABAa receptors are also mediators of drug-induced amnesia for different types of memory.…”

“…Another anxioselective compound, Ocinaplon (pyrazolopyrimidine) has affinity to all DS isoforms, with higher affinity to α1 compared to α5 ( Lippa et al, 2005 ). The GABAa agonist gaboxadol is known to bind to GABAa receptors containing the α4 and ბ subunits ( Zanettini et al, 2016 ; Sente et al, 2022 ).…”