An Inverse Agonist Selective for α5 Subunit-Containing GABA_A Receptors Enhances Cognition

Abstract

ABSTRACT␣5IA is a compound that binds with equivalent subnanomolar affinity to the benzodiazepine (BZ) site of GABA A receptors containing an ␣1, ␣2, ␣3, or ␣5 subunit but has inverse agonist efficacy selective for the ␣5 subtype. As a consequence, the in vitro and in vivo effects of this compound are mediated primarily via GABA A receptors containing an ␣5 subunit. In a mouse hippocampal slice model, ␣5IA significantly enhanced the burst-induced long-term potentiation of the excitatory postsynaptic potential in the CA1 region but did not cause an increase in the paroxysmal burst discharges that are characteristic of convulsant and proconvulsant drugs. These in vitro data suggesting that ␣5IA may enhance cognition without being proconvulsant were confirmed in in vivo rodent models. Hence, ␣5IA significantly enhanced performance in a rat hippocampaldependent test of learning and memory, the delayed-matchingto-position version of the Morris water maze, with a minimum effective oral dose of 0.3 mg/kg, which corresponded to a BZ site occupancy of 25%. However, in mice ␣5IA was not convulsant in its own right nor did it potentiate the effects of pentylenetetrazole acutely or produce kindling upon chronic dosing even at doses producing greater than 90% occupancy. Finally, ␣5IA was not anxiogenic-like in the rat elevated plus maze nor did it impair performance in the mouse rotarod assay. Together, these data suggest that the GABA A ␣5-subtype provides a novel target for the development of selective inverse agonists with utility in the treatment of disorders associated with a cognitive deficit.Agonists at the benzodiazepine (BZ) binding site of the GABA A receptor, such as diazepam, enhance the inhibitory effects of GABA and have been used as anxiolytics and hypnotics for more than 40 years (Argyropoulos and Nutt, 1999). In addition, they have therapeutic utility in inducing not only sedation and muscle relaxation but also amnesia before surgical procedures (Williams and Bowie, 1999). Although the amnesic effects of BZ agonists in animals and humans have been known for some time (Ghoneim and Mewaldt, 1990), the precise nature of the processes underlying these effects are still uncertain. Since the anterograde rather than retrograde amnesia (McNaughton and Morris, 1987) produced by BZ agonists is similar to deficits induced by hippocampal lesions in animals and humans, it has been suggested that these drugs may exert their amnesic effects by modulating hippocampal function.At present, 19 GABA A receptor subunits have been identified (␣1-␣6, ␤1-␤3, ␥1-␥3, ␦, ⑀, , 1-3, and ; Simon et al.,

FG 7142 Specifically Reduces Meal Size and the Rate and Regularity of Sustained Feeding in Female Rats: Evidence that Benzodiazepine Inverse Agonists Reduce Food Palatability

“…Recently, it was proposed that a2/a3 subunit-containing GABA A receptors are the receptor populations involved in the specific control of food intake behavior (Cooper, 2005). The present results are partly consistent with this hypothesis as FG 7142 is a much more potent inverse agonist at a2 subunitcontaining GABA A receptors (EC 50 ¼ 5.9 nM) than at a5 or a3 subunit-containing isoforms (EC 50 ¼ 1439 and 1020 nM, respectively), although it ultimately has similar efficacy at each (Dawson et al, 2005). Future studies that compare ligands with subunit-selective inverse agonist efficacy at a2 subunit-containing receptors as opposed to those with preferential a1, a3, or a5 intrinsic efficacy could further define the role of a2-containing GABA A receptors in controlling the rate and regularity of sustained feeding.…”

“…Future studies that compare ligands with subunit-selective inverse agonist efficacy at a2 subunit-containing receptors as opposed to those with preferential a1, a3, or a5 intrinsic efficacy could further define the role of a2-containing GABA A receptors in controlling the rate and regularity of sustained feeding. To the degree that a1, a3, and a5 subunit-containing GABA A receptors, respectively, mediate sedative/proconvulsant, anxiety-related and cognitive actions of benzodiazepine receptor ligands (Dawson et al, 2005), a selective a2-subunit inverse agonist perhaps could be useful in treating forms of overeating characterized by high, sustained rates of eating, including some forms of binge eating.…”

Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits

“…Similarly, the selective inverse agonist at alpha5-subunit containing GABA receptors may enhance hippocampus-dependent memory by enhancing the amplitude of hippocampal neural activity, while leaving the temporal pattern of neural activity largely unaffected (this is consistent with in vitro evoked potential findings that the drug enhances LTP induction, without affecting stimulation-evoked field potential bursting; Dawson et al 2006). In contrast, hippocampal neural disinhibition caused by picrotoxin in the present study altered the temporal organization of hippocampal neural activity (enhancing burst-pattern firing).…”

“…Moreover, systemic injection of a selective inverse agonist to negatively modulate GABA-A receptors containing the alpha5 subunit, which are predominantly expressed in hippocampus and constitute about 20% of hippocampal GABA-A receptors, has been suggested to facilitate hippocampal plasticity and memory (Dawson et al 2006), although transgenic reduction of alpha5 subunit-containing GABA-A receptor expression in the hippocampus has also been reported to disrupt aspects of hippocampus-dependent memory (Prut et al 2010;Engin et al 2015).…”

Outwardly Rectifying Tonically Active GABAAReceptors in Pyramidal Cells Modulate Neuronal Offset, Not Gain

“…Tonic conductances in the hippocampus modulate cognitive function: genetic deletion or pharmacological inhibition of ␣5 subunit-containing GABA A Rs, which contribute to tonic inhibition in CA1 pyramidal cells (Caraiscos et al, 2004;Scimemi et al, 2005;Prenosil et al, 2006;Glykys et al, 2008), improves spatial learning and memory (Collinson et al, 2002;Atack et al, 2006;Dawson et al, 2006). A possible mechanism linking tonically active GABA A Rs to cognition is the modulation of long-term potentiation (Cheng et al, 2006).…”