Anxiogenic properties of an inverse agonist selective for α3 subunit‐containing GABA_A receptors

Abstract

1 a3IA (6-(4-pyridyl)-5-(4-methoxyphenyl)-3-carbomethoxy-1-methyl-1H-pyridin-2-one) is a pyridone with higher binding and functional affinity and greater inverse agonist efficacy for GABA A receptors containing an a3 rather than an a1, a2 or a5 subunit. If doses are selected that minimise the occupancy at these latter subtypes, then the in vivo effects of a3IA are most probably mediated by the a3 subtype. 2 a3IA has good CNS penetration in rats and mice as measured using a [ 3 H]Ro 15-1788 in vivo binding assay. 3 At doses in rats that produce relatively low levels of occupancy (12%) in the cerebellum (i.e. a1-containing receptors), a3IA (30 mg kg À1 i.p.), like the nonselective partial inverse agonist N-methyl-bcarboline-3-carboxamide (FG 7142), not only caused behavioural disruption in an operant, chainpulling assay but was also anxiogenic in the elevated plus maze, an anxiogenic-like effect that could be blocked with the benzodiazepine antagonist Ro 15-1788 (flumazenil). 4 Neurochemically, a3IA (30 mg kg À1 i.p.) as well as FG 7142 (15 mg kg À1 i.p.) increased the concentration of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in rat medial prefrontal cortex by 74 and 68%, respectively, relative to vehicle-treated animals, a response that mimicked that seen following immobilisation stress. 5 Taken together, these data demonstrate that an inverse agonist selective for GABA A receptors containing an a3 subunit is anxiogenic, and suggest that since a3-containing GABA A receptors play a role in anxiety, then agonists selective for this subtype should be anxiolytic.

PWZ-029, a compound with moderate inverse agonist functional selectivity at GABAA receptors containing α5 subunits, improves passive, but not active, avoidance learning in rats

“…anxiety (cf. Atack et al, 2005). However, such an activity was not seen with PWZ-029 in the EPM test, nor was its hypolocomotor effect disproportionately more pronounced in the central, more exposed, and hence 'emotional', zone of the chamber, but was notably different from standard patterns of activity of a nonselective inverse agonist (i.e.…”

Evidence for a Significant Role of α3-Containing GABAAReceptors in Mediating the Anxiolytic Effects of Benzodiazepines

“…However, although there is general agreement that the ␣1 subtype mediates the sedative effects of BZs (Rudolph et al, 1999;McKernan et al, 2000) and the ␣5 subtype plays a role in aspects of cognition (Collinson et al, 2002;Crestani et al, 2002), there remains controversy over which of the subtypes, ␣2 versus ␣3, is associated with anxiolysis (Low et al, 2000;Atack et al, 2005). Thus, using a molecular genetic approach, the anxiolytic effects of diazepam were absent in ␣2H101R mice but retained in ␣3H126R mice (Low et al, 2000), suggesting a role for the ␣2 subtype in mediating the anxiolytic effects of diazepam.…”

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

“…These effects translate into the anxiolytic, anticonvulsant, myorelaxant, sedative, and cognitive impairing properties observed clinically. Recently, studies using molecular genetic (␣ subunit point mutation mice) or pharmacological (subtype-selective compound) approaches suggest that GABA A receptors containing an ␣1 subunit mediate the sedative/myorelaxant effects of diazepam, whereas those with an ␣2 or ␣3 subunit account for the anxiolytic/anticonvulsant effects (Rudolph et al, 1999;McKernan et al, 2000;Rudolph and Möhler, 2004;Atack et al, 2005). In contrast, the functions of GABA A receptors containing an ␣5 subunit are less well defined.…”