Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype

Abstract

Inhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha1 H101R) with a diazepam-insensitive alpha1 subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

“…Furthermore, a stereoisomer of SH-053-S-CH3 functionally selective for GABA A receptors containing the a5 subunit, SH-053-R-CH3, exerted in the locomotor activity paradigm a significant hypolocomotor effect comparable to diazepam, without observable anti-anxiety or ataxic activity in the EPM, and rotarod test, respectively. These findings were somewhat unexpected, since both motor incoordination and sedation have been ascribed to the a1 subunit-mediated action of diazepam (Rudolph et al, 1999;McKernan et al, 2000). Hence, either these three compounds were not silent at the a1 subtype when dosed at 30 mg/kg, or some non-a1-subunit-containing receptors contribute to the hypolocomotor action of BZ site agonists.…”

“…Although the absence of occupancy data for distinct receptor subtypes precludes drawing firm conclusions, high minimal incapacitating doses of the present functionally selective ligands in the rotarod test could be seen as indirect evidence for lack of involvement of GABA A receptors containing the a 1 subunit in behavioral actions of 30 mg/kg doses. Specifically, diazepam-induced loss of motor coordination in the rotarod test was linked to the a1 subunit McKernan et al, 2000), and the sevenfold differences in effective doses of SH-053-S-CH3 and SH-053-S-CH3-2 0 F in rotarod vs SLA test could hardly exist if substantial modulation at a1 subunit containing GABA A receptors were attained already at 30 mg/kg. However, there may exist marked differences in fractional occupancy of GABA A receptors containing the a 1 subunit needed for producing behavioral effects of a BZ site agonist in these two tests, meaning that low-to-moderate modulation at such receptors is sufficient for eliciting sedative, but not rotarod-incapacitating, action (cf.…”

“…Indeed, recent genetic and pharmacological studies pointed to the specific contribution of individual receptor subtypes to the spectrum of behavioral actions of BZ site ligands. Specifically, sedative effects of BZs were principally attributed to a 1 -containing GABA A receptor subtypes, anxiolytic actions to the a 2 -/a 3 -containing receptors, anterograde amnesic effects to the a 1 /a 5 subtypes, anticonvulsant activity partially to the a 1 -containing receptors, and muscle relaxant effects largely to a 2 -containing receptors (Atack et al, 2006a;Low et al, 2000;McKernan et al, 2000;Rudolph and Möhler, 2006;Rudolph et al, 1999). Moreover, it appears that L-838417, a ligand with zero efficacy at the a 1 subtype, is unable to engender sedation in rodents or monkeys , and similar conclusions were drawn from behavioral experiments with other compounds functionally selective for receptors other than a 1 -containing receptors (Atack et al, 2006c;Dias et al, 2005;Licata et al, 2005).…”

“…To date, all apparently non-sedating BZ site ligands, which are devoid of activity at a 1 -containing GABA A receptors, engendered essentially antagonist (Atack et al, 2006c;Dias et al, 2005) or only partial agonist efficacy at a 5 -containing GABA A receptors (Griebel et al, 2001;McKernan et al, 2000). Therefore, it cannot be ruled out that substantial efficacy at a 5 -containing GABA A receptors may contribute to sedative effects.…”

Advances in the treatment of anxiety: Targeting glutamate

“…Many new theories and compounds have been proposed, including those based on 5-HT 1A agonists 10 and other specific serotonin-based compounds, 30,31 NK-1 antagonists and other Substance P-related species, 28 neuropeptides (NPY, NPS), 29,32 more specific GABA A agonists, 33,34 CRF antagonists, 35,36 glutamate modulators, and ␤-blockers, 37,38 among others.…”