Related Experiment Video
Updated: Sep 29, 2026

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
GABA(A) receptor alpha-1 subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses
J E Kralic1, T K O'Buckley, R T Khisti
1Department of Pharmacology, University of North Carolina at Chapel Hill, 27599, USA.
Abstract:
Potentiation of GABA(A) receptor activation through allosteric benzodiazepine (BZ) sites produces the anxiolytic, anticonvulsant and sedative/hypnotic effects of BZs. Using a mouse line lacking alpha1 subunit expression, we investigated the contribution of the alpha1 subunit to GABA(A) receptor pharmacology, function and related behaviors in response to BZ site agonists. Competitive [(3)H]flunitrazepam binding experiments using the Type I BZ site agonist, zolpidem, and the Type I and II BZ site non-specific agonist, diazepam, demonstrated the complete loss of Type I BZ binding sites in alpha1(-/-) mice and a compensatory increase in Type II BZ binding sites (41+/-6%, P<0.002). Chloride uptake analysis in alpha1(-/-) mice revealed an increase (108+/-10%, P<0.001) in the efficacy (E(max)) of flunitrazepam while the EC(50) of zolpidem was increased 495+/-26% (alpha1(+/+): 184+/-56 nM; alpha1(-/-): 1096+/-279 nM, P<0.01). An anxiolytic effect of diazepam was detected in both alpha1(+/+) and alpha1(-/-) mice as measured on the elevated plus maze; however, alpha1(-/-) mice exhibited a greater percentage of open arm entries and percentage of open arm time following 0.6 mg/kg diazepam. Furthermore, alpha1(-/-) mice were more sensitive to the motor impairing/sedative effects of diazepam (1-10 mg/kg) as measured by locomotor activity in the open field. Knockout mice were insensitive to the anticonvulsant effect of diazepam (1-15 mg/kg, P<0.001). The hypnotic effect of zolpidem (60 mg/kg) was reduced by 66% (P<0.001) in alpha1(-/-) mice as measured by loss of righting reflex while the effect of diazepam (33 mg/kg) was increased 57% in alpha1(-/-) mice (P<0.05). These studies demonstrate that compensatory adaptations in GABA(A) receptor subunit expression result in subunit substitution and assembly of functional receptors. Such adaptations reveal important relationships between subunit expression, receptor function and behavioral responses.
More Related Videos
07:51Inhibitory Synapse Formation in a Co-culture Model Incorporating GABAergic Medium Spiny Neurons and HEK293 Cells Stably Expressing GABAA Receptors
Published on: November 14, 2014
08:04Identification and Classification of Position-specific GABAA Receptor Subunit Missense Variants for Their Role In Hippocampal Pyramidal Neurons
Published on: June 6, 2025
Related Concept Videos
Sedatives and Hypnotics Drugs: Benzodiazepines
Benzodiazepines work by enhancing the effects of the inhibitory neurotransmitter GABA. They bind to the GABAA receptor, increasing its affinity for GABA, which opens chloride...
Anxiolytic Drugs: Benzodiazepines and Buspirone
CNS Depressants: Barbiturates and Benzodiazepines
Antiepileptic Drugs: GABAergic Pathway Potentiators
The key GABA pathway potentiators used in epilepsy management are as follows.
Benzodiazepines are a well-known class of drugs used for their...
Sedatives and Hypnotics Drugs: Miscellaneous Agents
Melatonin congeners like ramelteon (Rozerem) and tasimelteon (Hetlioz) selectively bind to melatonin receptors (MT1 and MT2) and thus mimic the actions of melatonin, a hormone that regulates sleep-wake cycles. Tasimelteon is primarily used for non-24-hour sleep-wake disorder, common in blind patients. They are also used to treat conditions like insomnia...
Ligand-Gated Ion Channel Receptor: Gating Mechanism