Gabapentin is not a GABAB receptor agonist

Area of Science:

• Neuropharmacology
• Molecular Neuroscience
• Receptor Pharmacology

Background:

• Functional gamma-aminobutyric acid type B (GABA(B)) receptors require co-expression of GABA(B1) and GABA(B2) subunits.
• Previous research suggested gabapentin acts as a subunit-selective agonist at GABA(B1a) but not GABA(B1b) receptors.
• This proposed pharmacological diversity necessitates further investigation.

Purpose of the Study:

• To re-evaluate the proposed agonist activity of gabapentin at GABA(B) receptors.
• To determine if gabapentin exhibits subunit selectivity between GABA(B1a) and GABA(B1b) containing receptors.
• To investigate gabapentin's effects on native GABA(B) receptors in the hippocampus.

Main Methods:

• [35S]-GTPgammaS binding assays to assess G-protein activation.
• Second messenger assays to measure downstream signaling.
• Electrophysiological recordings in rodent hippocampal slices (CA1 and CA3 pyramidal neurons).

Main Results:

• Gabapentin showed no agonist activity at recombinant GABA(B) receptors containing GABA(B1a)/GABA(B2) or GABA(B1b)/GABA(B2) subunits.
• No agonist effects of gabapentin were observed on pre- or post-synaptic GABA(B) receptors in hippocampal slices.
• Gabapentin demonstrated agonist activity at GABA(A) receptors, mediating chloride conductance.

Conclusions:

• Gabapentin is not a GABA(B) receptor agonist.
• The proposed subunit selectivity of gabapentin for GABA(B) receptors is not supported by these findings.
• Gabapentin's effects are mediated through GABA(A) receptors, not GABA(B) receptors.