Dataset Information

Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABA_A receptors by two distinct mechanisms.

ABSTRACT:

Background and purpose

Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABA_A receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal α5 subunit-containing GABA_A receptors. The purpose of this study is to investigate the effects of tricyclic compounds on α5 subunit-containing receptor subtypes.

Experimental approach

Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABA_A receptor subtypes by two-electrode voltage-clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the α5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings.

Key results

The antipsychotic drugs clozapine and chlorpromazine exerted functional inhibition on multiple GABA_A receptor subtypes, including those containing α5-subunits. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in α5 GABA_A receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands.

Conclusion and implications

Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The chlorpromazine site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABA_A receptor subtypes.

SUBMITTER: Bampali K

PROVIDER: S-EPMC9314015 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:GABAA receptors containing the α5 subunit mediate tonic inhibition and are widely expressed in the limbic system. In animals, activation of α5-containing receptors impairs hippocampus-dependent memory. Temporal lobe epilepsy is associated with memory impairments related to neuron loss and other changes. The less selective PET ligand [11C]flumazenil has revealed reductions in GABAA receptors. The hypothesis that α5 subunit receptor alterations are present in temporal lobe epilepsy and could contribute to impaired memory is untested. We compared α5 subunit availability between individuals with temporal lobe epilepsy and normal structural MRI ('MRI-negative') and healthy controls, and interrogated the relationship between α5 subunit availability and episodic memory performance, in a cross-sectional study. Twenty-three healthy male controls (median ± interquartile age 49 ± 13 years) and 11 individuals with MRI-negative temporal lobe epilepsy (seven males; 40 ± 8) had a 90-min PET scan after bolus injection of [11C]Ro15-4513, with arterial blood sampling and metabolite correction. All those with epilepsy and six controls completed the Adult Memory and Information Processing Battery on the scanning day. 'Bandpass' exponential spectral analyses were used to calculate volumes of distribution separately for the fast component [V F; dominated by signal from α1 (α2, α3)-containing receptors] and the slow component (V S; dominated by signal from α5-containing receptors). We made voxel-by-voxel comparisons between: the epilepsy and control groups; each individual case versus the controls. We obtained parametric maps of V F and V S measures from a single bolus injection of [11C]Ro15-4513. The epilepsy group had higher V S in anterior medial and lateral aspects of the temporal lobes, the anterior cingulate gyri, the presumed area tempestas (piriform cortex) and the insulae, in addition to increases of ∼24% and ∼26% in the ipsilateral and contralateral hippocampal areas (P < 0.004). This was associated with reduced V F:V S ratios within the same areas (P < 0.009). Comparisons of V S for each individual with epilepsy versus controls did not consistently lateralize the epileptogenic lobe. Memory scores were significantly lower in the epilepsy group than in controls (mean ± standard deviation -0.4 ± 1.0 versus 0.7 ± 0.3; P = 0.02). In individuals with epilepsy, hippocampal V S did not correlate with memory performance on the Adult Memory and Information Processing Battery. They had reduced V F in the hippocampal area, which was significant ipsilaterally (P = 0.03), as expected from [11C]flumazenil studies. We found increased tonic inhibitory neurotransmission in our cohort of MRI-negative temporal lobe epilepsy who also had co-morbid memory impairments. Our findings are consistent with a subunit shift from α1/2/3 to α5 in MRI-negative temporal lobe epilepsy.

Dataset Information

Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABA_A receptors by two distinct mechanisms.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two distinct mechanisms.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABA_A receptors by two distinct mechanisms.