GL-II-73, a Positive Allosteric Modulator of α5GABA<sub>A</sub> Receptors, Reverses Dopamine System Dysfunction Associated with Pilocarpine-Induced Temporal Lobe Epilepsy
Although seizures are a hallmark feature of temporal lobe epilepsy (TLE), psychiatric comorbidities, including psychosis, are frequently associated with TLE and contribute to decreased quality of life. Currently, there are no defined therapeutic protocols to manage psychosis in TLE patients, as anti...
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MDPI AG
2023-07-01
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| Series: | International Journal of Molecular Sciences |
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| author | Alexandra M. McCoy Thomas D. Prevot Dishary Sharmin James M. Cook Etienne L. Sibille Daniel J. Lodge |
| author_facet | Alexandra M. McCoy Thomas D. Prevot Dishary Sharmin James M. Cook Etienne L. Sibille Daniel J. Lodge |
| author_sort | Alexandra M. McCoy |
| collection | DOAJ |
| description | Although seizures are a hallmark feature of temporal lobe epilepsy (TLE), psychiatric comorbidities, including psychosis, are frequently associated with TLE and contribute to decreased quality of life. Currently, there are no defined therapeutic protocols to manage psychosis in TLE patients, as antipsychotic agents may induce epileptic seizures and are associated with severe side effects and pharmacokinetic and pharmacodynamic interactions with antiepileptic drugs. Thus, novel treatment strategies are necessary. Several lines of evidence suggest that hippocampal hyperactivity is central to the pathology of both TLE and psychosis; therefore, restoring hippocampal activity back to normal levels may be a novel therapeutic approach for treating psychosis in TLE. In rodent models, increased activity in the ventral hippocampus (vHipp) results in aberrant dopamine system function, which is thought to underlie symptoms of psychosis. Indeed, we have previously demonstrated that targeting α5-containing γ-aminobutyric acid receptors (α5GABA<sub>A</sub>Rs), an inhibitory receptor abundant in the hippocampus, with positive allosteric modulators (PAMs), can restore dopamine system function in rodent models displaying hippocampal hyperactivity. Thus, we posited that α5-PAMs may be beneficial in a model used to study TLE. Here, we demonstrate that pilocarpine-induced TLE is associated with increased VTA dopamine neuron activity, an effect that was completely reversed by intra-vHipp administration of GL-II-73, a selective α5-PAM. Further, pilocarpine did not alter the hippocampal α5GABA<sub>A</sub>R expression or synaptic localization that may affect the efficacy of α5-PAMs. Taken together, these results suggest augmenting α5GABA<sub>A</sub>R function as a novel therapeutic modality for the treatment of psychosis in TLE. |
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| language | English |
| last_indexed | 2024-03-11T01:00:34Z |
| publishDate | 2023-07-01 |
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| spelling | doaj.art-5431d54356ae4830ad503389385e32912023-11-18T19:41:49ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-07-0124141158810.3390/ijms241411588GL-II-73, a Positive Allosteric Modulator of α5GABA<sub>A</sub> Receptors, Reverses Dopamine System Dysfunction Associated with Pilocarpine-Induced Temporal Lobe EpilepsyAlexandra M. McCoy0Thomas D. Prevot1Dishary Sharmin2James M. Cook3Etienne L. Sibille4Daniel J. Lodge5Department of Pharmacology and Center for Biomedical Neuroscience, UT Health San Antonio, San Antonio, TX 78229, USACampbell Family Mental Health Research Institute of CAMH, Toronto, ON M5S 2S1, CanadaDepartment of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USADepartment of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USACampbell Family Mental Health Research Institute of CAMH, Toronto, ON M5S 2S1, CanadaDepartment of Pharmacology and Center for Biomedical Neuroscience, UT Health San Antonio, San Antonio, TX 78229, USAAlthough seizures are a hallmark feature of temporal lobe epilepsy (TLE), psychiatric comorbidities, including psychosis, are frequently associated with TLE and contribute to decreased quality of life. Currently, there are no defined therapeutic protocols to manage psychosis in TLE patients, as antipsychotic agents may induce epileptic seizures and are associated with severe side effects and pharmacokinetic and pharmacodynamic interactions with antiepileptic drugs. Thus, novel treatment strategies are necessary. Several lines of evidence suggest that hippocampal hyperactivity is central to the pathology of both TLE and psychosis; therefore, restoring hippocampal activity back to normal levels may be a novel therapeutic approach for treating psychosis in TLE. In rodent models, increased activity in the ventral hippocampus (vHipp) results in aberrant dopamine system function, which is thought to underlie symptoms of psychosis. Indeed, we have previously demonstrated that targeting α5-containing γ-aminobutyric acid receptors (α5GABA<sub>A</sub>Rs), an inhibitory receptor abundant in the hippocampus, with positive allosteric modulators (PAMs), can restore dopamine system function in rodent models displaying hippocampal hyperactivity. Thus, we posited that α5-PAMs may be beneficial in a model used to study TLE. Here, we demonstrate that pilocarpine-induced TLE is associated with increased VTA dopamine neuron activity, an effect that was completely reversed by intra-vHipp administration of GL-II-73, a selective α5-PAM. Further, pilocarpine did not alter the hippocampal α5GABA<sub>A</sub>R expression or synaptic localization that may affect the efficacy of α5-PAMs. Taken together, these results suggest augmenting α5GABA<sub>A</sub>R function as a novel therapeutic modality for the treatment of psychosis in TLE.https://www.mdpi.com/1422-0067/24/14/11588dopaminetemporal lobe epilepsyelectrophysiology |
| spellingShingle | Alexandra M. McCoy Thomas D. Prevot Dishary Sharmin James M. Cook Etienne L. Sibille Daniel J. Lodge GL-II-73, a Positive Allosteric Modulator of α5GABA<sub>A</sub> Receptors, Reverses Dopamine System Dysfunction Associated with Pilocarpine-Induced Temporal Lobe Epilepsy International Journal of Molecular Sciences dopamine temporal lobe epilepsy electrophysiology |
| title | GL-II-73, a Positive Allosteric Modulator of α5GABA<sub>A</sub> Receptors, Reverses Dopamine System Dysfunction Associated with Pilocarpine-Induced Temporal Lobe Epilepsy |
| title_full | GL-II-73, a Positive Allosteric Modulator of α5GABA<sub>A</sub> Receptors, Reverses Dopamine System Dysfunction Associated with Pilocarpine-Induced Temporal Lobe Epilepsy |
| title_fullStr | GL-II-73, a Positive Allosteric Modulator of α5GABA<sub>A</sub> Receptors, Reverses Dopamine System Dysfunction Associated with Pilocarpine-Induced Temporal Lobe Epilepsy |
| title_full_unstemmed | GL-II-73, a Positive Allosteric Modulator of α5GABA<sub>A</sub> Receptors, Reverses Dopamine System Dysfunction Associated with Pilocarpine-Induced Temporal Lobe Epilepsy |
| title_short | GL-II-73, a Positive Allosteric Modulator of α5GABA<sub>A</sub> Receptors, Reverses Dopamine System Dysfunction Associated with Pilocarpine-Induced Temporal Lobe Epilepsy |
| title_sort | gl ii 73 a positive allosteric modulator of α5gaba sub a sub receptors reverses dopamine system dysfunction associated with pilocarpine induced temporal lobe epilepsy |
| topic | dopamine temporal lobe epilepsy electrophysiology |
| url | https://www.mdpi.com/1422-0067/24/14/11588 |
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