Kayla Lilly, Prithu Mondal, James M Cook, Stephanie M Perez, Daniel J Lodge
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引用次数: 0
Abstract
Rationale: Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition that can emerge following exposure to severe trauma and is frequently accompanied by comorbid psychiatric symptoms, including psychosis. Hallucinations and delusions associated with PTSD are thought to arise from dysregulated mesolimbic dopamine signaling; however, converging evidence indicates dopamine dysfunction is secondary to hippocampal hyperactivity driven by impaired GABAergic transmission. An emerging pharmacological strategy is the use of positive allosteric modulators (PAMs) of GABAA receptors. Given their dense expression within the hippocampus, receptors containing the α5 subunit (α5-GABAARs) have demonstrated antipsychotic-like efficacy across multiple preclinical models.
Objectives: Whether this therapeutic potential reflects α-subunit specificity or broader properties of structurally related PAMs remains unclear. We compared three structurally related GABAA receptor PAMs with distinct α-subunit selectivity.
Methods: Using an acute inescapable footshock stress model, which reliably produces increased mesolimbic dopamine activity, we performed in vivo extracellular electrophysiology to record dopamine neuron activity in the ventral tegmental area (VTA) after intra-hippocampal administration of GABAAR PAMs.
Results: MP-III-022, a selective α5-GABAAR PAM, normalized stress-induced elevations in VTA dopamine neuron population activity, consistent with prior reports. GL-I-54, which preferentially modulates α2/α3-GABAARs, failed to restore dopamine system function following stress, while modulation with the α5-preferring enantiomer GL-II-73 was associated with normalization of mesolimbic dopamine activity.
Conclusions: These findings indicate that stereochemical and subunit-selective modulation of GABAA receptors critically determines circuit-level outcomes following stress and reinforce α5-GABAA receptors as a key target for normalizing hippocampal-driven dopamine system dysfunction associated with psychosis-relevant states.
期刊介绍：
Official Journal of the European Behavioural Pharmacology Society (EBPS)
Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields:
Human Psychopharmacology: Experimental
This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered.
Human Psychopharmacology: Clinical and Translational
This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects.
Preclinical psychopharmacology: Behavioral and Neural
This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels.
Preclinical Psychopharmacology: Translational
This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways.
Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic
This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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