Prenatal ketamine exposure impairs prepulse inhibition via arginine vasopressin receptor 1A-mediated GABAergic neuronal dysfunction in the striatum.
Aeseul Kim, Sun Mi Gu, Haemiru Lee, Dong Eun Kim, Jin Tae Hong, Jaesuk Yun, Hye Jin Cha
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie April 1, 2023 DOI: 10.1016/j.biopha.2023.114318 via PubMed
Summary
AI-generated from the abstractPrenatal exposure to NMDA receptor antagonists like ketamine and methoxetamine in pregnant rats leads to psychosis-like behaviors in their offspring, including hyperactivity and reduced prepulse inhibition (PPI), a measure of sensorimotor gating. These effects are linked to increased expression of the arginine vasopressin receptor 1A (Avpr1a) in the striatum, and artificially overexpressing Avpr1a in the striatum also impairs PPI. Additionally, the treatments raise levels of glutamate decarboxylase 67 (GAD67) and GABA in the striatum, indicating that prenatal NMDA receptor blockade disrupts GABAergic neuron function and sensorimotor gating through Avpr1a regulation.
Study at a glance
| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Pregnant F344 rats and their offspring |
| Interventions | ketamine methoxetamine |
| Keywords | Methoxetamine N-methyl-d-aspartate receptor Prepulse inhibition Δ-aminobutyric acid |
| Citations | 5 |
| Key finding | Prenatal NMDA receptor antagonist treatment induces GABAergic neuronal dysfunction and abnormalities in sensorimotor gating via regulating Avpr1a expression in the striatum. |
Abstract
Ketamine is a widely used anesthetic with N-methyl-D-aspartate (NMDA) receptor antagonism. Exposure to ketamine and NMDA receptor antagonists may induce psychosis. However, the mechanism underlying the effects of ketamine on the immature brain remains unclear. In this study, NMDA receptor antagonists, ketamine and methoxetamine, were administered to pregnant F344 rats (E17). These regimens induce psychosis-like behaviors in the offspring, such as hyperlocomotion induced by MK-801, a non-competitive NMDA receptor antagonist. We also observed that prepulse inhibition (PPI) was significantly reduced. Interestingly, ketamine administration increased the arginine vasopressin receptor 1A (Avpr1a) expression levels in the striatum of offspring with abnormal behaviors. Methoxetamine, another NMDA receptor antagonist, also showed similar results. In addition, we demonstrated a viral vector-induced Avpr1a overexpression in the striatum-inhibited PPI. In the striatum of offspring, ketamine or methoxetamine treatment increased glutamate decarboxylase 67 (GAD67) and δ-aminobutyric acid (GABA) levels. These results show that prenatal NMDA receptor antagonist treatment induces GABAergic neuronal dysfunction and abnormalities in sensorimotor gating via regulating Avpr1a expression in the striatum.