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• W2026362148 startingPage "452" @default.
• W2026362148 abstract "Methamphetamine (METH) is an addictive stimulant drug. In addition to drug craving and lethargy, METH withdrawal is associated with stress-triggered anxiety. However, the cellular basis for this stress-triggered anxiety is not understood. The present results suggest that during METH withdrawal (24 h) following chronic exposure (3 mg/kg, i.p. for 3–5 weeks) of adult, male mice, the effect of one neurosteroid released by stress, 3α,5α-THP (3α-OH-5α-pregnan-20-one), and its 3α,5β isomer reverse to trigger anxiety assessed by the acoustic startle response (ASR), in contrast to their usual anti-anxiety effects. This novel effect of 3α,5β-THP was due to increased (three-fold) hippocampal expression of α4βδ GABAA receptors (GABARs) during METH withdrawal (24 h–4 weeks) because anxiogenic effects of 3α,5β-THP were not seen in α4−/− mice. 3α,5β-THP reduces current at these receptors when it is hyperpolarizing, as observed during METH withdrawal. As a result, 3α,5β-THP (30 nM) increased neuronal excitability, assessed with current clamp and cell-attached recordings in CA1 hippocampus, one CNS site which regulates anxiety. α4βδ GABARs were first increased 1 h after METH exposure and recovered 6 weeks after METH withdrawal. Similar increases in α4βδ GABARs and anxiogenic effects of 3α,5β-THP were noted in rats during METH withdrawal (24 h). In contrast, the ASR was increased by chronic METH treatment in the absence of 3α,5β-THP administration due to its stimulant effect. Although α4βδ GABARs were increased by chronic METH treatment, the GABAergic current recorded from hippocampal neurons at this time was a depolarizing, shunting inhibition, which was potentiated by 3α,5β-THP. This steroid reduced neuronal excitability and anxiety during chronic METH treatment, consistent with its typical effect. Flumazenil (10 mg/kg, i.p., 3×) reduced α4βδ expression and prevented the anxiogenic effect of 3α,5β-THP after METH withdrawal. Our findings suggest a novel mechanism underlying stress-triggered anxiety after METH withdrawal mediated by α4βδ GABARs." @default.
• W2026362148 created "2016-06-24" @default.
• W2026362148 creator A5010465466 @default.
• W2026362148 creator A5051542151 @default.
• W2026362148 creator A5062876714 @default.
• W2026362148 creator A5086051167 @default.
• W2026362148 date "2013-12-01" @default.
• W2026362148 modified "2023-10-18" @default.
• W2026362148 title "A stress steroid triggers anxiety via increased expression of α4βδ GABAA receptors in methamphetamine dependence" @default.
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