Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6274387 | Neuroscience | 2013 | 24 Pages |
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 α4â/â 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., 3Ã) 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.
Keywords
TTXPregnanoloneGbxmIPSCCA1 hippocampusCRFEGTA3α,5α-THPHEPESASRspontaneous inhibitory post-synaptic currentsIPSCethylene glycol tetraacetic acidStresshydroxyethyl piperazineethanesulfonic acidallopregnanolonetetrodotoxinanalysis of varianceANOVAminiature inhibitory post-synaptic currentcorticotropin-releasing factorFlumazenilMETHMethamphetamineinput resistanceacoustic startle responseGABARGABAA receptor
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Authors
H. Shen, A. Mohammad, J. Ramroop, S.S. Smith,