title: A stress steroid triggers anxiety via increased expression of α4βδ GABAA receptors in methamphetamine dependence.
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 (24h) following chronic exposure (3mg/kg, i.p. for 3-5weeks) 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 (24h-4weeks) 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 (30nM) increased neuronal excitability, assessed with current clamp and cell-attached recordings in CA1hippocampus, one CNS site which regulates anxiety. α4βδ GABARs were first increased 1h after METH exposure and recovered 6weeks after METH withdrawal. Similar increases in α4βδ GABARs and anxiogenic effects of 3α,5β-THP were noted in rats during METH withdrawal (24h). 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 (10mg/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.
authors.affiliation: Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, United States.
authors.forename: H
authors.initials: H
authors.lastname: Shen
authors.forename: A
authors.initials: A
authors.lastname: Mohammad
authors.forename: J
authors.initials: J
authors.lastname: Ramroop
authors.forename: S S
authors.initials: SS
authors.lastname: Smith
mesh_terms: D019969:Amphetamine-Related Disorders / Q000378:metabolism* / Q000523:psychology; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000633:toxicity; D051381:Rats; D020318:Rats, Long-Evans; D011963:Receptors, GABA-A / Q000096:biosynthesis*; D055139:Sensory Gating / Q000187:drug effects / Q000502:physiology; D013315:Stress, Psychological / Q000139:chemically induced / Q000378:metabolism / Q000523:psychology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000523:psychology
chemical_list: C546262:Gabra4 protein, rat; D011963:Receptors, GABA-A; C053623:pregnane-20-one; D008694:Methamphetamine; D011280:Pregnanolone
keywords: 3α,5α-THP; 3α,5β-THP; 3α-OH-5α-pregnan-20-one or allopregnanolone; 3α-OH-5β-pregnan-20-one or pregnanolone; ANOVA; ASR; CA1 hippocampus; CRF; EGTA; GABA(A) receptor; GABAR; GBX; HEPES; I-threshold; METH; Rm; TTX; The current threshold for triggering a spike; acoustic startle response; allopregnanolone; analysis of variance; corticotropin-releasing factor; ethylene glycol tetraacetic acid; flumazenil; gaboxadol or THIP (a GABA agonist); hydroxyethyl piperazineethanesulfonic acid; input resistance; mIPSC; methamphetamine; miniature inhibitory post-synaptic current; pregnanolone; sIPSC; spontaneous inhibitory post-synaptic current; stress; tetrodotoxin