A STRESS STEROID TRIGGERS ANXIETY VIA INCREASED EXPRESSION OF alpha 4 beta delta GABA(A) RECEPTORS IN METHAMPHETAMINE DEPENDENCE

作者：Shen H; Mohammad A; Ramroop J; Smith S S^*

来源：Neuroscience, 2013, 254: 452-475.

DOI：10.1016/j.neuroscience.2013.08.033

• CA1 hippocampus
• pregnanolone
• allopregnanolone
• stress
• flumazenil
• methamphetamine

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, 3 alpha,5 alpha-THP (3 alpha-OH-5 alpha-pregnan-20-one), and its 3 alpha,5 beta isomer reverse to trigger anxiety assessed by the acoustic startle response (ASR), in contrast to their usual anti-anxiety effects. This novel effect of 3 alpha,5 beta-THP was due to increased (three-fold) hippocampal expression of alpha 4 beta delta GABA(A) receptors (GABARs) during METH withdrawal (24 h-4 weeks) because anxiogenic effects of 3 alpha,5 beta-THP were not seen in alpha 4-/- mice. 3 alpha,5 beta-THP reduces current at these receptors when it is hyperpolarizing, as observed during METH withdrawal. As a result, 3 alpha,5 beta-THP (30 nM) increased neuronal excitability, assessed with current clamp and cell-attached recordings in CA1 hippocampus, one CNS site which regulates anxiety. alpha 4 beta delta GABARs were first increased 1 h after METH exposure and recovered 6 weeks after METH withdrawal. Similar increases in alpha 4 beta delta GABARs and anxiogenic effects of 3 alpha,5 beta-THP were noted in rats during METH withdrawal (24 h). In contrast, the ASR was increased by chronic METH treatment in the absence of 3 alpha,5 beta-THP administration due to its stimulant effect. Although alpha 4 beta delta 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 3,5D-THP. This steroid reduced neuronal excitability and anxiety during chronic METH treatment, consistent with its typical effect. Flumazenil (10 mg/kg, i.p., 3x) reduced alpha 4 beta delta expression and prevented the anxiogenic effect of 3 alpha,5 beta-THP after METH withdrawal. Our findings suggest a novel mechanismunderlying stress-triggered anxiety after METH withdrawal mediated by alpha 4 beta delta GABARs.

• 出版日期2013-12-19