| First Author | Shen H | Year | 2013 |
| Journal | Neuroscience | Volume | 254 |
| Pages | 452-75 | PubMed ID | 23994152 |
| Mgi Jnum | J:207436 | Mgi Id | MGI:5556367 |
| Doi | 10.1016/j.neuroscience.2013.08.033 | Citation | Shen H, et al. (2013) A stress steroid triggers anxiety via increased expression of alpha4betadelta GABAA receptors in methamphetamine dependence. Neuroscience 254:452-75 |
| abstractText | 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, 3alpha,5alpha-THP (3alpha-OH-5alpha-pregnan-20-one), and its 3alpha,5beta isomer reverse to trigger anxiety assessed by the acoustic startle response (ASR), in contrast to their usual anti-anxiety effects. This novel effect of 3alpha,5beta-THP was due to increased (three-fold) hippocampal expression of alpha4betadelta GABAA receptors (GABARs) during METH withdrawal (24h-4weeks) because anxiogenic effects of 3alpha,5beta-THP were not seen in alpha4-/- mice. 3alpha,5beta-THP reduces current at these receptors when it is hyperpolarizing, as observed during METH withdrawal. As a result, 3alpha,5beta-THP (30nM) increased neuronal excitability, assessed with current clamp and cell-attached recordings in CA1hippocampus, one CNS site which regulates anxiety. alpha4betadelta GABARs were first increased 1h after METH exposure and recovered 6weeks after METH withdrawal. Similar increases in alpha4betadelta GABARs and anxiogenic effects of 3alpha,5beta-THP were noted in rats during METH withdrawal (24h). In contrast, the ASR was increased by chronic METH treatment in the absence of 3alpha,5beta-THP administration due to its stimulant effect. Although alpha4betadelta 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 3alpha,5beta-THP. This steroid reduced neuronal excitability and anxiety during chronic METH treatment, consistent with its typical effect. Flumazenil (10mg/kg, i.p., 3x) reduced alpha4betadelta expression and prevented the anxiogenic effect of 3alpha,5beta-THP after METH withdrawal. Our findings suggest a novel mechanism underlying stress-triggered anxiety after METH withdrawal mediated by alpha4betadelta GABARs. |
