Stress steroid mediated withdrawal anxiety in methamphetamine dependent rats: Reversible by Flumazenil

“Methamphetamine is an addictive stimulant drug. Dependence on this drug is difficult to treat because of the severity of the symptoms of methamphetamine withdrawal,” said Dr. Smith. “In addition to drug craving and lethargy, withdrawal from methamphetamine is associated with stress-triggered anxiety that may compromise therapeutic intervention. In our recent publication, we show that the system that provides inhibitory control in the brain is dysregulated during methamphetamine dependence in laboratory rodents.”

The novel inhibitory receptor that is increased by exposure to methamphetamine is also the target for a stress steroid that produces anxiety during withdrawal from methamphetamine. This receptor is also a novel target for flumazenil, a drug commonly used to treat tranquilizer overdose. Flumazenil reduced expression of the inhibitory receptor and also prevented the anxiety triggered by the stress steroid during methamphetamine withdrawal. These findings suggest a novel mechanism for stress-triggered anxiety in methamphetamine dependence where flumazenil may have important therapeutic value.

One component of the stress response is the release of the steroid allopregnanolone or THP. This steroid modulates GABAA receptors, with α4βδ GABARs the most sensitive target. These receptors are extrasynaptic and generate a tonic current that is neuroprotective. They also exhibit a high degree of plasticity in response to increases in neuronal excitability, which would accompany METH exposure. In some cases, flumazenil was administered during the 24 hour withdrawal period. Although this drug is a benzodiazepine antagonist, it also binds to α4βδ GABARs and has been shown to regulate α4 expression.

The study results show that chronic METH treatment and its withdrawal significantly increased expression of α4 and δ GABAR subunits by 2 to 3-fold. This effect was prevented, however, by flumazenil administration during the withdrawal period.

Dr. Smith continued, “Our results suggest that increased α4βδ GABARs mediate the anxiety response to stress steroids after METH withdrawal, an effect prevented by flumazenil. Because stress-triggered anxiety can result in drug relapse, flumazenil may have important therapeutic benefit in METH dependence.”