Benzodiazepine dependence: from neural circuits to gene expression.

The neural mechanisms underlying benzodiazepine dependence remain equivocal. The present studies tested the hypothesis that similar neural systems are recruited during diazepam tolerance and withdrawal, and that these are associated with changes in GABA(A) receptor properties. 2-Deoxyglucose quantitative autoradiography was employed to map the brain structures affected during chronic treatment and withdrawal from diazepam (5 mg/kg i.p. daily) in rats. Acute administration of diazepam evoked widespread reductions in local rates of cerebral glucose (LCGU) utilization throughout the brain. Brain structures associated with sensory processing developed tolerance to these depressant effects of diazepam after 3 days of treatment, whereas tolerance occurred in the Papez circuit of emotion after 28 days of treatment. These data suggest that adaptive changes in different neuroanatomical circuits may underlie tolerance to the various effects of diazepam. During flumazenil-precipitated withdrawal from diazepam there were marked increases in glucose use in structures of the Papez circuit, the nucleus accumbens, and the basolateral amygdala. These data suggest that the Papez circuit features strongly in diazepam tolerance and withdrawal and supports a common adaptive process being involved in these phenomena. While GABA enhancement of benzodiazepine binding was reduced in the nucleus accumbens after repeated diazepam treatment, there was little evidence to support adaptive changes in GABA(A) receptors or GABA(A) subunit gene expression (gamma2, alpha1, or alpha4) as underlying the functional changes in the identified circuits. Alternative neurochemical mechanisms, such as changes in glutamatergic function should be considered.