Signs of physical dependence as a consequence of long-term drug use and a moderate abuse liability limit benzodiazepine clinical usefulness. Growing evidence suggests a role for volt- age-gated calcium channel (VGCC) regulation in mediating a range of chronic drug effects from drug withdrawal phenomena to dependence on a variety of drugs of abuse. High voltage- activated (HVA) calcium currents were measured in whole-cell recordings from acutely isolated hippocampal CA1 neurons after a 1-week flurazepam (FZP) treatment that results in with- drawal-anxiety. An 1.8-fold increase in Ca2 current density was detected immediately after and up to 2 days but not 3 or 4 days after drug withdrawal. Current density was unchanged after acute desalkyl-FZP treatment. A significant negative shift of the half-maximal potential of activation of HVA currents was also observed but steady-state inactivation remained un- changed. FZP and diazepam showed use- and concentration-Benzodiazepines, a group of positive allosteric modulators of GABAA receptors, are widely prescribed for the treatment of anxiety, insomnia, and seizure disorders. However, wide- spread legitimate prescription of benzodiazepines increases the proportion of patients who develop dependence. Reducing dependent inhibition of Ca2 currents in hippocampal cultured cells following depolarizing trains (FZP, IC50 1.8 M; diaze- pam, IC50 36 M), pointing to an additional mechanism by which benzodiazepines modulate HVA Ca2 channels. Systemic preinjection of nimodipine (10 mg/kg), an L-type (L)- VGCC antagonist, prevented the benzodiazepine-induced increase in -amino-3-hydroxy-5-methylisoxasole-4-propionic acid receptor (AMPAR)-mediated miniature excitatory post- synaptic current in CA1 neurons 2 days after FZP withdrawal, suggesting that AMPAR potentiation, previously linked to withdrawal-anxiety may require enhanced L-VGCC-mediated Ca2 influx. Taken together with prior work, these findings suggest that enhanced Ca2 entry through HVA Ca2 channels may contribute to hippocampal AMPAR plasticity and serve as a potential mechanism underlying benzodiazepine physical dependence.

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