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NEUROPHARMACOLOGY

Chronic Benzodiazepine Administration Potentiates High Voltage-Activated Calcium Currents in Hippocampal CA1 Neurons

Departments of Physiology and Pharmacology (K.X., D.E.E., K.M.D., L.J.G., E.I.T.), Neurosciences (D.R.G.), Neurology (L.J.G.), and Cellular and Molecular Neurobiology Program (K.X., D.E.E., K.M.D.), University of Toledo College of Medicine, Toledo, Ohio

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 voltage-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 withdrawal-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 unchanged. FZP and diazepam showed use- and concentration-dependent inhibition of Ca²⁺ currents in hippocampal cultured cells following depolarizing trains (FZP, IC₅₀ = 1.8 µM; diazepam, IC₅₀ = 36 µM), 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 postsynaptic 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.

Address correspondence to: Dr. Elizabeth I. Tietz, Department of Physiology and Pharmacology, University of Toledo College of Medicine (formerly Medical University of Ohio), University of Toledo Health Science Campus, 3000 Arlington Ave., Mailstop 1008, Toledo, OH 43614. E-mail: liz.tietz{at}utoledo.edu