Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 327, Issue 3, Pages 872-883Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.108.144444
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Funding
- National Institute on Drug Abuse [R01-DA-04075, R01-DA-18342]
- University of Toledo College of Medicine Biomedical Sciences Graduate Program
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA018342, R01DA004075] Funding Source: NIH RePORTER
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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 similar to 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 mu M; diazepam, IC50 = 36 mu 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 alpha-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.
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