Chronic benzodiazepine administration potentiates high voltage-activated calcium currents in hippocampal CA1 neurons
| Autor: | L. John Greenfield, Kun Xiang, David R. Giovannucci, Damien E. Earl, Kathleen M. Davis, Elizabeth I. Tietz |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
medicine.drug_class
Flurazepam Substance-Related Disorders Physical dependence AMPA receptor Pharmacology Hippocampus Benzodiazepines medicine Animals Benzodiazepine Voltage-dependent calcium channel Chemistry Calcium channel Pyramidal Cells Miniature Postsynaptic Potentials Excitatory Postsynaptic Potentials Rats Substance Withdrawal Syndrome Electrophysiology Receptors Glutamate Excitatory postsynaptic potential Molecular Medicine Calcium Calcium Channels medicine.symptom Diazepam medicine.drug |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 327(3) |
| ISSN: | 1521-0103 |
| Popis: | 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 approximately 1.8-fold increase in Ca(2+) 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 Ca(2+) currents in hippocampal cultured cells following depolarizing trains (FZP, IC(50) = 1.8 microM; diazepam, IC(50) = 36 microM), pointing to an additional mechanism by which benzodiazepines modulate HVA Ca(2+) 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 Ca(2+) influx. Taken together with prior work, these findings suggest that enhanced Ca(2+) entry through HVA Ca(2+) channels may contribute to hippocampal AMPAR plasticity and serve as a potential mechanism underlying benzodiazepine physical dependence. |
| Databáze: | OpenAIRE |
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