Duration of treatment and activation of α1-containing GABAA receptors variably affect the level of anxiety and seizure susceptibility after diazepam withdrawal in rats.
Long-term use of benzodiazepine-type drugs may lead to physical dependence, manifested by withdrawal syndrome after abrupt cessation of treatment. The aim of the present study was to investigate the influence of duration of treatment, as well as the role of α1-containing GABAA receptors, in development of physical dependence to diazepam, assessed through the level of anxiety and susceptibility to pentylenetetrazole (PTZ)-induced seizures, 24h after withdrawal from protracted treatment in rats. Withdrawal of 2mg/kg diazepam after 28, but not after 14 or 21 days of administration led to an anxiety-like behavior in the elevated plus maze. Antagonism of the diazepam effects at α1-containing GABAA receptors, achieved by daily administration of the neutral modulator βCCt (5mg/kg), did not affect the anxiety level during withdrawal. An increased susceptibility to PTZ-induced seizures was observed during diazepam withdrawal after 21 and 28 days of treatment. Daily co-administration of βCCt further decreased the PTZ-seizure threshold after 21 days of treatment, whilst it prevented the diazepam withdrawal-elicited decrease of the PTZ threshold after 28 days of treatment. In conclusion, the current study suggests that the role of α1-containing GABAA receptors in mediating the development of physical dependence may vary based on the effect being studied and duration of protracted treatment. Moreover, the present data supports previous findings that the lack of activity at α1-containing GABAA receptors is not sufficient to eliminate physical dependence liability of ligands of the benzodiazepine type.
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia.
Jovana
J
Kovačević
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia.
Tamara
T
Timić
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, P.O. Box 413, Milwaukee, WI 53201, USA.
Veera V
VV
Tiruveedhula
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia.
Bojan
B
Batinić
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, P.O. Box 413, Milwaukee, WI 53201, USA.
Ojas A
OA
Namjoshi
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia.
Marija
M
Milić
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia.
Srđan
S
Joksimović
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, P.O. Box 413, Milwaukee, WI 53201, USA.
James M
JM
Cook
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia. Electronic address: miroslav@pharmacy.bg.ac.rs.
Miroslav M
MM
Savić
D000818:Animals; D001007:Anxiety / Q000139:chemically induced*; D003975:Diazepam / Q000008:administration & dosage / Q000633:toxicity*; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D021122:Protein Subunits; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced*; D013375:Substance Withdrawal Syndrome / Q000523:psychology*
D058785:GABA-A Receptor Agonists; C546242:Gabra1 protein, rat; D021122:Protein Subunits; D011963:Receptors, GABA-A; D003975:Diazepam
Benzodiazepines; Elevated plus maze; Pentylenetetrazole test; Physical dependence