Chronic cocaine differentially affects diazepam's anxiolytic and anticonvulsant actions. Relationship to GABA(A) receptor subunit expression.
Benzodiazepines are used to treat the anxiety associated with cocaine withdrawal, as well as cocaine-induced seizures. Since cocaine exposure was shown to affect BZ binding density, abuse liability, subjective hypnotic actions and seizure susceptibility, we assessed whether chronic cocaine alters diazepam's anxiolytic and anticonvulsant actions. Changes in GABA(A) receptor subunit protein expression were also assessed as they may relate to BZ activity at the receptor. Male Sprague-Dawley rats were injected with cocaine-HCl (15 mg/kg, i.p.) or saline once daily for 14 days. One day after the last injection, DZP (1 mg/kg i.p.) significantly increased time spent on and entries into open arms of an elevated plus maze in both saline- and cocaine-treated groups, yet the effect was greater in cocaine-treated rats. Eight days after cessation of treatment DZP did not have a significant anxiolytic effect in either group. To assess the effect of cocaine on DZP's anticonvulsant actions, PTZ was infused at a constant rate via the lateral tail vein and clonus onset was recorded in the presence and absence of DZP (5 mg/kg, i.p). DZP significantly elevated seizure threshold in both groups of rats. Chronic cocaine also had no effect on the beta-CCM seizure threshold. Quantitative immunohistochemistry of GABA(A) receptor subunit protein demonstrated significant regulation of alpha2 (-10%) and beta3 (+9%) subunits in the hippocampal dentate gyrus and CA1 regions, respectively. Small changes in GABAR subunit expression in specific brain areas may relate to DZP's enhanced anxiolytic effectiveness whereas it's anticonvulsant actions likely remain intact following cocaine administration.
Lilly
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SM
Department of Pharmacology, Medical College of Ohio, Block Health Science Building, 3035 Arlington Avenue, Toledo, OH 43614, USA.
Tietz
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D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D000927:Anticonvulsants / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy*; D003042:Cocaine / Q000494:pharmacology*; D003292:Convulsants; D003975:Diazepam / Q000627:therapeutic use*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010433:Pentylenetetrazole; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D003292:Convulsants; D018765:Dopamine Uptake Inhibitors; D011963:Receptors, GABA-A; D003042:Cocaine; D003975:Diazepam; D010433:Pentylenetetrazole