Absence of tolerance to the excitatory effects of benzodiazepines: clonazepam-evoked shaking behavior in the rat.
Select benzodiazepine (BDZ) agonists, such as clonazepam, evoke wet-dog shakes (WDS) in the rat, a behavior which may be influenced by serotonergic drugs. To further study the role of serotonin (5-HT) and BDZ receptors in BDZ-induced WDS, we injected adult rats daily for 21 days with clonazepam and measured WDS and 5-HT1, 5-HT2, and BDZ receptors. Clonazepam 5 mg/kg upregulated 5-HT1 and 5-HT2 receptors in frontal cortex, but not in brainstem or spinal cord, compared to vehicle controls, without a change in BDZ receptors. A 10 mg/kg dose of the same drugs, however, did not alter 5-HT receptors. Chronic treatment with clonazepam failed to decrease clonazepam-induced WDS, resulting instead in a significant increase. The increase was prevented by chronic cotreatment with the 5-HT2 antagonist ketanserin, which significantly down-regulated 5-HT2 and BDZ sites. In vitro, clonazepam did not inhibit radioligand binding at 5-HT1 or 5-HT2 receptors in frontal cortex, brainstem, or spinal cord. Lack of tolerance to WDS evoked by clonazepam suggests different mechanisms for the excitatory and inhibitory effects of BDZs. The dose-independent effects of chronic clonazepam administration on 5-HT receptors are not mediated by activity of clonazepam at 5-HT receptor recognition sites.
Department of Neurology, George Washington University, Washington, DC.
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Pranzatelli
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Dailey
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Levy
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Dollison
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D002998:Clonazepam / Q000493:pharmacokinetics / Q000494:pharmacology; D004361:Drug Tolerance; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects
D014151:Anti-Anxiety Agents; D011963:Receptors, GABA-A; D002998:Clonazepam; D007650:Ketanserin