Benzodiazepine-induced shaking behavior in the rat: Structure-activity and relation to serotonin and benzodiazepine receptors

Abstract

In studying the role of serotonin (5-HT) in the mechanism of action of benzodiazepine(BDZ)-induced wetdog shakes (WDS), only certain 1,4-substituted BDZ agonists were found to induce WDS at doses up to 60 mg/kg in the rat with the rank order of potency at peak dose effect clonazepam > nitrazepam = flunitrazepam ⪢ nimetazepam = lorazepam. BDZs evoking WDS at lowest doses contained an R 7 nitro group on the A ring. Non-BDZ agonists (CL 218,872), inverse agonists (β-CCE), peripheral type receptor agonists (Ro 5-4864), and BDZ antagonists (Ro 15-1788) did not induce shaking behavior. Several 5-HT 1 and 5-HT 2 agonists and antagonists were tested as blockers, but only putative 5-HT 1A agonists reduced WDS, 8-OH-DPAT and ipsapirone but not PAPP and 5-MeO-DMT having a significant effect. The effect of 8-OH-DPAT was dose dependent, with an ID 50 of 0.86 mg/kg, but it was not reversed by 5-HT or adrenergic antagonists at the doses studied. Intracisternal 5,7-dihydroxytryptamine lesions did not alter frequency, latency, or time course of BDZ-induced WDS. BDZ-evoked WDS were enhanced by Ro 15-1788 (which inhibited ataxia) but were unaffected by the various types of BDZ agonists. Several BDZ agonists induced both WDS and ataxia, but ataxia was not blocked by serotonergic drugs. No significant correlation with ataxia, BDZ radioligand binding, antipentylenetetrazol activity, or other BDZ property was found. BDZ-evoked WDS may relate to the unique predominance of BDZ II and 5-HT 1A receptors in the hippocampus, an important site for WDS, but 5-HT 1A agonists appear to modulate WDS by opposing pharmacologic actions rather than by direct receptor antagonism. These data indicate a species difference in the shakes induced by BDZs in rats (5-HT 2 independent) and in mice (5-HT 2 related).