Enhancement of cocaine-induced hyperactivity in mice by benzodiazepines: evidence for an interaction of GABAergic processes with catecholaminergic neurons?
The effects of nine benzodiazepines on the locomotor stimulation induced in mice by cocaine (4 mg . kg-1 i.p.) were studied. These benzodiazepines markedly enhanced cocaine-induced hyperactivity. This effect was observed at low doses, e.g. doses at least 8 times lower than those required to depress the stimulation caused by cocaine. Nitrazepam-induced enhancement of the hyperactivity elicited by cocaine was reduced or suppressed by blocking dopaminergic receptors with pimozide (0.015--0.03 mg . kg-1), by interrupting GABAergic transmission with picrotoxin (0.25--0.5 mg . kg-1) or blocking alpha- or beta-adrenergic receptors with prazosin (0.25 mg . kg-1) or dl-propranolol (4 mg . kg-1) respectively. At these doses, neither pimozide, picrotoxin, prazosin nor propranolol were able to modify the spontaneous locomotor activity or the stimulation elicited by cocaine alone. Strychnine (0.25--0.50 mg . kg-1) or methysergide (2 mg . kg-1) failed to alter the enhancement by nitrazepam of cocaine-induced hyperactivity. These results suggest that an interaction of benzodiazepines with some catecholaminergic processes, either directly or through the involvement of a GABAergic link, may account for their facilitatory activity on cocaine-induced locomotor stimulation.
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D002395:Catecholamines / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced*; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D002395:Catecholamines; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; D003042:Cocaine