Noradrenergic mechanisms appear not to be involved in cocaine-induced seizures and lethality.
In the present study we have investigated the effects of compounds which increase synaptic levels of noradrenaline on cocaine-induced seizures and lethality in mice. The noradrenaline uptake blocker desipramine (0.3, 3, 30 mg/kg i.p.; 1h pretreatment) and the alpha 2-antagonists idazoxan (0.05, 0.5, 5 mg/kg i.p.; 15 min) and RX811059A (0.01, 0.1, 1 mg/kg i.p.; 15 min) neither reduced nor increased the number of animals having convulsions in the 10 min following administration of cocaine (45, 60 mg/kg i.p.). None of these drugs increased lethality when assessed 10 minutes after 60 mg/kg cocaine and the alpha 2-antagonists did not protect against the lethal effects of a 90 mg/kg dose. On the other hand, desipramine significantly reduced the number of animals dying after this high dose of cocaine. These results suggest that noradrenergic mechanisms do not promote cocaine-induced convulsions and lethality - an important observation in light of the growing use of desipramine for initiation of abstinence in cocaine-dependent outpatients.
Jackson
H C
HC
Reckitt & Colman Psychopharmacology Unit, Department of Pharmacology, School of Medical Sciences, University Walk, Bristol, U.K.
Ball
D M
DM
Nutt
D J
DJ
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000633:toxicity*; D003891:Desipramine / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D006948:Hyperkinesis / Q000139:chemically induced; D019329:Idazoxan / Q000031:analogs & derivatives; D007274:Injections, Intraperitoneal; D051379:Mice; D009638:Norepinephrine / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced* / Q000401:mortality
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; C065483:ethoxyidazoxan; D003042:Cocaine; D003891:Desipramine; D009638:Norepinephrine; D019329:Idazoxan