Therapeutic benefit of a K-channel opening drug in cocaine toxicity

Abstract

Background Outcome of cocaine abuse is poor, warranting discovery of effective therapies. As cocaine toxicity stems from a hyperadrenergic state, we tested whether targeted manipulation of KATP channel function, a recently discovered protective mechanism against catecholamine challenge, improves outcome. Methods Cocaine (100 mg/kg ip) was administered to wildtype or KATP channel-knockout mice, and pinacidil served as the prototypic KATP channel opener. Results Repetitive cocaine abuse (once a day for 3 days) was associated with 50% lethality in wildtype, with pinacidil (1 mg/kg sc) treatment reducing mortality by 40%. After a cocaine overdose in wildtype, the incidence of seizures, a hallmark of central nervous system toxicity, was also halved by pinacidil therapy (10 mg/kg sc). In the absence of KATP channels, pinacidil was deprived of protective action against cocaine toxicity. Ablation of KATP channels reduced survival following a single cocaine overdose from 15% to 33%. Deterioration in cardiovascular function induced by chronic cocaine abuse was also precipitated with lack of KATP channels. Conclusions KATP channels are thus critical to the adaptive response to cocaine distress, with targeted modulation of channel function defining outcome. Use of KATP channel openers may prove useful as an effective therapeutic modality against cocaine toxicity. Clinical Pharmacology & Therapeutics (2005) 77, P99–P99; doi: 10.1016/j.clpt.2005.01.008