K A Miller1, J M Witkin, J T Ungard, M Gasior. 1. Drug Development Group, NIDA, Addiction Research Center, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Abstract
RATIONALE: Convulsions associated with cocaine toxicity are a serious aspect of cocaine-related emergency room incidents. Seizures can result from a single high dose of cocaine, and evidence is accumulating that correlates repetitive administration of sub-convulsive doses of cocaine with a decreased seizure threshold, a phenomenon known as pharmacological kindling. A murine model of cocaine kindling has not been characterized. OBJECTIVES: To determine the necessary and sufficient conditions for generating increased sensitivity to the convulsive and lethal effects of cocaine and to characterize some of the basic pharmacological and behavioral consequences of this phenomenon in mice. METHODS: Male, Swiss-Webster mice were given repeated injections of cocaine. RESULTS: Daily administration of 60 mg/kg cocaine produced robust kindling; significant leftward shifts in the dose-effect curves for seizures were observed in cocaine-kindled mice. Cocaine kindling was enduring as these left shifts persisted for at least 20 days, indicating possible permanent synaptic changes. Induction of convulsions per se, utilizing 75 mg/kg cocaine, was not sufficient to engender kindling with a non-optimal dose (40 mg/kg). However, administration of a non-kindling dose of cocaine (40 mg/kg) for as few as four occasions produced increased seizure sensitivity to a 60-mg/kg cocaine challenge. The lethal potencies of cocaine and methamphetamine were significantly increased in cocaine-kindled mice. The baseline locomotor activity of kindled mice was not different from that of non-kindled mice. However, challenge doses of cocaine revealed significant differences in the vertically directed activity of kindled versus non-kindled mice. CONCLUSIONS: Overall, this study provides a description of important parameters for a model of cocaine kindling in mice that may be useful for the elucidation of mechanisms responsible for the long-term changes in sensitivity to cocaine and the discovery of novel pharmacological treatments.
RATIONALE: Convulsions associated with cocainetoxicity are a serious aspect of cocaine-related emergency room incidents. Seizures can result from a single high dose of cocaine, and evidence is accumulating that correlates repetitive administration of sub-convulsive doses of cocaine with a decreased seizure threshold, a phenomenon known as pharmacological kindling. A murine model of cocaine kindling has not been characterized. OBJECTIVES: To determine the necessary and sufficient conditions for generating increased sensitivity to the convulsive and lethal effects of cocaine and to characterize some of the basic pharmacological and behavioral consequences of this phenomenon in mice. METHODS: Male, Swiss-Webster mice were given repeated injections of cocaine. RESULTS: Daily administration of 60 mg/kg cocaine produced robust kindling; significant leftward shifts in the dose-effect curves for seizures were observed in cocaine-kindled mice. Cocaine kindling was enduring as these left shifts persisted for at least 20 days, indicating possible permanent synaptic changes. Induction of convulsions per se, utilizing 75 mg/kg cocaine, was not sufficient to engender kindling with a non-optimal dose (40 mg/kg). However, administration of a non-kindling dose of cocaine (40 mg/kg) for as few as four occasions produced increased seizure sensitivity to a 60-mg/kg cocaine challenge. The lethal potencies of cocaine and methamphetamine were significantly increased in cocaine-kindled mice. The baseline locomotor activity of kindled mice was not different from that of non-kindled mice. However, challenge doses of cocaine revealed significant differences in the vertically directed activity of kindled versus non-kindled mice. CONCLUSIONS: Overall, this study provides a description of important parameters for a model of cocaine kindling in mice that may be useful for the elucidation of mechanisms responsible for the long-term changes in sensitivity to cocaine and the discovery of novel pharmacological treatments.
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