Microelectrode Arrays: Architecture, Challenges and Engineering Solutions

Abstract

Chlormethiazole positively modulates the gamma-aminobutyric acid(GABA)(A) receptor complex and is primarily used to treat certainlife-threatening neurological events (e.g., refractory seizures andethanol withdrawal syndrome). On account of several experimental andclinical studies reporting effectiveness against the toxic effects ofheroin and methamphetamine, chlormethiazole was systematically tested inthe present study for its effectiveness against cocaine-induced seizuresand lethality in mice. The protective effects of chlormethiazole wereevaluated against single, submaximal convulsive (75 mg/kg) or lethal(110 mg/kg) doses of cocaine. Chlormethiazole also was tested againstthe expression (anticonvulsant effect) and development(antiepileptogenic effect) of cocaine- kindled seizures, and againstfully developed kindled seizures. Cocaine-kindled seizures were producedby a total of five daily treatments with 60 mg/kg cocaine. Theinverted-screen test was used to assess behavioral side effects ofchlormethiazole. Chlormethiazole protected against acute cocaine-induced convulsions (ED50 = 7.0 mg/kg) and lethality (ED50 = 21.8 mg/kg)with a robust separation {[}protective index (PI) = TD50/ED50 = 22.3 and7.2, respectively] from doses producing behavioral side effects (TD50 =156 mg/kg). Chlormethiazole suppressed the behavioral expression ofcocaine-kindled seizures and prevented the development of sensitizationto the convulsant effects of cocaine. It was also effective insuppressing fully developed kindled seizures. Relative to cocaineseizures in naive mice, chlormethiazole was equieffective, less potent(ED50 = 22.3 mg/kg), and had a reduced protective index (PI = 3.7)against cocaine-induced seizures in kindled mice. The protective profileand protective index of chlormethiazole were superior to those of thebenzodiazepines clonazepam and diazepam, which were of limited efficacyand had low protective indices (PI = similar to 1). The results of thisstudy predict the potential utility of chlormethiazole for the treatmentof life-threatening complications of cocaine abuse for which no specifictreatment has yet been identified.