Our group has continued its efforts to discover an efficacious and safe pharmacological treatment for acute and chronic cocaine poisoning. For this reporting period, we have identified a drug in clinical practice that has efficacy in our animal models of drug-resistant cocaine seizures. Chlormethiazole protected against acute cocaine seizures and lethality and blocked the expression of sensitization to the convulsant effects of cocaine. Further, chlormethiazole prevented the neural adaptation that resulted from repeated daily exposure to cocaine. Importantly the pharmacological profile of chlormethiazole was superior to that of the benzodiazepines, clonazepam and diazepam, which were of limited efficacy and had narrow therapeutic indices. The results of these studies predict the potential utility of chlormethiazole for the treatment of life-threatening complications of cocaine abuse for which no specific treatment has yet been identified. Our group has also begun investigations into the mechanisms underlying increased sensitivity to the toxic effects of cocaine with repeated drug exposure. In this area we have identified adenosine receptors as an important target. Both the behavioral effects and the toxic effects of adenosine ligands is enhanced with repeated cocaine treatment. Further studies are underway to determine the changes in dopamine D3 receptors in ventral striatum and the neurochemical changes in this and other brain areas that are associated with the increased toxicity to cocaine as well as the protection that is conferred by D3 receptor agonists as we reported earlier. Changes in gene expression and proteins in brains of sensitized animals are being explored based upon our pharmacological data of protective efficacies of pharmacologically selective agents.
