The objectives of this project are to study and manipulate the course of development of pharmacologically kindled seizures using the local anesthetics lidocaine and cocaine. In addition to seizures, other behavioral abnormalities are studied, including behavioral stereotypies with cocaine, aggression with lidocaine, and mortality related to cocaine seizures. The kindling effects of cocaine are likely related to its local anesthetic properties, as similar effects are seen with lidocaine but not with other psychomotor stimulants. The importance of local anesthetic mechanisms in human cocaine abuse remains to be determined, but aspects of cocaine-related panic disorder (which is reported by 50% of cocaine users calling a cocaine hotline) resemble kindled seizure development and thus provide an intriguing clinical-basic research overlap. Significant findings of this project include the demonstration that: 1) the development of local anesthetic-kindled seizures and their associated lethality can be prevented with chronic, but not acute or repeated acute, carbamazepine treatment; 2) the local anesthetic-kindled seizure model may offer a novel approach to examining carbamazepine's mechanisms of action in affective illness, which also requires chronic treatment; 3) chronic treatment with carbamazepine attenuates cocaine-induced dopamine overflow in the nucleus accumbens and decreases HVA levels; 4) the following systems have been ruled out as being necessary to carbamazepine's anticonvulsant effects in this seizure model: alpha-2-adrenergic receptors, peripheral-type benzodiazepine receptors, serotonin and somatostatin; 5) the stress-related peptide corticotropin releasing hormone (CRH) and the tricyclic antidepressant desmethylimipramine (DMI) potentiate cocaine kindled seizure development and lethality.
