PHARMACOLOGICAL KINDLING

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This project studies and manipulates the course of development of pharmacologically kindled seizures using the local anesthetics lidocaine, cocaine, and procaine. In addition to seizures, other behavioral abnormalities are studied, including behavioral stereotypys with cocaine, aggression with lidocaine and procaine, 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 and procaine 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, thus providing an intriguing clinical-basic research overlap. Significant findings of this project include 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 systems alpha-2-adrenergic receptors, peripheral-type benzodiazepine receptors, serotonin, and somatostatin can be ruled out as being necessary to carbamazepine's anticonvulsant effects in this seizure model; 5) the stress- related peptide corticotropin releasing hormone (CRH) and the tricyclic antidepressant desmethylimipramine (DMI) potentiate cocaine kindled seizure development and lethality; 6) procaine kindled-seizures are similar to lidocaine seizures - rats become aggressive after seizures develop, and they can sustain numerous bouts of seizures (unlike with cocaine, in which one or two seizure experiences induces lethality); chronic carbamazepine appears to inhibit the aggression while not affecting the fully developed seizures; 7) cholinergic manipulations markedly affect local anesthetic-kindled seizure development and are distinct for procaine and cocaine compared to lidocaine. Atropine blocks seizures induced by the former and potentiates seizures induced by the latter. Physostigmine attenuates lidocaine kindling; 8) Using the procaine kindling model, different drug administration regimens were evaluated for tolerance development and optimal prophylaxis.