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. Other behavioral abnormalities are studied, including behavioral stereotypies 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. Significant findings 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) 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; 4) 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). 5) 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; 6) Using the procaine kindling model, different drug administration regimens were evaluated for tolerance development and optimal prophylaxis. A descending dosing schedule of diazepam administration produced the most robust inhibition of kindling, even at dosages that were ineffective in the other two groups. The determination of carbamazepine's mechanism of action in these seizure models, which require chronic treatment, could be relevant to carbamazepine's effects in manic-depressive illness and may help in the development of other, more specific or more effective, treatment strategies. These studies may also suggest mechanistic insights into the differences in adaptive mechanisms that occur with chronic vs. acute or repeated intermittent drug treatment. The importance of local anesthetic mechanisms in human cocaine abuse remains to be determined, but aspects of cocaine-related panic disorder resemble kindled seizure development. Procaine's mechanisms of action will be of interest, since procaine is emerging as a useful clinical tool for distinguishing between certain types of psychiatric patients and controls, and because of procaine's high selectivity for limbic system substrates.