A primary health-related effect of cocaine is the initiation of seizure activity, which occurs in 2-9% of patients with cocaine toxicity. Cocaine is a strong reinforcing agent, i.e., use of cocaine increases the likelihood of readministration. Repeated administration of cocaine in animals produces stereotypical behavior and a motor sensitization that at higher doses culminates in seizure activity. These sensitized responses persist for months after cessation of cocaine. The mechanism of these processes is not understood. Cocaine's properties as a dopamine (DA)-uptake inhibitor and a local anesthetic may underlie its behavioral sensitization and seizure effects, respectively, however, it is not responsible for the maintenance or expression of increased motor activity. gamma-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, has extensive interconnections with the DA system. The GABAA receptor comprises multiple subunits and specific combinations of subunits produce receptors with different affinities for GABA, and alters functional responses to other drugs that act on the receptor. The effects of repeated cocaine administration on the GABAA receptor will be investigated: 1. Cocaine-induced behavioral sensitization and seizure effects will be compared. The contribution of DA uptake and local anesthetic properties will be assessed. 2. The longevity of changes will be established in cocaine-induced behavioral sensitization and seizures. The hypothesis guiding these investigations is that the GABAergic system is involved in the mechanism of stereotypical behaviors and seizure activity after repeated cocaine administration. GABAergic alterations will differ for sensitization and seizures. The level of expression of individual GABAA receptor subunit mRNA will be studied, in addition to receptor binding characteristics and allosteric interactions of the GABAA receptor. The effects of lidocaine (a local anesthetic without DA-uptake properties), and WIN 35,428 (a DA uptake inhibitor without anesthetic properties), will be compared with those of cocaine. It is anticipated that these studies will provide important new information regarding mechanisms of sensitization and seizure initiation in cocaine abuse, which may suggest new approaches in intervention in cocaine toxicity.
|Li, J; Olinger, A B; Dassow, M S et al. (2003) Up-regulation of GABA(B) receptor mRNA and protein in the hippocampus of cocaine- and lidocaine-kindled rats. Neuroscience 118:451-62|