Seizures are one of the most common presenting symptoms in the emergency room following COC and METH overdose. Because of increasing trends in the abuse of high quantities of COC and METH, it is important to elucidate the sequelae of toxic-dose consumption of these stimulants. Although the mechanisms of COC- and METH-mediated seizures are poorly defined, previous studies have demonstrated marked differences in the temporal and phenotypic features of seizures induced by COC and METH. More recent findings have demonstrated a differential sensitivity of COC and METH-induced seizure activity to established anti-epileptic drugs. These findings have led to the hypothesis that """"""""the neurochemical and neuroanatomical mechanisms of seizures induced by COC and METH are different."""""""" The overall objective of this proposal is to identify specific differences in the phenotypic and electrographic features of seizures induced by COC and METH. This will be achieved by conducting systematic comparative studies in well-define rat model systems.
In SPECIFIC AIM A we will identify the phenotypic and electrographic features of seizures induced by METH and COC by establishing the dose-dependent proconvulsant characteristics of METH and COC in normal rats. We also propose to assess the ability of COC and METH to modify seizure threshold and determine whether acute and chronic COC and METH exposure facilitates the expression and/or acquisition of limbic kindling.
In SPECIFIC AIM B we will employ pharmacological, anatomical, electrophysiological, and neurochemical approaches to delineate the mechanisms contributing to the proconvulsant properties of COC and METH. Results form studies outlined in SPECIFIC AIM C will determine whether prior METH or COC exposure alters the pro- convulsant properties of the stimulants. We believe these studies will elucidate the neurochemical and neuroanatomical mechanism(s) and consequences of stimulant-induced seizures, leading to the development of more rational and selective therapies to treat the short- and long-term consequences of stimulant-related seizures.
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