Abstracts

RATIONALE: Dopamine (DA) is believed to be an endogenous neuromodulator in the cerebral cortex and to be important for normal brain function. Clinical and experimental studies have also implicated DA in the pathogenesis of a number of neurological and psychiatric disorders, including epilepsy. DA has been shown to be an important modulator of epileptiform discharges in vivo and in vitro. The mechanisms underlying these effects are unclear. We have examined the effect of DA on EPSCs and the spatial-temporal spread of activity in neocortex.
METHODS: Experiments were performed in slices of rat neocortex maintained in vitro. Epileptiform activity was induced by bath application of bicuculline. Whole-cell voltage-clamp recordings were used to study synaptic activity evoked by intracortical stimulation. The voltage-sensitive dye RH 414 and a diode recording array was used to study the spatial-temporal spread of activity. Threshold for evoking epileptiform activty was assesed before and after bath application of 20 uM DA or 10 uM SKF 38393.
RESULTS: Weak intracortical stimulation did not evoke epileptiform activity under control conditions. Bath application of 20 uM DA had two effects in pyramidal cells. EPSC amplitude was increased by 16%. This was accompanied by the appearance of late epileptiform discharges of variable latency and amplitude. This activity presumably represents activity in recurrent excitatory pathways. Epileptiform discharges are generally thought to represent the synchronous discharge of a local population of neurons. The factors that determine whether a discharge stays localized or spreads are poorly understood. The spatial-temporal extent of neocortical avtivation was studied with voltage-sensitive dyes in 17 slices from 9 animals. DA enhanced the spatial extent of neocortical activation in response to subthreshold stimulation in 4 slices. The width of cortical area activated increased from 653 to 1586 microns. DA also increased the probability of evoking epileptiform discharges in 9 slices. In the presence of DA, previously subthresold stimuli triggered epileptiform discharges which could propagate throughout the slice. Similar results were obtained with the specific D1 receptor agonists SKF 38393 suggsting involvement of D1-like receptors.
CONCLUSIONS: DA enhanced the formation of dynamic assemblies of synchronized neurons in neocortical slices. This increased the initiation of propagating epiletiform discharges. It appears that activation of D1-like receptors can have a proconvulsant effects, altering the threshold for epileptiform activity and increasing the probability of spread of paroxysmal activity. These results suggest that treatment of other neurological disorders with DA agonists and antagonists could potentially impact patients with epilepsy.
[Supported by: NS18145 and NS22373]