Dopamine Receptors and Hippocampal Seizure Generation

Abstract

Purpose: We examined the effects of selective cyclic adenosine monophosphate (AMP) phosphodiesterase type 4 inhibitors and dopamine D1‐receptor agonists on hippocampal partial seizures induced by electrical stimulation at 2 Hz in freely moving rats. We also tested the effects of acute (single injections) and repeated (injections once per day for 21 days) administration of typical and atypical antipsychotic drugs. Methods: We used five seizure parameters to assess the effects of the drugs [i.e., pulse number threshold (threshold for the initial primary afterdischarges), duration of the primary afterdischarge, latency of the secondary afterdischarges, duration of the secondary afterdischarges, and duration of the behavioral seizures]. The detailed methods have been described elsewhere (Katsumori et al. Eur J Pharmucol 1996;311:37–44, and Synapse 1997;27, in press). Results: cAMP phosphodiesterase inhibitors (rolipram 1, 3, or 10 mg/kg, i.p.; RO 20–1724, 10 mg/kg, i.p.) and dopamine D,‐receptor agonists (SKF 38393, 1.5, 5, or 15 mgkg, i.p.; SKF 81297, 3 mgkg, i.p.) produced the same type of proconvulsive action, by selectively enhancing the generation of secondary afterdischarges. The dopamine D1‐receptor antagonist, SCH 23390 (0.5 mg/kg, i.p.) blocked the effect of SKF 38393 but not that of rolipram. The dopamine D1‐receptor antagonist, sulpiride (45 mg/kg, i.p.). showed no effect on the seizure parameters. A single injection of either 5 or 15 mg/kg of clozapine significantly decreased the pulse number threshold and significantly increased the duration of primary afterdischarges, indicating a proconvulsive action. The repeated administration of clozapine (1.5, 5, or 15 mg/kg, i.p.) produced dose‐dependent, proconvulsive effects by significantly decreasing the pulse number threshold and by significantly increasing the duration of primary afterdischarges. In contrast to clozapine, the short‐term administration of haloperidol (0.5 and 1.5 mg/kg, i.p.), unlike clozapine, significantly decreased the duration of primary afterdischarges, but did not alter the pulse number threshold. Conclusions: These results suggest that the proconvulsive action of dopamine D1‐receptor stimulation is, at least partially, due to the resulting increase in cAMP levels in the brain. Clozapine produces a greater proconvulsive action than haloperidol or sulpiride in this animal model of hippocampal seizures. It remains to be determined whether modulation of the secondary afterdischarges has any predictive value for specific aspects of hippocampal epileptogenesis.