raclopride and Seizures

This study examined the role of hippocampal dopamine D2 receptors in the genesis of limbic seizures induced by muscarinic agonists in the rat. Pilocarpine, 600 mg/kg, elicited rapid and usually fatal convulsions. These were not affected by focal injections of saline (1 microliter) into both hippocampi. Pretreatment of the dorsal, but not the lateral hippocampus, with the D2 agonist trans-(+)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-2H-pyrazolo-(3,4-g)quinol ine hydrochloride (LY 171555, 2 micrograms per side), did not alter the frequency of pilocarpine-induced convulsions, but significantly delayed their appearance and reduced their intensity. LY 171555 similarly increased the latency of seizures induced by focal hippocampal injection of carbachol (100 micrograms), without changing the frequency or the severity. The selective D2 antagonist raclopride, injected dorsally into both hippocampi dose-dependently facilitated motor seizures evoked by pilocarpine (100 mg/kg), the cholinomimetic at this dose being ineffective as a convulsant in saline-treated animals. Intrahippocampal administration of the D1 agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF 38393, 2 micrograms per side) did not facilitate pilocarpine seizures and did not potentiate the proconvulsant action of raclopride. These data demonstrate that activation of the dopaminergic system, via D2 receptors in the dorsal hippocampus, is capable of protecting the animal against limbic motor seizures arising from excessive muscarinic stimulation of the hippocampus. Since the blockade of D2 receptors in the hippocampus markedly lowered the seizure threshold to pilocarpine, this would suggest that the dopaminergic input to the hippocampus is normally tonically active and functions physiologically to prevent epileptogenesis.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Dopamine; Dopamine Agents; Dopamine D2 Receptor Antagonists; Ergolines; Female; Hippocampus; Injections; Male; Pilocarpine; Quinpirole; Raclopride; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Salicylamides; Seizures; Stereotaxic Techniques

To study whether it was possible to modify mesolimbic dopaminergic activity by intermittent electrical stimulations (IES), 44 rats were either electrically stimulated or sham-stimulated in the ventral tegmental area (VTA) once daily for 70 days. This was done through chronically implanted intracranial electrodes. The intensity of electrical stimulation was determined by the lowest current that elicited a definite motor response. Stimulated rats demonstrated a significantly potentiated behavioral response after 70 stimulations. Seven months after IES rats still demonstrated an increased sensitivity to electrical stimulations in the VTA. A new stimulation period only resulted in a modest additional fall in threshold values. There was a highly significant difference between the current needed to provoke a given response in sensitized rats and in sham-stimulated rats. The behavioral response to stimulation was suppressed both by the dopamine (DA) D2 receptor antagonists haloperidol and raclopride and by the DA D1 receptor antagonist SCH 23390. Furthermore, stimulated rats showed an enhanced response to stimulation with amphetamine and to a lesser extent with apomorphine. Between stimulation periods sensitized animals demonstrated a reduced social interaction. In conclusion intermittent electrical stimulations of the VTA resulted in a syndrome characterized by a hypersensitive response to electrical and pharmacological DA provocation combined with abnormal social interaction. This animal model has points of resemblance with recent interpretations of the DA hypothesis for schizophrenia.

Topics: Amphetamine; Animals; Apomorphine; Benzazepines; Disease Models, Animal; Dopamine D2 Receptor Antagonists; Electric Stimulation; Electroencephalography; Habituation, Psychophysiologic; Haloperidol; Limbic System; Male; Models, Neurological; Motor Activity; Raclopride; Rats; Rats, Wistar; Receptors, Dopamine D1; Salicylamides; Schizophrenia; Seizures; Stereotyped Behavior; Tegmentum Mesencephali; Time Factors