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Involvement of dopamine in pilocarpine-induced limbic motor seizures in the rat

Alam, Abdul Munaf; (1995) Involvement of dopamine in pilocarpine-induced limbic motor seizures in the rat. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

1. The present study employed systemic administration of the cholinergic agonist, pilocarpine, to induce intractable limbic motor seizures in the rat. Stereotaxic microinjections of and Dg agonists and antagonists into the hippocampus, via implanted guide cannulae, were used to examine whether dopamine D1 and D2 receptors modify this seizure activity. Pilocarpine-induced convulsions were attenuated by intrahippocampal injections of the D2/D3 agonist LY 171555, and by the D1antagonist SCH 23390, whereas the D2 antagonist, raclopride, promoted seizures. Stimulating hippocampal D1 receptors with SKF 38393 was without effect on seizure activity. These data suggest that dopamine exerts a dual effect on seizure activity in this area of the rat brain. 2. Stereotaxic studies were also performed to investigate the possibility that D3 receptors are capable of attenuating seizure propagation in the nucleus accumbens and Islands of Calleja. Intra-accumbens pretreatment with the D3>D2 agonist RU 24213, protected animals against seizures, whilst the more selective D3>>2 agonists LY 171555 and 7-OH-DPAT were less potent, and only attenuated seizures at non-D3 receptor selective doses. Apomorphine, a D1/D2/D3 agonist, delayed seizure onset, but not at higher doses. Similar results were obtained with these drugs when microinjected into the islands of Calleja. These findings provide evidence that dopamine systems limit seizure propagation through the limbic forebrain, but suggest this effect is mediated by D2 rather than D3 receptors. 3. The effects of pilocarpine-induced status epilepticus on the levels of dopamine, ant its metabolites DOPAC (4-hydroxy-3-methoxyphenylaceticacid) and HVA (3, 4-dihydroxyphenylacetic acid) in eight brain regions were determined by high performance liquid chromatography. In seizing animals dopamine was found to be raised in the striatum, and in both dorsal and ventral aspects of the hippocampus. Metabolite levels were elevated in striatum, substantia nigra, nucleus accumbens and cingulate cortex, and fell in the hippocampus, but remained unchanged in the olfactory tubercle and amygdala. These changes translated into an increase in dopamine turnover in the striatum, nigra, accumbens and cingulate cortex, and a fall in dopamine turnover in the hippocampus, with no change in the olfactory tubercle or amygdala. While these alterations do not permit a precise definition of dopamine's role in the pilocarpine-induced seizure process, it would seem that changes in some areas are likely to exacerbate (nigra, hippocampus) and in others to ameliorate (striatum, accumbens) seizure activity. It is most unlikely, therefore, that such alterations in dopaminergic activity represent a concerted effort by the brain to restore normality. The effects of dopaminergic ligands on spontaneous zero Mg2+-induced epileptiform activity were examined in the rat cingulate cortex slice. Dopamine either suppressed or facilitated paroxysmal discharges. The inhibitory effects were mediated by receptors since they were mimicked by a range of D1-selective ligands and blocked by the antagonist SCH 39166. Conversely, the facilitatory response was Dg receptor-mediated, since Dg receptor stimulation was found to augment epileptiform discharges in a Dg antagonist-sensitive manner. These findings lend further support to the proposition that dopamine is an important modulator of epileptiform activity in the intact brain, and that this involves both and Dg receptors working in opposition to each other.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Involvement of dopamine in pilocarpine-induced limbic motor seizures in the rat
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Dopamine; Limbic; Motor; Pilocarpine-induced; Seizures
URI: https://discovery.ucl.ac.uk/id/eprint/10104866
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