Dopaminergic modulation of low‐Mg²⁺‐induced epileptiform activity in the intact hippocampus of the newborn mouse in vitro

Abstract

To investigate whether epileptiform activity in the immature brain is modulated by dopamine, we examined the effects of dopaminergic agonists and antagonists in an intact in vitro preparation of the isolated corticohippocampal formation of immature (postnatal days 3 and 4) C57/Bl6 mice using field potential recordings from CA3. Epileptiform discharges were induced by a reduction of the extracellular Mg(2+) concentration to 0.2 mM. These experiments revealed that low concentrations of dopamine (<0.3 μM) attenuated epileptiform activity, whereas >3 μM dopamine enhanced epileptiform activity. The D1-agonist SKF38393 (10 μM) had a strong proconvulsive effect, and the D2-like agonist quinpirole (10 μM) mediated a weak anticonvulsive effect. The proconvulsive effect of 10 μM dopamine was completely abolished by the D1-like receptor antagonist SCH39166 (2 μM) or the D2-like antagonist sulpiride (10 μM), whereas the D2 antagonist L-741626 (50 nM) and the D3 antagonist SB-277011-A (0.1 μM) were without effect. The anticonvulsive effect of 0.1 μM dopamine could be suppressed by D1-like, D2, or D3 receptor antagonists. A proconvulsive effect of 10 μM dopamine was also observed when AMPA, NMDA, or GABA(A) receptors were blocked. In summary, these results suggest that 1) dopamine influences epileptiform activity already at early developmental stages; 2) dopamine can bidirectionally influence the excitability; 3) D1-like receptors mediate the proconvulsive effect of high dopamine concentrations, although the pharmacology of the anticonvulsive effect is less clear; and 4) dopamine-induced alterations in GABAergic and glutamatergic systems may contribute to this effect.

Nucleus accumbens shell modulates seizure propagation in a mouse temporal lobe epilepsy model

“…Frontiers in Cell and Developmental Biology frontiersin.org contrary, D2R is coupled with Gi protein so that inactivation of D2R-MSN can be fulfilled through agonizing D2R. Controversial effects of dopaminergic agonists and antagonists applied in in vitro or systematic ways on seizures have been reported, but in most cases, it was reported that dopamine D1R agonists are proconvulsant and that D2R agonists are anticonvulsant (Wahnschaffe and Loscher, 1991;Starr, 1996;Sharopov et al, 2012;Brodovskaya and Kapur, 2021). In line with these previous studies showing D1R antagonists and D2R agonists are antiepileptic, our results of chemogenetic inhibition of either D1R-MSN or D2R-MSN in the NAc shell proves to be protective for the brain from more severe seizure insult.…”

Identification and Validation of a Dysregulated miRNA-Associated mRNA Network in Temporal Lobe Epilepsy

“…Evidence has indicated that dopamine can aggravate epileptiform activity by decreasing the Mg 2+ concentration in the newborn mouse hippocampus in vitro. Furthermore, the induction of changes in the GABAergic and glutamatergic systems leads to increased neuron excitability and the involvement of these dysregulated systems in epileptogenesis [17]. Glutamate receptors, including AMPA receptors, are characterized by influencing the alternation of Ca 2+ concentrations, thus causing neuronal death and becoming involved in the epilepsy pathophysiology [18,19].…”

Current Study of the Mechanism of Action of the Potential Anti-Epileptic Agent Q808

“…Rat hippocampal slices were prepared as previously reported [ 27 , 28 , 29 , 30 , 31 ]. All efforts were made to minimize the number of animals used and their suffering.…”