sb-277011 and Magnesium-Deficiency

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.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Animals, Newborn; Benzazepines; Data Interpretation, Statistical; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Epilepsy; Hippocampus; Indoles; Magnesium Deficiency; Mice; Mice, Inbred C57BL; Nitriles; Piperidines; Quinpirole; Receptors, Dopamine D2; Synapses; Tetrahydroisoquinolines