Dopamine D2 receptor signaling controls neuronal cell death induced by muscarinic and glutamatergic drugs.
Dopamine (DA), through D1/D2 receptor-mediated signaling, plays a major role in the control of epileptic seizures arising in the limbic system. Excitotoxicity leading to neuronal cell death in the affected areas is a major consequence of seizures at the cellular level. In this respect, little is known about the role of DA receptors in the occurrence of epilepsy-induced neuronal cell death. Here we analyze the occurrence of seizures and neurotoxicity in D2R -/- mice treated with the cholinergic agonist pilocarpine. We compared these results with those previously obtained with kainic acid (KA), a potent glutamate agonist. Importantly, D2R -/- mice develop seizures at doses of both drugs that are not epileptogenic for WT littermates and show greater neurotoxicity. However, pilocarpine-induced seizures result in a more widespread neuronal death in both WT and D2R -/- brains in comparison to KA. Thus, the absence of D2R lowers the threshold for seizures induced by both glutamate and acetylcholine. Moreover, the dopaminergic control of epilepsy-induced neurodegeneration seems to be mediated by distinct interactions of D2R signaling with these two neurotransmitters.
Bozzi
Yuri
Y
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Illkirch, C. U. de Strasbourg, France.
Borrelli
Emiliana
E
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005260:Female; D005838:Genotype; D018698:Glutamic Acid / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D010862:Pilocarpine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000172:deficiency* / Q000235:genetics; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D018690:Excitatory Amino Acid Agonists; D018721:Muscarinic Agonists; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D011976:Receptors, Muscarinic; D010862:Pilocarpine; D018698:Glutamic Acid; D000109:Acetylcholine; D007608:Kainic Acid