Dopamine D2 receptor signaling controls neuronal cell death induced by muscarinic and glutamatergic drugs

Mol Cell Neurosci. 2002 Feb;19(2):263-71. doi: 10.1006/mcne.2001.1064.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism
  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Cell Death / drug effects
  • Cell Death / genetics*
  • Dose-Response Relationship, Drug
  • Epilepsy / chemically induced
  • Epilepsy / genetics
  • Epilepsy / metabolism*
  • Excitatory Amino Acid Agonists / pharmacology*
  • Female
  • Genotype
  • Glutamic Acid / metabolism
  • Kainic Acid / pharmacology
  • Limbic System / drug effects
  • Limbic System / metabolism*
  • Limbic System / physiopathology
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Muscarinic Agonists / pharmacology*
  • Nerve Degeneration / chemically induced
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism*
  • Pilocarpine / pharmacology
  • RNA, Messenger / metabolism
  • Receptors, Dopamine D2 / deficiency*
  • Receptors, Dopamine D2 / genetics
  • Receptors, Muscarinic / drug effects
  • Receptors, Muscarinic / genetics
  • Receptors, Muscarinic / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology

Substances

  • Excitatory Amino Acid Agonists
  • Muscarinic Agonists
  • RNA, Messenger
  • Receptors, Dopamine D2
  • Receptors, Muscarinic
  • Pilocarpine
  • Glutamic Acid
  • Acetylcholine
  • Kainic Acid

Associated data

  • GENBANK/J04192
  • GENBANK/X63473