M5 muscarinic receptors are needed for slow activation of dopamine neurons and for rewarding brain stimulation

John Yeomans, Gina Forster, Charles Blaha

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Mesopontine cholinergic neurons (Ch5 and Ch6 cell groups) activate the cerebral cortex via thalamic projections, and activate locomotion and reward via dopamine neurons in the substantia nigra and ventral tegmental area (VTA). Nicotinic receptors in VTA activate dopamine neurons quickly, and are needed for the stimulant and rewarding effects of nicotine in rats. Muscarinic receptors in VTA activate dopamine neurons slowly, and are needed for the rewarding effects of hypothalamic stimulation, but do not increase locomotion. Antisense oligonucleotides targetting M5 mRNA, when infused into the VTA, inhibited M5 receptor binding and rewarding hypothalamic stimulation. Mutant mice with truncated M5 muscarinic receptor genes drank more water than wild-type controls. Spontaneous locomotion and locomotor responses to amphetamine and scopolamine were unchanged. Electrical stimulation near Ch6 induced dopamine release in the nucleus accumbens in two phases, an early phase (0–2 min after stimulation) dependent on nicotinic and gluatamatergic receptors in VTA, and a late phase (8–50 min after stimulation) dependent on muscarinic receptors in VTA. The late phase was lost in M5 mutant mice, while the early phase was unchanged. M5 muscarinic receptors bind slowly to muscarinic ligands, and appear to mediate slow secretions.
Original languageEnglish
Pages (from-to)2449-2456
Number of pages8
JournalLife Sciences
Volume68
Issue number22-23
DOIs
Publication statusPublished - 2001

Keywords

  • locomotion
  • chronoamperommetry
  • mutants
  • antisense oligonucleotides
  • nicotinic
  • cholinergic
  • mesolimbic
  • nigrostriatal

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