Decreased amphetamine-induced locomotion and improved latent inhibition in mice mutant for the M5 muscarinic receptor gene found in the human 15q schizophrenia region

Haoran Wang, Karen Ng, David Hayes, Xiangrong Gao, Gina Forster, Charles Blaha, John Yeomans

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

M5 muscarinic receptors are coexpressed with D2 dopamine receptors in the ventral tegmentum and striatum, and are important for reward in rodents. Previously, we reported that disruption of the M5 receptor gene in mice reduced dopamine release in the nucleus accumbens. In this study, we established a polymerase chain reaction (PCR) genotyping method for M5 mutant mice, and, using RT-PCR, found that M5 mRNA expression was highest in the ventral tegmentum, striatum, and thalamus in wild-type mice. In the M5 mutant mice, D2 mRNA expression was increased in several brain structures, including the striatum. Genome mapping studies showed the M5 gene is localized to chromosome 2E4 in mice, and to 15q13 in humans in the region that has been linked to schizophrenia. Amphetamine-induced locomotion, but not baseline locomotion or motor functions, decreased in M5 mutant mice, consistent with lower accumbal dopamine release. Previous reports found latent inhibition improvement in rats following nucleus accumbens lesions, or blockade of dopamine D2 receptors with neuroleptic drugs. Here, latent inhibition was significantly increased in M5 mutant mice as compared with controls, consistent with reduced dopamine function in the nucleus accumbens. In summary, our results showed that M5 gene disruption in mice decreased amphetamine-induced locomotion and increased latent inhibition, suggesting that increased M5 mesolimbic function may be relevant to schizophrenia.

Original languageEnglish (US)
Pages (from-to)2126-2139
Number of pages14
JournalNeuropsychopharmacology
Volume29
Issue number12
DOIs
StatePublished - Dec 1 2004

Fingerprint

Muscarinic M5 Receptors
Amphetamine
Locomotion
Schizophrenia
Genes
Nucleus Accumbens
Dopamine
Dopamine D2 Receptors
Polymerase Chain Reaction
Messenger RNA
Inhibition (Psychology)
Chromosome Mapping
Thalamus
Reward
Antipsychotic Agents
Rodentia
Chromosomes

Keywords

  • Cholinergic
  • Dopamine
  • Linkage
  • Mesolimbic
  • Mesopontine
  • Nucleus accumbens

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Decreased amphetamine-induced locomotion and improved latent inhibition in mice mutant for the M5 muscarinic receptor gene found in the human 15q schizophrenia region. / Wang, Haoran; Ng, Karen; Hayes, David; Gao, Xiangrong; Forster, Gina; Blaha, Charles; Yeomans, John.

In: Neuropsychopharmacology, Vol. 29, No. 12, 01.12.2004, p. 2126-2139.

Research output: Contribution to journalArticle

Wang, Haoran ; Ng, Karen ; Hayes, David ; Gao, Xiangrong ; Forster, Gina ; Blaha, Charles ; Yeomans, John. / Decreased amphetamine-induced locomotion and improved latent inhibition in mice mutant for the M5 muscarinic receptor gene found in the human 15q schizophrenia region. In: Neuropsychopharmacology. 2004 ; Vol. 29, No. 12. pp. 2126-2139.
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