Tph2 gene deletion enhances amphetamine-induced hypermotility

Effect of 5-HT restoration and role of striatal noradrenaline release

Mirjana Carli, Chrysaugi Kostoula, Giuseppina Sacchetti, Pierangela Mainolfi, Alessia Anastasia, Claudia Villani, Roberto William Invernizzi

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Variants of tryptophan hydroxylase-2 (Tph2), the gene encoding enzyme responsible for the synthesis of brain serotonin (5-HT), have been associated with neuropsychiatric disorders, substance abuse and addiction. This study assessed the effect of Tph2 gene deletion on motor behavior and found that motor activity induced by 2.5 and 5 mg/kg amphetamine was enhanced in Tph2-/- mice. Using the in vivo microdialysis technique we found that the ability of amphetamine to stimulate noradrenaline (NA) release in the striatum was reduced by about 50% in Tph2-/- mice while the release of dopamine (DA) was not affected. Tph2 deletion did not affect the release of NA and DA in the prefrontal cortex. The role of endogenous 5-HT in enhancing the effect of amphetamine was confirmed showing that treatment with the 5-HT precursor 5-hydroxytryptophan (10 mg/kg) restored tissue and extracellular levels of brain 5-HT and the effects of amphetamine on striatal NA release and motor activity in Tph2-/- mice. Treatment with the NA precursor dihydroxyphenylserine (400 mg/kg) was sufficient to restore the effect of amphetamine on striatal NA release and motor activity in Tph2-/- mice. These findings indicate that amphetamine-induced hyperactivity is attenuated by endogenous 5-HT through the inhibition of striatal NA release. Tph2-/- mice may be a useful preclinical model to assess the role of 5-HT-dependent mechanisms in the action of psychostimulants.

Original languageEnglish
Pages (from-to)674-685
Number of pages12
JournalJournal of Neurochemistry
Volume135
Issue number4
DOIs
Publication statusPublished - Nov 1 2015

Fingerprint

Tryptophan Hydroxylase
Corpus Striatum
Gene Deletion
Amphetamine
Restoration
Serotonin
Norepinephrine
Genes
Motor Activity
Substance-Related Disorders
Dopamine
Brain
5-Hydroxytryptophan
Gene encoding
Aptitude
Microdialysis
Prefrontal Cortex
Mouse Tph2 protein
Tissue
Enzymes

Keywords

  • amphetamine
  • motor activity
  • noradrenaline
  • serotonin
  • striatum
  • tryptophan hydroxylase-2

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Tph2 gene deletion enhances amphetamine-induced hypermotility : Effect of 5-HT restoration and role of striatal noradrenaline release. / Carli, Mirjana; Kostoula, Chrysaugi; Sacchetti, Giuseppina; Mainolfi, Pierangela; Anastasia, Alessia; Villani, Claudia; Invernizzi, Roberto William.

In: Journal of Neurochemistry, Vol. 135, No. 4, 01.11.2015, p. 674-685.

Research output: Contribution to journalArticle

Carli, Mirjana ; Kostoula, Chrysaugi ; Sacchetti, Giuseppina ; Mainolfi, Pierangela ; Anastasia, Alessia ; Villani, Claudia ; Invernizzi, Roberto William. / Tph2 gene deletion enhances amphetamine-induced hypermotility : Effect of 5-HT restoration and role of striatal noradrenaline release. In: Journal of Neurochemistry. 2015 ; Vol. 135, No. 4. pp. 674-685.
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