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 language | English |
|---|---|
| Pages (from-to) | 674-685 |
| Number of pages | 12 |
| Journal | Journal of Neurochemistry |
| Volume | 135 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Nov 1 2015 |
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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 journal › Article
}
TY - JOUR
T1 - Tph2 gene deletion enhances amphetamine-induced hypermotility
T2 - Effect of 5-HT restoration and role of striatal noradrenaline release
AU - Carli, Mirjana
AU - Kostoula, Chrysaugi
AU - Sacchetti, Giuseppina
AU - Mainolfi, Pierangela
AU - Anastasia, Alessia
AU - Villani, Claudia
AU - Invernizzi, Roberto William
PY - 2015/11/1
Y1 - 2015/11/1
N2 - 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.
AB - 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.
KW - amphetamine
KW - motor activity
KW - noradrenaline
KW - serotonin
KW - striatum
KW - tryptophan hydroxylase-2
UR - http://www.scopus.com/inward/record.url?scp=84946494695&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84946494695&partnerID=8YFLogxK
U2 - 10.1111/jnc.13280
DO - 10.1111/jnc.13280
M3 - Article
VL - 135
SP - 674
EP - 685
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 4
ER -