title: Tph2 gene deletion enhances amphetamine-induced hypermotility: effect of 5-HT restoration and role of striatal noradrenaline release.
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. Acute sensitivity to the motor effects of amphetamine has been associated to increased risk of psychostimulant abuse. Here, we show that deletion of Tph2, the gene responsible for brain 5-HT synthesis, enhances the motor effect of amphetamine in mice through the inhibition of striatal NA release. This suggests that Tph2(-/-) mice is a useful preclinical model to assess the role of 5-HT-dependent mechanisms in psychostimulants action. Tph2, tryptophan hydroxylase-2.
authors.affiliation: Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Lab. Neurochemistry and Behavior, Milano, Italy.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Carli
authors.affiliation: Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Lab. Neurochemistry and Behavior, Milano, Italy.
authors.forename: Chrysaugi
authors.initials: C
authors.lastname: Kostoula
authors.affiliation: Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Lab. Neurochemistry and Behavior, Milano, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Sacchetti
authors.affiliation: Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Lab. Neurochemistry and Behavior, Milano, Italy.
authors.forename: Pierangela
authors.initials: P
authors.lastname: Mainolfi
authors.affiliation: Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Lab. Neurochemistry and Behavior, Milano, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Anastasia
authors.affiliation: Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Lab. Neurochemistry and Behavior, Milano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Villani
authors.affiliation: Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Lab. Neurochemistry and Behavior, Milano, Italy.
authors.forename: Roberto William
authors.initials: RW
authors.lastname: Invernizzi
mesh_terms: D006916:5-Hydroxytryptophan / Q000494:pharmacology; D018759:Adrenergic Uptake Inhibitors / Q000633:toxicity*; D000661:Amphetamine / Q000633:toxicity*; D000818:Animals; D002230:Carbidopa / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006948:Hyperkinesis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009638:Norepinephrine / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D013997:Time Factors; D014365:Tryptophan Hydroxylase / Q000172:deficiency* / Q000235:genetics
chemical_list: D018759:Adrenergic Uptake Inhibitors; D015259:Dopamine Agents; D012701:Serotonin; D006916:5-Hydroxytryptophan; D000661:Amphetamine; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase; D002230:Carbidopa; D009638:Norepinephrine
keywords: amphetamine; motor activity; noradrenaline; serotonin; striatum; tryptophan hydroxylase-2