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 À/À 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 À/À 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 À/À 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 À/À mice. These findings indicate that amphetamineinduced hyperactivity is attenuated by endogenous 5-HT through the inhibition of striatal NA release. Tph2 À/À mice may be a useful preclinical model to assess the role of 5-HTdependent mechanisms in the action of psychostimulants.

Acute treatment with 5-hydroxytryptophan increases social approach behaviour but does not activate serotonergic neurons in the dorsal raphe nucleus in juvenile male BALB/c mice: A model of human disorders with deficits of sociability

“…Peripheral decarboxylase inhibitors increase central availability of exogenous 5-HTP (Magnussen, 1984) and central levels of serotonin (Itskovitz et al, 1989). However, this finding was unexpected given that the carbidopa is not thought to pass the blood brain-barrier (Porter et al, 1962; Yee et al, 2001), and when administered alone, it has no effect on endogenous central 5-HT, noradrenaline or dopamine in Tph2 knockout mice, nor does it affect 5-HTP or L-DOPA within the cortex or striatum of wild-type mice (Carli et al, 2015). In addition, humans treated with carbidopa, endogenous 5-HTP is not synthesised in sufficient quantity in the periphery to affect brain serotonin functioning (Young et al, 1982).…”

Gestational exposure to perfluorooctanoic acid (PFOA): Alterations in motor related behaviors

“…Several studies have demonstrated that intrinsic 5-HT 2 receptors can modify dopaminergic function (Lucas et al, 2000; Porras et al, 2002) with 5-HT 2 A antagonists reducing hyperactivity induced by amphetamine (O'Neill et al, 1999). In addition, striatal noradrenaline release can modulate the motor effects of amphetamine (Carli et al, 2015). Thus, the observed effects may be related to alterations in the serotonin system, which would require further focused experimental examination.…”