Effects of norepinephrine and serotonin transporter inhibitors on hyperactivity induced by neonatal 6-hydroxydopamine lesioning in rats.

Abstract	Consistent with their clinical effects in attention deficit-hyperactivity disorder (ADHD), the stimulants methylphenidate and amphetamine reduce motor hyperactivity in juvenile male rats with neonatal 6-hydroxydopamine (6-OHDA) lesions of the forebrain dopamine (DA) system. Since stimulants act on several aminergic neurotransmission systems, we investigated underlying mechanisms involved by comparing behavioral actions of d-methylphenidate, selective inhibitors of the neuronal transport of DA [GBR-12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine dihydrochloride), amfonelic acid], serotonin [5-hydroxytryptamine (5-HT), citalopram, fluvoxamine], and norepinephrine (NE; desipramine, nisoxetine) in 6-OHDA lesioned rats. Selective dopamine lesions were made using 6-OHDA (100 microg, intracisternal) on postnatal day (PD) 5 after desipramine pretreatment (25 mg/kg, s.c.) to protect noradrenergic neurons. Rats were given test agents or vehicle, intraperitoneally, before recording motor activity for 90 min at PD 25 in a novel environment. d-Methylphenidate stimulated motor activity in sham controls and antagonized hyperactivity in lesioned rats. Selective DA transport inhibitors GBR-12909 and amfonelic acid greatly stimulated motor activity in sham control subjects, too, but did not antagonize hyperactivity in lesioned rats. In contrast, all selective 5-HT and NE transporter antagonists tested greatly reduced motor hyperactivity in 6-OHDA lesioned rats but did not alter motor activity in sham controls. The findings indicate that behavioral effects of stimulants in young rats with neonatal 6-OHDA lesions may be mediated by release of NE or 5-HT and support interest in using drugs that increase activity of norepinephrine or serotonin to treat ADHD.
Authors	Eugen Davids, Kehong Zhang, Nora S Kula, Frank I Tarazi, Ross J Baldessarini
Journal	The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 301 Issue 3 Pg. 1097-102 (Jun 2002) ISSN: 0022-3565 [Print] United States
PMID	12023542 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Adrenergic Agents Adrenergic Uptake Inhibitors Carrier Proteins Membrane Glycoproteins Membrane Transport Proteins Nerve Tissue Proteins Norepinephrine Plasma Membrane Transport Proteins Serotonin Plasma Membrane Transport Proteins Serotonin Uptake Inhibitors Slc6a2 protein, rat Slc6a4 protein, rat Symporters Serotonin Oxidopamine Norepinephrine
Topics	Adrenergic Agents Adrenergic Uptake Inhibitors (pharmacology, therapeutic use) Animals Animals, Newborn Carrier Proteins (antagonists & inhibitors, physiology) Hyperkinesis (chemically induced, drug therapy, physiopathology) Male Membrane Glycoproteins (antagonists & inhibitors, physiology) Membrane Transport Proteins Motor Activity (drug effects, physiology) Nerve Endings (drug effects, physiology) Nerve Tissue Proteins Norepinephrine (metabolism) Norepinephrine Plasma Membrane Transport Proteins Oxidopamine Rats Rats, Sprague-Dawley Serotonin (metabolism) Serotonin Plasma Membrane Transport Proteins Selective Serotonin Reuptake Inhibitors (pharmacology, therapeutic use) Symporters (antagonists & inhibitors, physiology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!