Effects of Norepinephrine and Serotonin Transporter Inhibitors on Hyperactivity Induced by Neonatal 6-Hydroxydopamine Lesioning in Rats

• Published in: The Journal of pharmacology and experimental therapeutics 2002-06, Vol.301 (3), p.1097-1102
• Main Authors: Davids, Eugen, Zhang, Kehong, Kula, Nora S, Tarazi, Frank I, Baldessarini, Ross J
• Format: Article
• Language: English
• Subjects: Adrenergic Agents; Adrenergic Uptake Inhibitors - pharmacology; Adrenergic Uptake Inhibitors - therapeutic use; Animals; Animals, Newborn; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - physiology; Hyperkinesis - chemically induced; Hyperkinesis - drug therapy; Hyperkinesis - physiopathology; Male; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - physiology; Membrane Transport Proteins; Motor Activity - drug effects; Motor Activity - physiology; Nerve Endings - drug effects; Nerve Endings - physiology; Nerve Tissue Proteins; Norepinephrine - metabolism; Norepinephrine Plasma Membrane Transport Proteins; Oxidopamine; Rats; Rats, Sprague-Dawley; Serotonin - metabolism; Serotonin Plasma Membrane Transport Proteins; Serotonin Uptake Inhibitors - pharmacology; Serotonin Uptake Inhibitors - therapeutic use; Symporters - antagonists & inhibitors; Symporters - physiology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.301.3.1097

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 μg, 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.