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 ofd-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.
Footnotes
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Supported in part by a Deutsche Forschungsgemeinschaft award (DA 516/1-1 to E.D.), a Livingston Fellowship from Harvard Medical School (to K.Z.), a National Alliance for Research on Schizophrenia and Depression Young Investigator Award and Theodore and Vada Stanley Foundation (to F.I.T.), National Institutes of Health Grants MH-34006 and MH-47370, a grant from the Bruce J. Anderson Foundation, and the McLean Hospital Private Donors Neuropharmacology Research Fund (to R.J.B.).
- Abbreviations:
- ADHD
- attention deficit-hyperactivity disorder
- β-CIT
- 2-β-carbomethoxy-3-β-[4′-iodophenyl]tropane
- CPu
- caudate-putamen
- DA
- dopamine
- DAT
- dopamine transporter
- 5-HT
- 5-hydroxytryptamine (serotonin)
- NAc
- nucleus accumbens septi
- NE
- norepinephrine
- 6-OHDA
- 6-hydroxydopamine
- PD
- postnatal day
- SRI
- serotonin reuptake inhibitor
- Received November 2, 2001.
- Accepted March 8, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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