Proposed animal model of attention deficit hyperactivity disorder.
Dopamine (DA) neurons are implicated in the hyperlocomotion of neonatal 6-hydroxydopamine (6-OHDA)-lesioned rats, an animal model of attention deficit hyperactivity disorder (ADHD). Because serotonin (5-HT) neurons mediate some DA agonist effects, we investigated the possible role of 5-HT neurons on locomotor activity. Rats were treated at 3 days after birth with vehicle or 6-OHDA (134 micrograms ICV; desipramine pretreatment, 20 mg/kg IP, 1 h), and at 10 weeks with vehicle or 5,7-dihydroxytryptamine (5,7-DHT; 75 micrograms ICV; pretreatment with desipramine and pargyline, 75 mg/kg IP, 30 min), to destroy DA and/or 5-HT fibers. Intense spontaneous hyperlocomotor activity was produced in rats lesioned with both 6-OHDA and 5,7-DHT. Locomotor time in this group was 550 +/- 17 s in a 600 s session, vs. 127 +/- 13 s in the 6-OHDA group and < 75 s in 5,7-DHT and intact control groups (p < 0.001). Oral activity dose-effect curves established that 5,7-DHT attenuated DA D1 receptor supersensitivity and further sensitized 5-HT2c receptors. Acute treatment with dextroamphetamine (0.25 mg/kg SC) reduced locomotor time in 6-OHDA + 5,7-DHT-lesioned rats to 76 +/- 37 s (p < 0.001). Striatal DA was reduced by 99% and 5-HT was reduced by 30% (vs. 6-OHDA group). Because combined 6-OHDA (to neonates) and 5,7-DHT (to adults) lesions produce intense hyperlocomotion that is attenuated by amphetamine, we propose this as a new animal model of ADHD. The findings suggest that hyperactivity in ADHD may be due to injury or impairment of both DA and 5-HT neurons.
Kostrzewa
R M
RM
Department of Pharmacology, Quillen College of Medicine, East Tennessee State University, Johnson City 37614.
Brus
R
R
Kalbfleisch
J H
JH
Perry
K W
KW
Fuller
R W
RW
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001289:Attention Deficit Disorder with Hyperactivity / Q000503:physiopathology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D005260:Female; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009068:Movement / Q000187:drug effects; D009412:Nerve Fibers / Q000502:physiology*; D016627:Oxidopamine / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D013239:Stereotyped Behavior / Q000187:drug effects
D015259:Dopamine Agents; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D016627:Oxidopamine; D004298:Dopamine