Amphetamine-induced abnormal movements occur independently of both transplant- and host-derived serotonin innervation following neural grafting in a rat model of Parkinson's disease.
Serotonin has been postulated to play a role in the transplant-induced involuntary movements that occur following intrastriatal grafts of ventral mesencephalic tissue in the treatment of Parkinson's disease. Serotonin innervation of the striatum may be derived from either the donor graft tissue or the normal host projections from the midbrain. In two sets of experiments we study the impact of graft- versus host-derived serotonin innervation. All experiments were performed in l-DOPA treated rats with unilateral 6-hydroxydopamine lesions. As expected, following intrastriatal transplantation of embryonic ventral mesencephalon all the transplanted rats exhibited pronounced contralateral rotation in response to amphetamine and some animals also showed severe abnormal involuntary movements (AIMs). In the first set of experiments, all types of AIMs (axial, limb, orolingual and locomotor) were markedly reduced when amphetamine was co-administered with either the D(2) dopamine receptor antagonist raclopride or the D(1) receptor antagonist SCH23390. Cotreatment with the 5-HT(1A) agonist 8-OH-DPAT significantly attenuated the amphetamine-induced axial and limb dyskinesias, whilst locomotor scores remained unchanged. These data point to a major role for dopamine receptors, and to a modulatory role for 5-HT(1A) receptors, in post-grafting dyskinesias. In the second experiment, grafted rats exhibiting amphetamine-induced dyskinesia were subjected to 5,7-dihydroxytryptamine injections into the midbrain in order to destroy the host serotonin innervation. This intervention had no effect on either amphetamine-induced AIMs or contralateral rotation. Histological examination of all grafted rats showed similar numbers of dopaminergic neurons and a very low number of serotonin neurons within the transplants, regardless of AIMs expression. Our results suggest that amphetamine-induced AIMs in grafted animals primarily depend on an activation of dopamine receptors, and that serotonin neurons within either the grafts or the host brain play a negligible role.
Lane
Emma Louise
EL
Neuronal Survival Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund, Sweden. LaneEL@cardiff.ac.uk
Brundin
Patrik
P
Cenci
M Angela
MA
D015116:5,7-Dihydroxytryptamine / Q000633:toxicity; D018663:Adrenergic Agents / Q000633:toxicity; D000661:Amphetamine / Q000633:toxicity*; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity*; D020820:Dyskinesias / Q000209:etiology*; D004622:Embryo, Mammalian; D005260:Female; D007980:Levodopa / Q000627:therapeutic use; D008636:Mesencephalon / Q000637:transplantation*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology / Q000601:surgery*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000633:toxicity; D019737:Transplants; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D018765:Dopamine Uptake Inhibitors; D018490:Serotonin Agents; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D007980:Levodopa; D016627:Oxidopamine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase