Alpha4beta2 Nicotinic Receptors Play a Role in the nAChR-Mediated Decline in l-Dopa-Induced Dyskinesias in Parkinsonian Rats

Abstract

l-dopa-induced dyskinesias are a serious long-term side effect of dopamine replacement therapy for Parkinson’s disease for which there are few treatment options. Our previous studies showed that nicotine decreased l-dopa-induced abnormal involuntary movements (AIMs). Subsequent work with knockout mice demonstrated that alpha6beta2* nicotinic receptors (nAChRs) play a key role. The present experiments were done to determine if alpha4beta2* nAChRs are also involved in l-dopa-induced dyskinesias. To approach this, we took advantage of the finding that alpha6beta2* nAChRs are predominantly present on striatal dopaminergic nerve terminals, while a significant population of alpha4beta2* nAChRs are located on other neurons. Thus, a severe dopaminergic lesion would cause a major loss in alpha6beta2*, but not alpha4beta2* nAChRs. Experiments were therefore done in which rats were unilaterally lesioned with 6-hydroxydopamine, at a dose that lead to severe nigrostriatal damage. The dopamine transporter, a dopamine nerve terminal marker, was decreased by >99%. This lesion also decreased striatal alpha6beta2* nAChRs by 97%, while alpha4beta2* nAChRs were reduced by only 12% compared to control. A series of beta2* nAChR compounds, including TC-2696, TI-10165, TC-8831, TC-10600 and sazetidine reduced l-dopa-induced AIMs in these rats by 23-32%. TC-2696, TI-10165, TC-8831 were also tested for parkinsonism, with no effect on this behavior. Tolerance did not develop with up to 3 months of treatment. Since alpha4alpha5beta2 nAChRs are also predominantly on striatal dopamine terminals, these data suggest that drugs targeting alpha4beta2 nAChRs may reduce l-dopa-induced dyskinesias in late stage Parkinson’s disease.

Keywords: Dyskinesia, L-dopa, nicotine, nicotinic, Parkinson’s disease, sazetidine