title: α4β2 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 α6β2* nicotinic receptors (nAChRs) play a key role. The present experiments were done to determine if α4β2* nAChRs are also involved in l-dopa-induced dyskinesias. To approach this, we took advantage of the finding that α6β2* nAChRs are predominantly present on striatal dopaminergic nerve terminals, while a significant population of α4β2* nAChRs are located on other neurons. Thus, a severe dopaminergic lesion would cause a major loss in α6β2*, but not α4β2* nAChRs. Experiments were therefore done in which rats were unilaterally lesioned with 6-hydroxydopamine, at a dose that led to severe nigrostriatal damage. The dopamine transporter, a dopamine nerve terminal marker, was decreased by >99%. This lesion also decreased striatal α6β2* nAChRs by 97%, while α4β2* nAChRs were reduced by only 12% compared to control. A series of β2* 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 α4α5β2 nAChRs are also predominantly on striatal dopamine terminals, these data suggest that drugs targeting α4β2 nAChRs may reduce l-dopa-induced dyskinesias in late stage Parkinson's disease.
authors.affiliation: Center for Health Sciences, SRI International, 333 Ravenswood Ave., Menlo Park, CA 94025, USA. maryka.quik@sri.com
authors.forename: Maryka
authors.initials: M
authors.lastname: Quik
authors.forename: Carla
authors.initials: C
authors.lastname: Campos
authors.forename: Tanuja
authors.initials: T
authors.lastname: Bordia
authors.forename: Jon-Paul
authors.initials: JP
authors.lastname: Strachan
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhang
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Sharon
authors.initials: S
authors.lastname: Letchworth
authors.forename: Kristen
authors.initials: K
authors.lastname: Jordan
mesh_terms: D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000627:therapeutic use; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000627:therapeutic use; D053961:Azabicyclo Compounds / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003521:Cyclopropanes / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000009:adverse effects / Q000627:therapeutic use; D004361:Drug Tolerance; D004409:Dyskinesia, Drug-Induced / Q000517:prevention & control*; D005260:Female; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy*; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D018726:Anti-Dyskinesia Agents; D000978:Antiparkinson Agents; D053961:Azabicyclo Compounds; D003521:Cyclopropanes; D018491:Dopamine Agonists; D009419:Nerve Tissue Proteins; D018722:Nicotinic Agonists; D021122:Protein Subunits; D011978:Receptors, Nicotinic; C588225:TC-8831; C403531:nicotinic receptor alpha4beta2; D007980:Levodopa