title: The impact of a parkinsonian lesion on dynamic striatal dopamine transmission depends on nicotinic receptor activation.
abstract: Dopamine function is disturbed in Parkinson's disease (PD), but whether and how release of dopamine from surviving neurons is altered has long been debated. Nicotinic acetylcholine receptors (nAChRs) on dopamine axons powerfully govern dopamine release and could be critical contributing factors. We revisited whether fundamental properties of dopamine transmission are changed in a parkinsonian brain and tested the potentially profound masking effects of nAChRs. Using real-time detection of dopamine in mouse striatum after a partial 6-hydroxydopamine lesion and under nAChR inhibition, we reveal that dopamine signals show diminished sensitivity to presynaptic activity. This effect manifested as diminished contrast between DA release evoked by the lowest versus highest frequencies. This reduced activity-dependence was underpinned by loss of short-term facilitation of dopamine release, consistent with an increase in release probability (Pr). With nAChRs active, the reduced activity-dependence of dopamine release after a parkinsonian lesion was masked. Consequently, moment-by-moment variation in activity of nAChRs may lead to dynamic co-variation in dopamine signal impairments in PD.
authors.affiliation: Department of Physiology, Anatomy Genetics, Oxford Parkinson's Disease Centre, Parks Road, Oxford OX1 3PT, UK. Electronic address: katie.jennings@dpag.ox.ac.uk.
authors.forename: Katie A
authors.initials: KA
authors.lastname: Jennings
authors.affiliation: Department of Physiology, Anatomy Genetics, Oxford Parkinson's Disease Centre, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Platt
authors.affiliation: Department of Physiology, Anatomy Genetics, Oxford Parkinson's Disease Centre, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Cragg
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D046509:Tissue Culture Techniques
chemical_list: D018765:Dopamine Uptake Inhibitors; D011978:Receptors, Nicotinic; D016627:Oxidopamine; D003042:Cocaine; D004298:Dopamine
keywords: 6-OHDA; Acetylcholine; Dopamine; Fast-scan cyclic voltammetry; Nicotinic receptors; P(r); Parkinsonian; Phasic dopamine; Release probability; Striatum