title: Ni(2+) affects dopamine uptake which limits suitability as inhibitor of T-type voltage-gated Ca(2+) channels.
abstract: Neuronal T-type voltage-gated Ca(2+) channels are reported to have physiological roles that include regulation of burst firing, Ca(2+) oscillations, and neurotransmitter release. These roles are often exposed experimentally by blocking T-type channels with micromolar Ni(2+). We used Ni(2+) to explore the role of axonal T-type channels in dopamine (DA) release in mouse striatum, but identified significant off-target effects on DA uptake. Ni(2+) (100 μM) reversibly increased electrically evoked DA release and markedly extended its extracellular lifetime, detected using fast-scan cyclic voltammetry. Prior inhibition of the DA transporter (DAT) by cocaine (5 μM) occluded the facilitatory action of Ni(2+) on DA release and conversely, allowed Ni(2+) to inhibit release, presumably through T-channel inhibition. Ni(2+) further prolonged the timecourse of DA clearance suggesting further inhibition of DA uptake. In summary, Ni(2+) has major effects on DA transmission besides those due to T-channels that likely involve inhibition of the DAT.
authors.affiliation: Department of Physiology, Anatomy and Genetics, and ‡Oxford Parkinson's Disease Centre, University of Oxford , Oxford OX1 3PT, United Kingdom.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Brimblecombe
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Cragg
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D055664:Electrochemical Techniques; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D009532:Nickel / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D015259:Dopamine Agents; D004079:Dihydro-beta-Erythroidine; C022838:nickel chloride; D009532:Nickel; D000109:Acetylcholine; D004298:Dopamine
keywords: Dopamine; Ni2+; T-type VGCC; dopamine transporter; voltammetry