Ni2+ Affects Dopamine Uptake Which Limits Suitability as Inhibitor of T-Type Voltage-Gated Ca2+ Channels

Neuronal T-type voltage-gated Ca2+ channels are reported to have physiological roles that include regulation of burst firing, Ca2+ oscillations, and neurotransmitter release. These roles are often exposed experimentally by blocking T-type channels with micromolar Ni2+. We used Ni2+ 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. Ni2+ (100 mu M) 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 mu M) occluded the facilitatory action of Ni2+ on DA release and conversely, allowed Ni2+ to inhibit release, presumably through T-channel inhibition. Ni2+ further prolonged the timecourse of DA clearance suggesting further inhibition of DA uptake. In summary, Ni2+ has major effects on DA transmission besides those due to T-channels that likely involve inhibition of the DAT.