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Download fileReversal of dopamine inhibition of dopaminergic neurons of the ventral tegmental area is mediated by protein kinase C
journal contribution
posted on 2013-11-15, 00:00 authored by Sudarat Nimitvilai, Devinder S. Arora, Mark S. BrodieAdaptation of putative dopaminergic (pDA) neurons in the ventral tegmental area (VTA) to drugs of
abuse may alter information processing related to reward and reinforcement and is a key factor in the
development of addiction. We have demonstrated that prolonged increases in the concentration of
dopamine (DA) result in a time-dependent decrease in sensitivity of pDA neurons to DA, which we
termed dopamine inhibition reversal (DIR). In the present study, we used extracellular recordings to
examine factors mediating DIR. A 40 min administration of DA (2.5-10 μM), but not the DA D2
receptor agonist quinpirole (50-200 nM), resulted in inhibition of neuronal firing followed by DIR.
In the presence of 100 nM cocaine, inhibition followed by DIR was seen with much lower DA
concentrations. Reversal of quinpirole inhibition could be induced by an activator of protein kinase
C, but not of protein kinase A. Inhibitors of protein kinase C or phospholipase C blocked the
development of DIR. Disruption of intracellular calcium release also prevented DIR. Reduction of
extracellular calcium or inhibition of store-operated calcium entry blocked DIR, but the L-type
calcium channel blocker nifedipine did not. DIR was age-dependent and not seen in pDA VTA
neurons from rat pups younger than 15 days postnatal. Our data indicate that DIR is mediated by
protein kinase C, and implicate a conventional protein kinase C. This characterization of DIR gives
insight into the regulation of autoinhibition of pDA VTA neurons, and the resulting long-term
alteration in information processing related to reward and reinforcement.