Implication of protein kinase C in the orexin‐induced elevation of extracellular dopamine levels and its rewarding effect

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Abstract
In the present study, we investigated the role of orexinergic systems in the activation of midbrain dopamine neurons. In anin vitrostudy, exposure to either orexin A or orexin B under superfusion conditions produced a transient increase in the intracellular Ca2+concentration through the phospholipase C (PLC)/protein kinase C (PKC) pathway via Gq11α or Gβγ subunits in midbrain cultured neurons, which were shown to be tyrosine hydroxylase (TH)‐positive cells, but not in purified midbrain astrocytes. Here we show thatin vivoinjection with a selective PKC inhibitor chelerythrine chloride or 2‐{8‐[(dimethylamino)methyl]‐6,7,8,9‐tetrahydropyrido[1,2‐a]indol‐3‐yl}‐3‐1‐methyl‐1H‐indol‐3‐ylmaleimide HCl (Ro‐32–0432) into the ventral tegmental area (VTA) significantly suppressed the place preference and increased levels of dopamine in the nucleus accumbens (NAcc) induced by intra‐VTA injection of orexins. These results strongly support the idea that activation of the orexin‐containing neuron in the VTA leads to the direct activation of mesolimbic dopamine neurons through the activation of the PLC/PKC pathway via Gq11α or Gβγ‐subunit activation, which could be associated with the development of its rewarding effect.

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