Fig. 6.

Scheme illustrating a possible mechanism by which chronic morphine or cocaine exposure increases ERK activity in the VTA. The neurotrophins, e.g., BDNF, regulate neuronal function via activation of Trk receptors, which leads to the activation of Ras and a protein kinase cascade involving Raf, MEK, and ERK. Activation of ERK then leads to the direct phosphorylation of effector proteins (one example of which is TH), as well as of transcription factors and other protein kinases, which results in the regulation of many additional effector proteins. Chronic morphine and cocaine treatments have been shown to increase levels of specific glutamate receptor subunits (NMDAR1 and GluR1) selectively in the VTA. This increase could account for the increased firing rate of VTA dopamine neurons demonstrated under drug-treated conditions which, in turn, would be expected to increase intracellular Ca²⁺ levels. Increased Ca²⁺ levels would then lead to activation of the ERK cascade, as has been demonstrated in cultured cells, although the exact mechanisms remain unknown. The resulting increase in ERK activity would then result in a multitude of downstream effects, including increases in TH expression, as has also been observed in cultured cells.