Figure 1.

Diagram of the major kinase signaling cascades involved in drug addiction. Dopamine receptors activate heterotrimeric G-proteins. D1 receptors activate stimulatory G_s, D2 receptors activate inhibitory G_i/o, and D1/D2 heteromers activate stimulatory G_q. Cannabinoid CB1 receptors and opioid receptors also activate G_i/o. Gα_s and Gβγ released from G_i/o activate adenylyl cyclase, leading to increased cAMP levels which activate PKA. Induction of the transcription factor deltaFosB increases Cdk5 expression. Differential phosphorylation of DARPP-32 by PKA and Cdk5 inhibits or facilitates PKA signaling. Gβγ also activates GIRK channels leading to inhibition of excitability. Gα_q and Gβγ activate PLC and PLD, leading to the activation of PKC. Several downstream PKA and PKC targets are listed at the bottom. Activation of ionotropic glutamate receptors and L-type calcium channels increases intracellular calcium levels, leading to activation of the Ras-Raf-MEK-ERK pathway. Activation of TrkB receptors also activates the ERK pathway, leading to the phosphorylation of transcription factors CREB and Elk-1. Examples of cross-talk between the PKA, PKC, Cdk5, and ERK signaling pathways are illustrated. This diagram is a simplification that does not incorporate differential expression of kinases in different brain regions and cell types.