Molecular targets of major abused drugs. Cannabinoids, like opiates, activate a G-protein-coupled receptor, in this case the CB1R, which couples to transduction mechanisms, mainly adenylyl cyclase (AC), and voltage-gated potassium, and calcium channels through the small GTP-binding proteins G_s/olf and G_i/o. CB1 receptors thereby modulate the resting membrane potential and intracellular concentrations of cAMP. Subsequent modification of the activity of specific protein kinases, primarily PKA, but also mitogen-activated protein kinases, leads to both acute responses (modulation of neurotransmitter release or firing rates) and long-term adaptations associated with dependence and withdrawal.