Schematic illustration of cellular mechanisms of neurotransmission in the mesolimbic dopamine (DA) reward pathway. Shown is a synapse between a ventral tegmental area DA neuron axon terminal and a medium spiny neuron (MSN) in the nucleus accumbens (NAc) in the ventral striatum. Transmission begins with an action potential that arrives to the terminal, inducing synaptic vesicle fusion and release of DA. The release of DA into the NAc stimulates various populations of MSNs, whose response to the transmitter depends on the types of DA receptors they express. DA stimulation of neurons containing D1 or D5 receptors (so-called D1-like receptors) results in activation of heterotrimeric Golf/Gs proteins, which activate the enzyme adenylyl cyclase, resulting in the synthesis of the second messenger cAMP. In contrast to this mechanism, DA stimulation of MSNs that express D2, D3 or D4 (or D2-like receptors) activate sheterotrimeric Gi/Go proteins, which inhibit adenylyl cyclase activity to decrease cAMP. The level of intracellular cAMP controls the activation of protein kinase A, which regulates additional signaling molecules including dopamine- and cAMP-regulated neuronal phosphoprotein of 32 kDa (DARPP-32) and the transcription factor cAMP response element binding (CREB) protein, both of which can modulate gene expression and additional cellular responses. The response to DA is generally terminated when DA is removed from the synapse by reuptake via the DA transporter (DAT). After reuptake, the transmitter can be repackaged into synaptic vesicles or may be degraded by the enzyme monoamine oxidase, resulting in the DA metabolite homovanillic acid. In addition, the enzyme catechol-o-methyltransferase (COMT) may also control DA levels by breaking down DA to 3-methoxytyramine (3-MT), AC, adenylyl cyclase; ATP; adensosine triphosphate; cAMP; cyclic adenosine monophosphate; HVA, homovanillic acid; MAO, monoamine oxidase; VTA, ventral tegmental area.