Dopamine (DA) acts a neurotransmitter and neuromodulator in the brain and peripherally as an autocrine/paracrine hormone. Dopamine exerts its major role in the nervous system where it is involved in motor control and action selection, reward and motivation, behavior, memory and cognition. The many effects are achieved through the projections dopaminergic (DA-producing) neurons establish and the inputs they receive and which shape DA release. DA neurons in midbrain areas such as the substantia ni
gra pars compacta (SNc) and the ventral tegmental area (VTA), project to the striatum or the cerebral cortex to form specific neural pathways. Projections from the SNc to the dorsal striatum (caudate-putamen in primates), form the nigrostriatal system; from the VTA to the nucleus accumbens (NAc) and from the VTA (and SNc in primates) to the cortex, in particular the frontal lobes (prefrontal cortex, PFC), form the mesolimbic and the mesocortical system, respectively, sometimes collectively referred to as the mesocorticolimbic system. The three systems (shown) are the principal DA neural pathways (a fourth, the tuberoinfundibular system, regulates secretion of prolactin). The dorsal striatum/caudate-putamen and the NAc are major regions of the striatum, the largest of the basal ganglia (BG) nuclei and its major recipient of information. BG represent a group of subcortical nuclei interconnected with the cortical and thalamic regions of the brain, associated with movement, behavior and cognition. The striatum is largely composed of medium spiny neurons (MSN), also known as spiny projection neurons (SPN), GABAergic neurons. Depending on the dopamine receptor types they express, SPNs belong to distinct populations. The five G protein-coupled (GPCR) DA receptors are subdivided into two subtypes: D1-like type with dopamine receptors 1 (Drd1) and 5 (Drd5) and D2-like type with dopamine receptors 2 (Drd2), 3 (Drd3) and 4 (Drd4). One SPN population expresses D1-like receptors, substance P and dynorphin; another SPN population expresses D2-like receptors and enkephalin. Dopamine exerts a modulatory role: signaling via the D1-like receptor type increases short-term excitability and promotes long-term potentiation (LTP); signaling via the D2-like receptor type decreases short-term excitability and promotes long-term depression (LDP). Dopaminergic afferents form triads at glutamatergic synapses to alter synaptic strength. Inputs from target and other brain areas impact on DA release from DA neurons. Two action potential discharge modes are observed: a tonic, low-frequency (1-5/8Hz) mode and a transient, high-frequency (>15Hz) bursting mode. Predictive and expectation cues play important roles in the discharge mode elicited or whether there will be no electrical activity of DA neurons. The slow-transmitting DA underlies its modulatory properties, accounting for its pervasive use across many systems.
The five GPCR DA receptors vary in expression and ligand affinity and the two receptor-types couple to distinct alpha subunits of heterotrimeric G proteins. D1-like receptors signal via Gnal (Golf variant of Gnas, highly expressed in striatum) while the D2-like receptors signal via Galphai (Gnao1 or Gnai2) to promote or inhibit adenylyl cyclase (Adcy5), cAMP production, and PKA signaling, respectively. Drd1 and Drd2 are the most expressed receptors and there are two splice variants of Drd2. Drd2 has a higher affinity for DA than Drd1. A heteromeric D1-D2 receptor signals via Galphaq to promote IP3 and DAG production and stimulate calcium release/signaling and PKC signaling, respectively. Concurrent activation of D1-D2 receptors is necessary for the observed effect. Several other heteromers are reported but D1-D2 is the better characterized one. A major substrate of PKA in the dopamine pathway is PPP1R1B (Darpp-32) phosphatase; phosphorylation of threonine 34 renders it an inhibitor of PP1. PP1 is a prominent member of the phosphoprotein phosphatases (PPPs) superfamily; PP1 targets are thought to include many, if not the majority of serine/threonine phosphorylated proteins, including PKA targets. Ppp1r1b is subject to phosphorylation/dephosphorylation by several other kinases/phosphatases at distinct threonine and serine sites to elicit a range of responses. For instance, phosphorylation of threonine 75 by Cdk5 results in inhibition of PKA while phosphorylation of several serine residues by casein kinase 1 or 2 promotes T34 phosphorylation, nuclear import or diminishes dephosphorylation by calcineurin. Calcineurin and PP2A phosphatases are involved in Ppp1r1b dephosphorylation. Ppp1r1b is equally present in D-1 and D-2 expressing neuronal populations but is differentially regulated. Phosphorylation of Ptpn5 (known as striatal-enriched protein phosphatase, Step) by Pp1 is required for its activity. Activated Ptpn5 dephosphorylates Erk1/2 and inhibits this signaling cascade; Pp1 inactivation relieves the inhibition. Other important elements are RGS proteins (regulators of G protein signaling), GRK kinases (G protein-coupled receptor kinase) and beta-arrestins. RGSs prompt GTP hydrolysis of GTP-bound G alpha subunits thus terminating their activity. GRKs phosphorylate the receptors which are then recognized by beta-arrestins (Arrb1 and 2), precluding the interaction of receptors with the G alpha subunit and triggering receptor internalization. In addition, beta-arrestins can fulfill signaling roles independent of G protein-mediated routes. Arrb2 in complex with Drd2 and phosphoprotein phosphatase 2 promotes inactivation of PI3K/Akt signaling and activation of glycogen synthase kinases whose phosphorylation by Akt is inhibitory. The nigrostriatal, mesolimbic and mesocortical DA systems are presented in more detail below.
Nigrostriatal system
In the nigrostriatal system, the GABAergic striatal spiny projection neurons (SPNs) in the dorsal striatum/caudate-putamen receive excitatory glutamatergic inputs from the cortex and thalamus and modulatory DA inputs from SNc. The D1-expressing SPN population projects directly to BG output nuclei in the substantia nigra pars reticulata (SNr)/globus pallidus internal (GPi) - the direct pathway (dSPN); the D2-expressing SPN population projects indirectly to the SNr - the indirect pathway (iSPN). The GABAergic SNr neurons project to the cortex via the thalamus. Activation of dSPN suppresses SNr GABAergic inhibition of glutamatergic thalamic neurons projecting to the cortex, thus promoting action selection - the 'go' pathway. The iSPN has the opposite effect: via two intermediate relays - the GABAergic neurons in the globus pallidus external (GPe) and the glutamatergic neurons in the subthalamic nucleus (STN), it activates the SNr neurons resulting in inhibition of thalamic input to the cortex and suppression of action selection - the 'no-go' pathway. Dopamine modulates these responses: signaling via the D1-like receptor type increases short-term excitability and promotes long-term potentiation (LTP); signaling via the D2-like receptor type decreases short-term excitability and promotes long-term depression (LDP). The bi-directional modulation of these neuronal populations by dopamine regulates choices and is thought to also shape future decisions and behaviors. The DA innervation of the dorsal striatum is lost in Parkinson disease (PD) as the projecting SNc DA neurons are selectively lost in affected individuals. The classical model posits that hypo-activity in dSPN and hyper-activity in iSPN converge in disinhibition of BG output and suppression of movement. In Huntington's disease (HD), another neurodegenerative condition associated with movement disorder, the SPNs in the caudate-putamen nuclei are prone to degeneration, particularly those in the indirect pathway; other areas are also affected and undergo a size reduction.
Mesolimbic system
In the mesolimbic system, the nucleus accumbers (NAc) receives excitatory inputs from the cortical areas and prefrontal cortex (PFC) and modulatory DA inputs from the VTA. The NAc projects to the ventral pallidum (VP) BG output nuclei as well as the VTA and the SNr to promote motivation and social behavior, reward and aversive learning. The system is implicated in addiction and plays possible roles in schizophrenia. Like the dorsal striatum SPNs, the GABAergic SPNs in the NAc have two populations of neurons expressing the D1-like or the D2-like DA receptors. However, unlike the dorsal striatum, there are not segregated 'dSNP' and 'iSNP' projection routes; D1-like and D2-like expressing SNPs in the NAc target the VP. A smaller, third population of neurons expressing both receptor types is mostly present in the NAc shell; the NAc is composed of a core and a shell subdivision. SNPs expressing D1-like receptors project to the VP, VTA and SNr; those expressing D2-like receptors project to the VP. VP output nuclei project to target thalamic nuclei whose glutamatergic neurons project to cortical areas. Activation of the D1 receptor is thought to mediate reward while inactivation of the D2-like receptor suppresses aversive responses.
Mesocortical system
The prefrontal cortex (PFC) receives DA inputs from the VTA and the SNc in primates and from the VTA in rodents. DA modulates PFC function via the two receptor types of which D1 (a D1-like) and D4 (a D2-like) receptors are primarily expressed in PFC neurons, and the D1 receptor may the most abundant one. Receptors are found in excitatory pyramidal neurons and inhibitory interneurons of the PFC. PFC neurons project back to the VTA, specifically the VTA regions from which they receive DA afferents, and they also project to the NAc (see the mesolimbic system above). The PFC is considered the center of executive functions such as working memory, selective attention, cognitive flexibility and associative learning. The PFC responds to both rewarding and aversive cues; as in other systems, dopamine exerts a modulatory role.
