228 As a slow-acting neurotransmitter, or neuromodulator, DA’s synaptic effects unfold over hundreds of milliseconds and may last a minute or more. In contrast, glutamate and GABA, when acting through ionotropic receptors, produce

their corresponding depolarizing and hyperpolarizing postsynaptic effects within a millisecond of binding to their individual receptors, and these effects last only from about a millisecond to a few tens of milliseconds, respectively. DA receptors belong to the A family of seven-transmembrane Inhibitors,research,lifescience,medical receptors and are grouped into two subclasses, d1 and d2, based on their Wee1 inhibitor coupling to G-proteins that either increase (d1-like) or decrease (d2-like) cytoplasmic cyclic adenosine monophosphate (cAMP).229 The d2 subclass includes the d1 and d5 receptors, and the d2 subclass comprises d2, d3, and d4 receptors.229 DA’s synaptic actions are mediated through intracellular signaling Inhibitors,research,lifescience,medical pathways that regulate the phosphorylation of DARPP32 (DA and cAMP-regulated phosphoprotein, molecular weight = 32 kda), which in turn controls the sensitivity of Inhibitors,research,lifescience,medical glutamate and GABA receptors.230 By controlling the particular sites and level of DARPP-32 phosphorylation, DA exerts an indirect but powerful influence over the efficacy of converging synaptic actions of the fast-acting neurotransmitters glutamate

and GABA.231 This control is imposed through DARPP-32′s regulation of the phosphorylation of synaptic receptors for these and other neurotransmitters. Activation of Inhibitors,research,lifescience,medical d1-like receptors leads to increased phosphorylation – and hence increased sensitivity – of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid) and NMDA glutamate receptors as well as GABAA receptors.231 Activation of d2-like receptors leads to the opposite effect: decreased phosphorylation and sensitivity of AMPA, NMDA, and GABAA receptors to their Inhibitors,research,lifescience,medical respective agonists. DARPP-32

is heavily concentrated within the spines of MSNs.232,233 While nigrostriatal DA neurons send topographical projections to restricted foci within the striatum, the striatonigral input, they receive in turn is convergent, arising from much broader segments of the striatum than the circumscribed territories Phosphatidylinositol diacylglycerol-lyase they themselves innervate.234 For example, ventrolateral SNc DA neurons that project selectively to the sensorimotor territory within the putamen receive striatonigral input not only from putamen but from associative (caudate nucleus) and limbic striatum as well.234 This multimodal striatal input may account for the remarkable fact that the activity of midbrain DA neurons appears to encode a secondary reinforcement signal distilled in real time from complex contingencies implicit in a subject’s ongoing behavior.