Psychomotor activation is regulated in striatum via both the direct and indirect pathways. A1AR-D1R and A2AAR-D2R colo-calize as heterodimers on the MSN of the direct and indirect pathways, respectively. Molecular interactions within the complex allow one receptor of the pair to readily affect its counterpart. DR-mediated neurotransmission ultimately promotes behavioral activation, as reflected by increased voluntary locomotor activity. Stimulation of A1AR and A2AAR respectively counteracts D1R- and D2R-mediated neurotransmission, tending to reduce locomotor activity, and antagonism of either of these 2 AR promotes locomotor activity.
For example, selective A1AR antagonists promote D1R agonist-induced motor activation, whereas A1AR agonists attenuate D1R-induced locomotor activation in mice. A1AR activation also reduces the proportion of high-affinity D1R and uncouples D1R from Gs/olf. As with A1AR-D1R interactions, activation of A2AAR reduces the binding affinity of D2R for agonists by direct intramembrane receptor-receptor interactions.
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A1AR and D1R interactions also influence common cytosolic signaling molecules, as exemplified by A1AR-mediated inhibition of D1R-induced activation of AC in rat striatal homogenates. Differential regulation of cAMP production can contribute to mutually inhibitory interactions. When stimulated by endogenous adenosine and dopamine, A1AR and D2R inhibit cAMP production, whereas D1R and A2AAR promote cAMP production, thereby respectively suppressing and promoting PKA-mediated phosphorylation of signaling molecules (extracellular signal-related kinase [ERK] 1, ERK2, and cAMP response element binding protein [CREB]), and NMDA-AMPA glutamate receptors (Figure 5). The subsequent changes in expression of immediate early genes (IEG) and calcium influx modulate neuronal excitability.
Figure 5. Intracellular signaling molecules associated with adenosine and dopamine receptors.
For example, selective A1AR antagonists promote D1R agonist-induced motor activation, whereas A1AR agonists attenuate D1R-induced locomotor activation in mice. A1AR activation also reduces the proportion of high-affinity D1R and uncouples D1R from Gs/olf. As with A1AR-D1R interactions, activation of A2AAR reduces the binding affinity of D2R for agonists by direct intramembrane receptor-receptor interactions.
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A1AR and D1R interactions also influence common cytosolic signaling molecules, as exemplified by A1AR-mediated inhibition of D1R-induced activation of AC in rat striatal homogenates. Differential regulation of cAMP production can contribute to mutually inhibitory interactions. When stimulated by endogenous adenosine and dopamine, A1AR and D2R inhibit cAMP production, whereas D1R and A2AAR promote cAMP production, thereby respectively suppressing and promoting PKA-mediated phosphorylation of signaling molecules (extracellular signal-related kinase [ERK] 1, ERK2, and cAMP response element binding protein [CREB]), and NMDA-AMPA glutamate receptors (Figure 5). The subsequent changes in expression of immediate early genes (IEG) and calcium influx modulate neuronal excitability.
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