Abstract
The release of dopamine (DA) into target brain areas is considered an essential event for the modulation of many physiological effects. While the anterior cingulate cortex (ACC) has been implicated in pain related behavioral processes, DA modulation of synaptic transmission within the ACC and pain related phenotypes remains unclear. Here we characterized a Crispr/Cas9 mediated somatic knockout of the D1 receptor (D1R) in all neuronal subtypes of the ACC and find reduced mechanical thresholds, without affecting locomotion and anxiety. Further, the D1R high-efficacy agonist SKF 81297 and low efficacy agonist (±)-SKF-38393 inhibit α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) currents in the ACC. Paradoxically, the D1R antagonists SCH-23390 and SCH 33961 when co-applied with D1R agonists produced a robust short-term synergistic depression of AMPAR currents in the ACC, demonstrating an overall inhibitory role for D1R ligands. Overall, our data indicate that absence of D1Rs in the ACC enhanced peripheral sensitivity to mechanical stimuli and D1R activation decreased glutamatergic synaptic transmission in ACC neurons.
Highlights
Dopamine (DA) binds to two classes of G proteincoupled receptor subtypes (GPCRs), classified as D1-like (D1/D5) and D2-like (D2–D4) receptors [1, 2]
In the dark-light emergence test (DLET) as an additional measure of anxiety, we found no significant difference between control and ACC_D1R-KO mice (Fig. 2f)
Excitation of cortical brain regions is consistently observed in animal models of chronic pain [15], and enhanced AMPA R mediated Evoked EPSCs (eEPSCs) responses are one of the established mechanisms for this observed effect [17,18,19,20, 26, 37, 59]
Summary
Dopamine (DA) binds to two classes of G proteincoupled receptor subtypes (GPCRs), classified as D1-like (D1/D5) and D2-like (D2–D4) receptors [1, 2]. Human imaging studies have shown excitation of ACC neurons with noxious stimuli [14] and animals models suggest that the activity of ACC glutamatergic synapses is integral for encoding chronic pain [15, 16] and anxiety [17]. In the ACC, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors (AMPA Rs) mediated excitatory postsynaptic currents (EPSCs) are enhanced in brain slices from animal models of chronic pain [17,18,19,20,21]. The ACC expresses both D1- and D2-like receptors [22, 23], with transcripts of both receptors showing a decrease following nerve injury [24]. It has been shown that the ACC potentiates spinal cord transmission by forming direct facilitating glutamatergic synapses with spinal dorsal horn neurons (SDH), while optogenetic activation of ACC-SDH projecting neurons increased mechanical sensitivity [26]
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