Dopamine D2 Receptor-Mediated AKT/PKB Signalling: Initiation by the D2S Receptor and Role in Quinpirole-Induced Behavioural Activation

Abstract

The short and long isoforms of the dopamine D2 receptor (D2S and D2L respectively) are highly expressed in the striatum. Functional D2 receptors activate an intracellular signalling pathway that includes a cAMP-independent route involving Akt/GSK3 (glycogen synthase kinase 3). To investigate the Akt/GSK3 response to the seldom-studied D2S receptor, we established a rat D2S receptor-expressing cell line [HEK (human embryonic kidney)-293/rD2S]. We found that in HEK-293/rD2S cells, the D2/D3 agonists bromocriptine and quinpirole significantly induced Akt and GSK3 phosphorylation, as well as ERK1/2 (extracellular-signal-regulated kinase 1/2) activation. The D2S receptor-induced Akt signals were profoundly inhibited by the internalization blockers monodansyl cadaverine and concanavalin A. Activation of the D2S receptor in HEK-293/rD2S cells appeared to trigger Akt/phospho-Akt translocation to the cell membrane. In addition to our cell culture experiments, we studied D2 receptor-dependent Akt in vivo by systemic administration of the D2/D3 agonist quinpirole. The results show that quinpirole evoked Akt-Ser473 phosphorylation in the ventral striatum. Furthermore, intra-accumbens administration of wortmannin, a PI3K (phosphoinositide 3-kinase) inhibitor, significantly suppressed the quinpirole-evoked behavioural activation. Overall, we demonstrate that activation of the dopamine D2S receptor stimulates Akt/GSK3 signalling. In addition, in vivo Akt activity in the ventral striatum appears to play an important role in systemic D2/D3 agonist-induced behavioural activation.

Strength of cholinergic tone dictates the polarity of dopamine D2 receptor modulation of striatal cholinergic interneuron excitability in DYT1 dystonia

“…These ligands have recently been developed and characterized based on the scaffold of the unbiased D2R ligand aripiprazole and they do not elicit any G i/o agonist activity downstream of D2Rs but have partial agonist activity mediated through β-arrestin recruitment (Allen et al, 2011; Chen et al, 2012). Recently, the β-arrestin-biased D2R ligand UNC9994 has been reported to enhance the firing of parvalbumin-positive (PV) fast-spiking interneurons (FSIs) of the prefrontal cortex (PFC), suggesting that D2R-βarrestin agonism drives cortical FSIs excitability (Urs et al, 2016).…”

Potential link between genetic polymorphisms of <em>catechol-O-methyltransferase </em>and dopamine receptors and treatment efficacy of risperidone on schizophrenia

“… 38 Desensitization and internalization of DRD2 might also be subject to regulation of the proportions of Ser311 and Cys311, which could lead to conformational change of DRD2 with the new disulfide bond established. 41 Above all, variants of DRD2 would contribute much to functional differences of patients with schizophrenia in response to treatment. With regard to other subtypes of dopamine receptors, no significant link has been found between the SNPs involved and patients’ responses to risperidone in this study; but it is still unclear whether polymorphisms of DRD1 , DRD3 , and DRD5 participated in risperidone metabolism because just parts of their SNPs were investigated in our study.…”

A dose–response study of separate and combined effects of the serotonin agonist 8-OH-DPAT and the dopamine agonist quinpirole on locomotor sensitization, cross-sensitization, and conditioned activity

“…Accordingly, locomotor sensitization ensues from the relatively selective, and repeated, activation of postsynaptic D2 receptors, raising D2 receptor efficacy (Szumlinski et al, 1997;. The increase in efficacy may stem from the quinpirole sensitization regimen inducing a higher density of dopamine D2-like receptors in the nucleus accumbens , increasing the proportion of dopamine D2 receptors in the high-affinity state (Seeman et al, 2006;Perreault et al, 2007), or altering dopamine second-messenger transduction pathways (Culm et al, 2004;Beaulieu and Gainetdinov, 2011;Chen et al, 2012;Liu et al, 2015). Furthermore, the increase in efficacy could be more indirect and result from neuroplastic changes produced by repeated quinpirole administration, such as morphological alterations in postsynaptic dendritic complexity (Dvorkin et al, 2008;Lalchandani et al, 2013), reduction in prefrontal glutamate neurotransmission (Escobar et al, 2015), or inhibition of neuronal activity in several brain regions (Carpenter et al, 2003;Richards et al, 2005Richards et al, , 2007.…”