A physiological role for the dopamine D5 receptor as a regulator of BDNF and Akt signalling in rodent prefrontal cortex

Abstract

The dopamine D5 receptor (D5R) exhibits a wide distribution in prefrontal cortex (PFC) but its role in this region has not yet been elucidated. In the present study we identified a novel physiological function for the D5R as a regulator of BDNF and Akt signalling in PFC. Specifically, acute activation of the D5R by the dopamine agonist SKF 83959 enhanced BDNF expression and signalling through its receptor, TrkB, in rats and in mice gene-deleted for the D1 receptor but not the D5R. These changes were concomitant with increased expression of GAD67, a protein whose downregulation has been implicated in the etiology of schizophrenia. Furthermore, D5R activation increased phosphorylation of Akt at the Ser473 site, consequently decreasing the activity of its substrate GSK-3β. These findings could have wide-reaching implications given evidence showing activation of these pathways in PFC has therapeutic effects in neuropsychiatric disorders such as drug addiction, schizophrenia and depression.

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

“…As a physiologically relevant fraction of MSNs within the NAc and globus pallidus express the D1-D2 receptor heteromer (Perreault et al, 2010), together these findings strongly implicate this receptor complex as being significant to dopamine transmission and should be investigated as a therapeutic target for schizophrenia. Further support for a potential role for the D1-D2 heteromer in schizophrenia comes from a recent finding demonstrating that activation of the D1-D2 receptor heteromer could inactivate glycogen synthase kinase-3b (GSK-3b) in rodent prefrontal cortex (PFC) (Perreault et al, 2013) (Figure 1). In schizophrenia, cortical GSK-3b activation is upregulated (Emamian et al, 2004) and has been implicated as contributing to cognitive dysfunction in the disorder Karam et al, 2010).…”

Neurotrophic factors in women with crack cocaine dependence during early abstinence: the role of early life stress

“…12,13 Their effects on dopaminergic neuronal function in particular may be a critical path for drug addiction because the dopamine (DA) system is a key component of the brain circuitry of motivation and reward. [14][15][16] Preclinical investigations have demonstrated that cocaine administration can increase the levels of BDNF in rodents. 17,18 Furthermore, recent studies have shown a significant increase in BDNF levels over the first days of cocaine abstinence in both preclinical and clinical models, which is most likely due to compensatory mechanisms activated in response to the neurotoxic effects of chronic cocaine exposure.…”

Dopamine D₁-D₂ Receptor Heteromer Regulates Signaling Cascades Involved in Addiction: Potential Relevance to Adolescent Drug Susceptibility

“…In addition, phosphorylation by CaMKII is also involved in the functional regulation of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR) [44], thus contributing to AMPAR-induced changes in synaptic plasticity that mediate the development of addiction [44,45,46]. As D 1 -D 2 heteromer activation has been shown to be associated with changes in the expression and/or activation of BDNF [23,25,31,47], GSK-3 [48] and AMPARs [26] in vivo, the present review will discuss the potential contribution of these signaling cascades in addiction, thus highlighting their possible contribution to adolescent addiction susceptibility and a possible role for the D 1 -D 2 heteromer in regulating addiction processes.…”

“…Phosphorylation of GSK-3β has been shown to occur by numerous mechanisms including direct phosphorylation by protein kinase C [85,86], CaMKII [38] and Akt [87], as well as indirectly via β-arrestin1 [88,89], cyclin-dependent kinase 5 [90], and following activation of tyrosine receptor kinases such as the insulin receptor [87,91] or the BDNF receptor, TrkB [92,93]. Importantly, in recent years dopamine has been shown to be a key mediator in the regulation of GSK-3β activity [48,94,95]. In two distinguished studies by Beaulieu et al [94,95] dopamine was identified to increase the activation of striatal GSK-3α and GSK-3β via a mechanism involving β-arrestin2 signaling, mediated by the D 2 R, and a process that was induced in mice following AMPH administration.…”

“…Using an agonist selective for Gq-coupled dopamine receptors, in combination with mice gene-deleted for the D 1 R or the D 5 R, it was reported that activation of the D 1 -D 2 heteromer resulted in the phosphorylation of Akt and inhibition of GSK-3β in the PFC [48]. In this study activation of the D 5 R, also known to couple to the Gq protein [96,97] as well as Gs, also inhibited GSK-3β, albeit by a different mechanism.…”