Dopamine D3 receptor gene variation: impact on electroconvulsive therapy response and ventral striatum responsiveness in depression

Abstract

Dysfunction of dopamine D₃ receptors, particularly in the mesocorticolimbic system, has been linked to the pathogenesis of major depression. Preclinical data show enhanced D₃ receptor binding in the striatum upon antidepressant medication and electroconvulsive therapy (ECT). Thus, the potential impact of dopamine D₃ receptor gene (DRD3) variation on ECT outcome in treatment-resistant major depression was evaluated by applying a combined molecular and imaging genetic approach. Altogether, 10 representative variants covering 95.4% of DRD3 gene variation were investigated for association with response to ECT in a sample of 104 (71 female, 33 male) Caucasian patients with pharmacorefractory major depression. Additionally, ventral striatum responsiveness to happy faces was assessed in two independent samples of depressed patients (total N=54) by means of functional magnetic resonance imaging at 3 T. Significant association of DRD3 rs3732790, rs3773679 and rs9817063 variants with response (uncorrected p=0.02-0.03) and remission (uncorrected p=0.01) after ECT was discerned. Logistic regression analyses revealed association of rs3732790 (uncorrected p=0.009; corrected p=0.045) and rs3773679 (uncorrected p=0.009; corrected p=0.045) with remission when applying a recessive model of inheritance. The rs3732790T allele conferring a more favourable treatment response was furthermore found to be associated with stronger striatal responsiveness to happy facial expressions (sample 1: cluster-corrected p=0.002; sample 2: p=0.023). In summary, the present study suggests some impact of DRD3 gene variation on ECT response, potentially mediated by alteration of striatal engagement during the processing of emotionally rewarding stimuli.

The Dopamine D2 Receptor Polymorphism (DRD2 TaqIA) Interacts with Maternal Parenting in Predicting Early Adolescent Depressive Symptoms: Evidence of Differential Susceptibility and Age Differences

“…Research has consistently demonstrated that depressive symptoms are often induced by impaired functioning of the dopaminergic system, particularly dopamine receptors (e.g., Dannlowski et al 2013;Kapur and Mann 1992). The dopamine D2 receptor gene (DRD2), located on chromosome 11 q2.2-2.3, is responsible for encoding of the D2 subtype of the dopamine receptor.…”

Association between genetic variants related to glutamatergic, dopaminergic and neurodevelopment pathways and white matter microstructure in child and adolescent patients with obsessive–compulsive disorder

“…Interestingly, two other polymorphisms located in the same genes (SLC6A3 rs4975646 and DRD3 rs3773679) were significantly associated (after Bonferroni correction) with WM microstructure in our OCD sample, and a further three polymorphisms (SLC6A3 rs1048953, DRD3 rs2087017 and DRD3 rs167771) also showed non-significant trends (p r0.0028; data not shown). Although these polymorphisms have not previously been related to OCD, some of them have been associated with the pathophysiology or pharmacological treatment of other psychiatric disorders (Dannlowski et al, 2013, De Krom et al, 2009Gassó et al, 2009). Clinical evidence and molecular imaging studies support the involvement of dopamine in OCD.…”

Role of Nicotine Dependence in the Association between the Dopamine Receptor Gene DRD3 and Major Depressive Disorder

“…It is plausible that the scarcity of association findings for DRD3 and for the other dopamine receptor genes is partly due to complexity of the underlying mechanisms and inability to capture the signal when investigating one phenotype at a time. To date, single studies have identified specific DRD3 variants associating with FTND defined ND [46], heaviness of smoking index, and time to first cigarette in the morning [11], as well as treatment response and remission in depression patients [47].…”