Uncoupling the dopamine D1-D2 receptor complex exerts antidepressant-like effects

Abstract

We report that coupling between dopamine D1 and D2 receptors was markedly increased in postmortem brain of subjects suffering from major depression. Biochemical analyses revealed that D1 and D2 receptors form heterodimers via a direct protein-protein interaction. Administration of an interfering peptide that disrupts the D1-D2 receptor complex substantially reduced immobility in the forced swim test (FST) without affecting locomotor activity, and decreased escape failures in learned helplessness tests in rats.

Knockout subtraction autoradiography: A novel ex vivo method to detect heteromers finds sparse KOP receptor/DOP receptor heterodimerization in the brain

“…As binding properties (Kd, Bmax) of bremazocine and naltrindole at the MOPr, DOPr, KOPr and their heterodimers differ considerably (Jordan and Devi, 1999), we are confident that these concentrations of radioligand would be adequate to detect heterodimers, should they exist. Although we failed to find evidence for widespread heterodimerisation in normal tissue the potential role for heteromers in mouse models of disease states (Pei et al, 2010), or after chronic drug treatment (Gupta et al, 2010) should be recognized. Indeed using KSA after treatment conditions might be another approach to address the importance of heterodimerisation after disease or chronic treatment intervention.…”

“…More recent studies have focused on conditions that might drive the process of opioid heterodimerisation and evidence has been provided that chronic morphine treatment increases the abundance of heteromers (Gupta et al, 2010), which might be of relevance to the treatment of addiction disorders (Stockton and Devi, 2012). Moreover for other G-protein coupled receptors (e.g dopamine and adenosine) there is evidence that implicates heteromer dysfunction in diseases such as depression (Pei et al, 2010) and schizophrenia (Faron-Górecka et al, 2008). (Harrison and van der Graaf, 2006), including biochemical (co-immunoprecipitation and western blotting), biophysical (fluorescence resonance energy transfer, FRET and bioluminescence resonance energy transfer, BRET) and pharmacological (competitive ligand binding) approaches, only one method in intact physiological tissue has to date been advanced (Gupta et al, 2010).…”

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

“…Using a disrupting peptide in rats, the authors further showed that disruption of the D1-D2 heteromer in the PFC, but not in the NAc or hippocampus, resulted in anti-depressant-like effects in the forced swim test. Similarly, in a learned helplessness paradigm, enhanced association of the D1R and D2R was reported in the PFC and striatum of rats following inescapable foot shock, an effect diminished in the presence of the antidepressant imipramine (Pei et al, 2010). Although the distribution of the D1-D2 heteromer in PFC has not been characterized, approximately 15-25% of the pyramidal neurons in rodent medial PFC coexpress the D1R and D2R (Zhang et al, 2010), implicating these neurons in the antidepressant-like effects of D1-D2 heteromer disruption.…”

“…A potential involvement of the D1-D2 receptor heteromer in depression came to light when it was demonstrated in the postmortem striatum of depressed patients that there was an increased interaction between D1R and D2R (Pei et al, 2010). Using a disrupting peptide in rats, the authors further showed that disruption of the D1-D2 heteromer in the PFC, but not in the NAc or hippocampus, resulted in anti-depressant-like effects in the forced swim test.…”

“…A peptide generated based on these findings from the D1R was found to disrupt the D1-D2 receptor heteromer physically in brain and to inhibit its calcium-mediated signaling pathway with behavioral consequences (Hasbi et al, under review). Another peptide generated from the region of D2LR that is lacking in the D2SR was also reported to disrupt the D1-D2 receptor heteromer and showed antidepressant-like effects in mice (Pei et al, 2010). In the absence of specific antagonists for the heteromers, this disrupting peptide strategy may be very useful in studying the biology of receptor heteromers as well as their link to disease pathophysiologies in animal models.…”