Dopamine receptor D1 and postsynaptic density gene variants associate with opiate abuse and striatal expression levels

Abstract

Opioid drugs are highly addictive and their abuse has a strong genetic load. Dopamine-glutamate interactions are hypothesized to be important for regulating neural systems central for addiction vulnerability. Balanced dopamine-glutamate interaction is mediated through several functional associations, including a physical link between discs, large homolog 4 (Drosophila) (DLG4, PSD-95) and dopamine receptor 1 (DRD1) within the postsynaptic density to regulate DRD1 trafficking. To address whether genetic associations with heroin abuse exist in relation to dopamine and glutamate and their potential interactions, we evaluated single nucleotide polymorphisms of key genes within these systems in three populations of opiate abusers and controls, totaling 489 individuals from Europe and the USA. Despite significant differences in racial makeup of the separate samples, polymorphisms of DRD1 and DLG4 were found to be associated with opiate abuse. In addition, a strong gene-gene interaction between homer 1 homolog (Drosophila) (HOMER1) and DRD1 was predicted to occur in Caucasian subjects. This interaction was further analyzed by evaluating DRD1 genotype in relation to HOMER1b/c protein expression in postmortem tissue from a subset of Caucasian subjects. DRD1 rs265973 genotype correlated with HOMER1b/c levels in the striatum, but not cortex or amgydala; the correlation was inversed in opiate abusers as compared to controls. Cumulatively, these results support the hypothesis that there may be significant, genetically-influenced interactions between glutamatergic and dopaminergic pathways in opiate abusers.

Regulation and Function of Activity-Dependent Homer in Synaptic Plasticity

“…Multiple genomic studies in patients have revealed associations between single-nucleotide polymorphisms in the human HOMER1 gene with a variety of psychiatric disorders including schizophrenia [128, 129], autism spectrum disorder [130], major depressive disorder [131], suicide attempt [132, 133], cocaine dependence [134], and opiate abuse [135], although these genetic associations are not conclusive, requiring further replication. Meanwhile, functional studies in rodents point toward a major role for Homer1a in pathological processes related to neuropsychiatric disorders [122, 136] and antidepressant action [137, 138], including its induction in limbocorticostriatal circuits; the same circuits responsible for mediating cognitive and emotional functions in humans [139].…”

Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression

“…ISHH was performed on 20-μM coronal cryosections of human or rodent amygdala specimens as previously described (38). The high quality of the postmortem human brain samples suitable for mRNA expression studies is evident in our ability to routinely detect mRNAs of various genes in these samples (21,40,53,54).…”

Single-nucleotide polymorphisms in dopamine receptor D1 are associated with heroin dependence but not impulsive behavior

“…Postmortem analysis revealed the regulatory effects of DRD1 variation on its mRNA expression in the striatum, which were blunted by chronic opioid abuse (Kauer and Malenka, 2007). Our results demonstrate that a genetic change in DRD1 is linked to heroin dependence in humans, and extends the list of variants that may affect the development of heroin dependence (Jacobs et al, 2013;Peng et al, 2013).…”

“…However, few studies have examined the association between the DRD1 gene and opiate addiction. A study by Jacobs et al (2013) found that polymorphisms in the DRD1 gene were associated with opiate addiction, despite significant differences in the racial makeup of individual samples. Another study found that DRD1 gene rs5326 was associated with heroin dependence in African Americans, whereas the association was not significant after correction for multiple testing (Levran et al, 2009).…”