Effects of an opioid (proenkephalin) polymorphism on neural response to errors in health and cocaine use disorder

Abstract

Chronic exposure to drugs of abuse perturbs the endogenous opioid system, which plays a critical role in the development and maintenance of addictive disorders. Opioid genetics may therefore play an important modulatory role in the expression of substance use disorders, but these genes have not been extensively characterized, especially in humans. In the current imaging genetics study, we investigated a single nucleotide polymorphism (SNP) of the protein-coding proenkephalin gene (PENK: rs2609997, recently shown to be associated with cannabis dependence) in 55 individuals with cocaine use disorder and 37 healthy controls. Analyses tested for PENK associations with fMRI response to error (during a classical color-word Stroop task) and gray matter volume (voxel-based morphometry) as a function of Diagnosis (cocaine, control). Results revealed whole-brain Diagnosis × PENK interactions on the neural response to errors (fMRI error>correct contrast) in the right putamen, left rostral anterior cingulate cortex/medial orbitofrontal cortex, and right inferior frontal gyrus; there was also a significant Diagnosis × PENK interaction on right inferior frontal gyrus gray matter volume. These interactions were driven by differences between individuals with cocaine use disorders and controls that were accentuated in individuals carrying the higher-risk PENK C-allele. Taken together, the PENK polymorphism – and potentially opioid neurotransmission more generally – modulates functioning and structural integrity of brain regions previously implicated in error-related processing. PENK could potentially render a subgroup of individuals with cocaine use disorder (i.e., C-allele carriers) more sensitive to mistakes or other related challenges; in future studies, these results could contribute to the development of individualized genetics-informed treatments.

A dopamine-induced gene expression signature regulates neuronal function and cocaine response

“…Similarly, others have demonstrated that Penk expression is mediated by cocaine experience in rodents (47), and Penk knockout mice demonstrate reduced motivation to seek a cocaine reward (48). This work may be translationally relevant, as polymorphisms in the Penk gene have previously been implicated in substance use disorder in humans (49). Overall, our results add to the growing body of literature, suggesting that opioid neuropeptide systems affect DA transmission in reward neurocircuitry (50,51) and may play a critical role in psychostimulant abuse.…”

Integrative single-cell characterization of hypothalamus sex-differential and obesity-associated genes and regulatory elements

“…GABAergic neurons showed high expression levels of COL1A1, GRIP2 , and hydroxytryptamine receptor 2c ( HTR2C ), and dopamine receptor D1 ( DRD1 ) ( Fig.2d ). In the GABAergic neuronal population, we also found neurons expressing neuropeptides, such as vasoactive intestinal peptide ( VIP ), proenkephalin ( PENK ) which plays a role in pain perception and response to stress 65 , tachykinin ( TAC1 ) which is a ghrelin target and is involved in energy balance and food intake 66 , and thyrotropin releasing hormone ( TRH ) which stimulates the release of thyroid stimulating hormone ( TSH ) and prolactin from the anterior pituitary 67 ( Extended Data Fig.2d ). Interestingly, we identified two neural progenitor (NP) clusters that showed high expression of neural progenitor gene marker, Vimentin ( VIM ) and stem cell/progenitor marker, transcription factor HES1 ( Fig.2d ).…”

Abnormal response to methylphenidate across multiple fMRI procedures in cocaine use disorder: feasibility study

“…Participants performed three runs of this event-related task, with instructions to press for the ink color of color-words (red, blue, yellow, green) printed in their congruent (e.g., ‘blue’ in blue ink; 94% of trials) or incongruent (e.g., ‘blue’ in red ink; 6% of trials) fonts (Leung et al 2000; Moeller et al 2015; Moeller et al 2014a; Moeller et al 2014b; Moeller et al 2012a). Because of our implicit task baseline of correct events (see fMRI analysis below), the task did not contain a jittered intertrial interval.…”