Impact of COMT Val158Met‐polymorphism on appetitive conditioning and amygdala/prefrontal effective connectivity

Abstract

Appetitive conditioning is an important mechanism for the development, maintenance, and treatment of psychiatric disorders like substance abuse. Therefore, it is important to identify genetic variations, which impact appetitive conditioning. It has been suggested that the Val(158) Met-polymorphism in the Catechol-O-Methyl-Transferase (COMT) is associated with the alteration of neural processes of appetitive conditioning due to the central role of the dopaminergic system in reward processing. However, no study has so far investigated the relationship between variations in the COMT Val(158) Met-polymorphism and appetitive conditioning. In this fMRI study, an appetitive conditioning paradigm was applied, in which one neutral stimulus (CS+) predicted appetitive stimuli (UCS) while a second neutral stimulus (CS-) was never paired with the UCS. As a main result, we observed a significant association between the COMT Val(158) Met-genotype and appetitive conditioning: skin conductance responses (SCRs) revealed a significant difference between CS+ and CS- in Val/Val-allele carriers but not in the other genotype groups. Val/Val-allele carriers showed increased hemodynamic responses in the amygdala compared with the Met/Met-allele group in the contrast CS+ > CS-. In addition, psychophysiological-interaction analysis revealed increased effective amygdala/ventromedial prefrontal cortex connectivity in Met/Met-allele carriers. The increased amygdala activity points to facilitated appetitive conditioning in Val/Val-allele carriers while the amygdala/prefrontal connectivity results could be regarded as a marker for altered emotion regulation during conditioning, which potentially impacts appetitive learning sensitivity. The SCRs finding indicates a stronger conditioned response in the Val/Val-allele group and dovetails with the neural differences between the groups. These findings contribute to the current research on COMT in emotional processing.

COMT ValMet polymorphism is associated with post-traumatic stress disorder and functional outcome following mild traumatic brain injury

“…The Met 158 substitution reduces COMT enzymatic activity [10,11]. In areas with limited reuptake transporters, i.e., the prefrontal cortex, COMT -mediated inactivation is the principal mechanism of inactivation of dopaminergic signal transmission, and the Met 158 variant is associated with higher catecholamine bioavailability [12–14]. …”

Learned desires

“…In addition, we have shown that differences in learning histories (different reinforcement schedules) can influence conditioned appetitive responses as well: partial reinforcement led to a slower extinction of eating desires and US expectancies and to a less rapid reacquisition of US expectancies. There are several other factors that can potentially alter conditioned appetitive responses -such as certain genetic polymorphisms (Klucken et al, 2015;Klucken et al, 2013), gender (Klucken et al, 2009), and dieting status (Astur et al, 2015). Of note, the current studies have not addressed influences of differential states in explaining individual variability in responding -for example, food deprivation may potentiate conditioned appetitive responses (e.g., through elevated ghrelin levels; Astur et al, 2014;St-Onge, Watts, & Abizaid, 2016; see also Robinson & Berridge, 2013), as might selective restriction of e.g.…”

“…Skin conductance is thought to provide a nonspecific measure for arousal. It is heightened during food cue exposure (Nederkoorn et al, 2000) and to newly conditioned stimuli predictive for rewarding (e.g., drugs, sexual images), aversive (e.g., an electric shock), and relatively neutral outcomes (e.g., vibrotacticle stimulation) (Hamm & Vaitl, 1996;Klucken et al, 2015;Purkis & Lipp, 2001;Winkler et al, 2011). In addition, skin conductance seems very sensitive to US expectancies in fear conditioning (e.g., Sevenster, Beckers, & Kindt, 2012).…”

“…Skin conductance is heightened during exposure to the sight and smell of palatable food and other appetitive substances (e.g., Carter & Tiffany, 2001;Nederkoorn, Smulders, & Jansen, 2000), and it is widely used as a measure of differential responding in fear conditioning studies, in which it may primarily index explicit learning about the CS-US contingencies (Hamm & Weike, 2005). In the appetitive field, several conditioning studies have examined skin conductance, reporting a successful acquisition of conditioned skin conductance responses to reward-associated CSs (e.g., Glautier, Drummond, & Remington, 1994;Klucken et al, 2015; but see Field & Duka, 2001). The USs that were used in these studies rarely involved food intake, however.…”

Neuroticism and extraversion moderate neural responses and effective connectivity during appetitive conditioning

“…After a few pairings, the CS1 may elicit conditioned reactions (CRs) like changes in preference ratings, peripheral-physiological responses (e.g., SCRs), and brain activity [Andreatta and Pauli, 2015;Kirsch et al, 2003;Klucken et al, 2015b;Martin-Soelch et al, 2007]. In appe-titive conditioning paradigms, one formerly neutral stimulus (CS1) is associated with a reward stimulus, while a second neutral stimulus (CS2) predicts the absence of the reward.…”