In this three part blog we sill start to look more closely at the genetics of alcoholism, a subject area slightly neglected so far on this blog site.

I have often sat in the rooms of AA and wondered if there are different types of alcoholics. One old timer once said to me there were as many types of alcoholism as there are alcoholics but I disagree with this observation.

I do think there are certain types. In fact the “Doctor’s Opinion” in the Big Book of Alcoholics Anonymous mentions various types, however accurate or inaccurate these categories of alcoholics may be.

Generally I agree with Cloninger who states after much factoral analysis that there are essentially two types of alcoholics.

I think his observations of an alcoholic who is a more anxious type and an alcoholic who is more impulsive, conduct problem-based has been observed very roughly in the many meetings I have sat in over the years.

 Cloninger states there are  two “types” of alcoholics and two  pathways into alcoholism; the “externalising”, Type II alcoholics, usually the offpspring of alcoholics  which implicates lack of inhibition over impulsive behaviours, sensation seeking, risky behaviours and conduct problems and Type I  “internalizing” which is posited as involving affective dysregulation with drinking to medicate anxiety like symptoms – both also posited to be linked to the “warrior” and the “worrier” of the dopamine COMT  gene variants, Val158 and Met158 respectively.

As we shall observe in the next two blogs these gene varients of COMT are linked to emotion regulation – Met carriers are more anxious and do not process emotion as efficiently as Val carriers who are more efficient but more impulsive. Thus their type of emotion processing difficulty appears to result more in impulsive responding, which is as we have seen may be linked to lack of emotion differentiation when labeling emotions, resulting in impulsive decision making.

In simple terms Met leads to a slower more rigid responding and Val a quicker responding marked by lack of inhibition over action and behaviour.

Two different pathways to the same problem of alcohol dependence but useful to observe in terms of treatment specificity.

The role of the COMT gene, implicated in 60% of dopamine metabolism in the PFC, which plays a role in executive function as well as being associated with substance abuse, would be an interesting area to research in terms of genetic vulnerability, particularly as COMT also codes for noradrenaline (NE), another catecholamine involved in PFC and affective regulation. This may be particularly pertinent as COMT has been posited as having alleles responsible for separate functions, cognitive and affective regulation with the COMT Met allele linked to affective dysregulation while the Val allele has been associated with less efficient PFC activation during cognitive control.

The Met allele resulted in elevated startle responses (Armbruster et al. 2011; Montag et al. 2008) and in increased limbic and prefrontal activation in response to negative stimuli in functional magnetic resonance imaging (fMRI) studies (Drabant et al. 2006; Rasch et al. 2010; Smolka et al. 2005; Williams et al. 2010).

A recent meta-analysis on fMRI data concluded that Val allele carriers show advantages in emotional but disadvantages in cognitive paradigms while the opposite pattern applies to Met allele carriers (Mier et al. 2010). This trade-off had been earlier termed the warrior/worrier model (Goldman et al. 2005; Stein et al. 2006).

Those with valine (Val158) alleles have increased greater COMT activity and lower prefrontal extracellular dopamine compared with those with the methionine (Met158) substitution. Val158 alleles may be associated with an advantage in the processing of aversive stimuli (warrior strategy), while Met158 alleles may be associated with an advantage in memory and attention tasks (worrier strategy).

How this latter proposed inhibitory control problems result in impulsivity, sensation-seeking and conduct difficulties that are mediated by family-related factors, including parental substance abuse and chronic early life stress, moderate the relationship between genotype and these observed phenotypes is worthy of investigation and has important consequences for prevention strategies.

COMT Val158Met may confer their risk of alcohol dependence through reduced dopamine receptor sensitivity in the prefrontal cortex (PFC) .

COMT Val158Met also modulates the effect of childhood adverse experiences on the risk of alcohol dependence, which have been shown to reduce dopamine activity in the PFC and other areas.

Citing this study (1) we first we look at how the Met variant (the worrier) is associated with higher rates of alcohol dependence (Tiihonen et al. 1999; Wang et al. 2001) . Notably, Val158Met was recently linked to post-treatment relapse in alcohol-dependent individuals, such that Met carriers were about twice as likely to relapse in the year following treatment as those without the variant (Wojnar et al. 2009).

It is proposed that the Met variant could confer increased risk by way of differential dopamine-modulated reinforcement from acute intoxication, diminished ability to cope with negative emotional states and/or deficits in cognitive flexibility and task switching (Bilder et al. 2004; Oroszi & Goldman 2004; Enoch 2006).

This study (2) suggests that Met carriers display reduced processing efficiency and/or heightened neurobehavioral responses when presented with emotionally evocative stimuli (Enoch 2006; Heinz & Smolka 2006).

Accordingly, associations of the Met variant with alcohol use have been speculated to involve motivational pathways specific to the regulation of negative affect (Bilder et al. 2004; Enoch 2006).

If Met carriers show heightened neurobiological responses to cues signalling negative affect and/or diminished capacity to disengage from negative emotional states, these scenarios could potentially increase the likelihood of alcohol use in the context of negative affect, consistent with the current finding that Met carriers showed stronger associations between implicit coping motives and alcohol consumption.

This all ties in with our idea that emotion not processed effectively leads to distressing states which prompts more “implicit” coping or coping activated by implicit parts of the brain which are those of the dorsal striatum which appears to link distress to more automatic (or compulsive) responding to this distress, more so as the addiction cycle progresses.

TBC

References

1.  Schellekens, A. F., Franke, B., Ellenbroek, B., Cools, A., de Jong, C. A., Buitelaar, J. K., & Verkes, R. J. (2012). Reduced Dopamine Receptor Sensitivity as an Intermediate Phenotype in Alcohol Dependence and the Role of the COMT Val158Met and DRD2 Taq1A Genotypes. Archives of general psychiatry, 69(4), 339.

2. Hendershot, C. S., Lindgren, K. P., Liang, T., & Hutchison, K. E. (2012). COMT and ALDH2 polymorphisms moderate associations of implicit drinking motives with alcohol use. Addiction biology, 17(1), 192-201.