Family history of alcoholism mediates the frontal response to alcoholic drink odors and alcohol in at-risk drinkers

Abstract

Although a family history of alcoholism is the strongest risk factor for developing alcohol dependence, there are few studies of the association between familial alcoholism and the human brain's reward system activity. We used functional magnetic resonance imaging (fMRI) to determine how family history affects the brain's response to subjects' preferred alcoholic drink odors (AO) as compared to appetitive control odors (ApCO). Fourteen non-dependent heavy drinkers (HD) who were family history positive (FHP) participated, as did 12 HD who were family history negative (FHN). Subjects were imaged under both alcohol intoxication and placebo, using intravenous infusion and pharmacokinetic modeling to target a blood alcohol level of 50 mg%. Under placebo, HD-FHP had a larger medial frontal [AO > ApCO] effect than did HD-FHN. Alcohol intoxication dampened this response in the HD-FHP but potentiated it in the HD-FHN. This suggests that a family history of alcoholism and brain exposure to alcohol interact in heavy drinkers to differentially affect how the brain responds to alcohol cues.

Introduction

A family history of alcoholism doubles the odds of developing alcoholism (Hasin et al., 1997, Nurnberger et al., 2004). While environmental influences exert considerable influence in early adolescence, twin studies show an increasingly larger genetic influence by age 18 (Dick, Rose, and Kaprio, 2006), with a family history of alcoholism being a significant factor in the transition from abusive to dependent drinking (Hasin et al., 2001). This familial history also comprises particular neurobiological signatures, as those with a family history of alcoholism are more likely to have smaller electrophysiological responses to salient stimuli (Begleiter and Porjesz, 1999, Polich et al., 1994) and greater beta power in resting EEG (Rangaswamy et al., 2004). More recently, functional magnetic resonance imaging (fMRI) has shown the offspring of alcoholics to have smaller frontal responses to tasks requiring behavioral inhibition (Schweinsburg et al., 2004), a smaller amygdala response when perceiving fearful faces (Glahn et al., 2007), smaller frontal and temporal responses when inferring others' emotional states (Hill et al., 2007), and a larger response in the anterior cingulate and caudate during simulated gambling (Acheson et al., 2009). Bjork et al. (2008) used a monetary incentive task in adolescents with and without a family history of alcoholism (all of whom were healthy), but found no substantial differences between the groups in reward-related activation. While a number of studies have examined the human cerebral response to alcohol-related cues, particularly in alcoholics (e.g., Bragulat et al., 2008, Filbey et al., 2008b, Kareken et al., 2004, Myrick et al., 2008, Tapert et al., 2004, Wrase et al., 2007), very little research shows how familial alcoholism affects the brain response to alcohol-related cues—particularly in at-risk individuals who have yet to become dependent. In the closest study, Tapert et al. (2003) reported as a secondary finding greater frontal responses to pictures of alcoholic drinks in both control and alcohol use disordered teens (both dependent and abusive drinkers) with family histories of alcoholism when compared to those without such a family history.

Animal research suggests that selective breeding for alcohol preference might affect the heavily dopaminergic mesocorticolimbic reward system. For example, rodents selectively bred to prefer alcohol have reduced dopamine in the striatum (see Murphy et al., 2002, Strother et al., 2005) and medial prefrontal cortex (Engleman et al., 2006), but greater striatal dopaminergic responses to alcohol itself (Bustamante et al., 2008; also see Smith and Weiss, 1999, Weiss et al., 1993). In at least one case, alcohol-preferring rats (compared to Wistar rats) showed a greater dopaminergic response in the ventral striatum during alcohol anticipation (Katner et al., 1996). In non-abusive drinkers without a family history of alcoholism there is greater striatal dopamine receptor availability (Volkow et al., 2006), suggesting a potential protective factor.

In this study, we examined how family history affects the brain's response to alcohol's olfactory cues in non-dependent, at-risk heavy drinkers. We also sought to determine how acute alcohol exposure affects the reward system's response to alcohol's conditioned cues by using clamped intravenous (IV) alcohol infusion—a method that prescribes a constant level of brain alcohol exposure throughout functional image acquisition, and avoids the highly variable time courses of breath alcohol concentrations that accompany oral consumption (O'Connor et al., 1998, Plawecki et al., 2007, Ramachandi et al., 2004, Ramchandani et al., 1999). We hypothesized that a family history of alcoholism would be associated with stronger responses to alcoholic drink aromas in the mesocorticolimbic reward system, and that a low-level of steady-state brain exposure to alcohol would potentiate these stimulus-induced responses (Bragulat et al., 2008). Such a potentiation could reflect a possible substrate for priming, when alcohol exposure increases desire to drink (De Wit, 1996, De Wit, 2000). We focused our hypotheses on the ventral tegmental area (VTA) and ventral striatum, and on the medial frontal brain regions to which the VTA and ventral striatum directly project (Chiba et al., 2001, Haber et al., 2006, Williams and Goldman-Rakic, 1998).