Michael N. Smolka

Cue-induced activation of the striatum and medial prefrontal cortex is associated with subsequent relapse in abstinent alcoholics

RationaleAnimal experiments have provided evidence that the striatum and medial prefrontal cortex play a predominant role in the acquisition and maintenance of drug-seeking behavior.ObjectivesAlcohol-associated stimuli that were regularly paired with alcohol intake may become conditioned cues and elicit a motivational response that triggers relapse in alcohol-dependent patients.MethodsWe used functional magnetic resonance imaging and visual alcohol-associated and control cues to assess brain activation in ten abstinent alcoholics and control subjects. Patients were followed for 3xa0months, and alcohol intake was recorded.ResultsAlcohol-related versus neutral visual stimuli activated the putamen, anterior cingulate and adjacent medial prefrontal cortex in alcoholics compared with healthy controls. Cue-induced activation of these brain areas was pronounced in the five alcoholics who subsequently relapsed during the observation period. A multiple regression analysis showed that, in alcoholics, the amount of subsequent alcohol intake was associated with the intensity of cue-induced brain activation but not the severity of alcohol craving, amount of previous alcohol intake or duration of abstinence before scanning.ConclusionsThis pilot study showed that cue-induced activation of the anterior cingulate, medial prefrontal cortex and striatum may play a role in the attribution of incentive salience to alcohol-associated stimuli, thus increasing the motivational value and attentional processing of alcohol cues. Functional brain imaging may help to identify a group of alcoholics with an otherwise undetected high risk of relapse.

Association of Low Striatal Dopamine D2 Receptor Availability With Nicotine Dependence Similar to That Seen With Other Drugs of Abuse

OBJECTIVEnAll drugs of abuse induce a phasic dopamine release within the striatum that does not undergo habituation. Prolonged substance consumption impairs the natural function of the mesolimbic dopamine system, as shown by a decrease in the availability of striatal dopamine 2 (D(2)) receptors in patients suffering from cocaine, heroin, amphetamine, and alcohol dependence. However, it is unclear whether similar changes can also be observed in heavy-smoking nicotine-dependent smokers.nnnMETHODnIn vivo D(2)/D(3) receptor availability was determined with [ (18)F]fallypride positron emission tomography in 17 heavy-smoking nicotine-dependent subjects and in 21 age-matched never-smoking comparison subjects. The smokers were scanned twice: first, during a period of usual consumption and second, 24 hours after smoking cessation.nnnRESULTSnIndependent of the withdrawal status, the nicotine-dependent smokers displayed significantly less availability of D(2)/D(3) receptors within the bilateral putamen functionally covering parts of the dorsal striatum, as compared to the never-smoking subjects. Nicotine craving under the consumption condition correlated positively with D(2)/D(3) receptor availability within the ventral striatum but negatively with D(2)/D(3) receptor availability within the anterior cingulate and inferior temporal cortex.nnnCONCLUSIONSnSimilar to other types of substance abuse, nicotine dependence is associated with low availability of dorsal striatal D(2)/D(3) receptors. In contrast to previous findings on abstinent alcohol-dependent patients, nicotine craving seems to be maintained by a region-specific shift in D(2)/D(3) receptor availabilities, with higher availability within the ventral striatum but lower availability within the anterior cingulate and inferior temporal cortex.

Association of a regulatory polymorphism in the promoter region of the monoamine oxidase A gene with antisocial alcoholism

We analyzed a novel functional 30-bp repeat polymorphism in the promoter region of the X-chromosomal monoamine oxidase A gene (MAOA) to test whether length variation of the repeat polymorphism contributes to variation in the individual vulnerability to antisocial behavior and liability to alcohol dependence. The repeat number (3-5) of the MAOA polymorphism was assessed in 488 male subjects of German descent, a sample comprising 185 psychiatrically screened control subjects and 303 alcohol-dependent subjects including 59 alcoholics with antisocial personality disorder. The frequency of the low-activity 3-repeat allele was significantly increased in 59 antisocial alcoholics compared to 185 control subjects (51 vs. 35%; P = 0.031) and to 244 alcoholics without antisocial personality disorder (51 vs. 32%; P = 0.008), respectively. We found no significant difference in the frequency of the 3-repeat allele between 244 alcoholics without an antisocial personality disorder and the control subjects. Our findings suggest that the low-activity 3-repeat allele of the MAOA promoter polymorphism confers increased susceptibility to antisocial behavior rather than alcohol dependence per se in alcohol-dependent males.

Severity of nicotine dependence modulates cue-induced brain activity in regions involved in motor preparation and imagery

RationaleIn nicotine-dependent subjects, cues related to smoking elicit activity in brain regions linked to attention, memory, emotion and motivation. Cue-induced brain activation is associated with self-reported craving but further correlates are widely unknown.ObjectivesThis study was conducted to investigate whether brain activity elicited by smoking cues increases with severity of nicotine dependence and intensity of cue-elicited craving.MethodsTen healthy male smokers whose degree of nicotine dependence ranged from absent to severe were investigated. Visual smoking cues and neutral stimuli were presented in a block design during functional magnetic resonance imaging (fMRI). Using multiple linear regression analysis, the blood oxygen level dependent (BOLD) response to smoking cues was correlated with severity of nicotine dependence assessed with the Fagerström Test of Nicotine Dependence (FTND) and with cue-induced craving.ResultsSignificant positive correlations between the BOLD activity and FTND scores were found in brain areas related to visuospatial attention (anterior cingulate cortex, parietal cortex, parahippocampal gyrus and cuneus) and in regions involved in motor preparation and imagery (primary and premotor cortex, supplementary motor area). Intensity of cue-induced craving was significantly associated with greater BOLD activation in mesocorticolimbic areas engaged in incentive motivation and in brain regions related to episodic memory.ConclusionsOur study suggests that severity of nicotine dependence and intensity of craving are independently associated with cue-induced brain activation in separate neuronal networks. The observed association between severity of dependence and brain activity in regions involved in allocation of attention, motor preparation and imagery might reflect preparation of automated drug taking behavior thereby facilitating cue-induced relapse.

Amygdala Volume Associated With Alcohol Abuse Relapse and Craving

OBJECTIVEnAmygdala volume has been associated with drug craving in cocaine addicts, and amygdala volume reduction is observed in some alcohol-dependent subjects. This study sought an association in alcohol-dependent subjects between volumes of reward-related brain regions, alcohol craving, and the risk of relapse.nnnMETHODnBesides alcohol craving, the authors assessed amygdala, hippocampus, and ventral striatum volumes in 51 alcohol-dependent subjects and 52 age- and education-matched healthy comparison subjects after detoxification. After imaging and clinical assessment, patients were followed for 6 months and alcohol intake was recorded.nnnRESULTSnAlcohol-dependent subjects showed reduced amygdala, hippocampus, and ventral striatum volumes and reported stronger craving in relation to healthy comparison subjects. However, only amygdala volume and craving differentiated between subsequent relapsers and abstainers. A significant decrease of amygdala volume in alcohol-dependent subjects was associated with increased alcohol craving before imaging and an increased alcohol intake during the 6-month follow-up period.nnnCONCLUSIONSnThese findings suggest a relationship between amygdala volume reduction, alcohol craving, and prospective relapse into alcohol consumption.

Gene–gene effects on central processing of aversive stimuli

Emotional reactivity and regulation are fundamental to human behavior. As inter-individual behavioral variation is affected by a multitude of different genes, there is intense interest to investigate gene–gene effects. Functional sequence variation at two genes has been associated with response and resiliency to emotionally unpleasant stimuli. These genes are the catechol-O-methyltransferase gene (COMT Val158Met) and the regulatory region (5-HTTLPR) of the serotonin transporter gene. Recently, it has been proposed that 5-HTT expression is not only affected by the common S/L variant of 5-HTTLPR but also by an A to G substitution. Using functional magnetic resonance imaging, we assessed the effects of COMT Val158Met and both 5-HTT genotypes on brain activation by standardized affective visual stimuli (unpleasant, pleasant, and neutral) in 48 healthy subjects. Based on previous studies, the analysis of genotype effects was restricted to limbic brain areas. To determine allele-dose effects, the number of COMT Met158 alleles (i.e., lower activity of COMT) and the number of 5-HTT low expressing alleles (S and G) was correlated with the blood oxygen level-dependent (BOLD) response to pleasant or unpleasant stimuli compared to neutral stimuli. We observed an additive effect of COMT and both 5-HTT polymorphisms, accounting for 40% of the inter-individual variance in the averaged BOLD response of amygdala, hippocampal and limbic cortical regions elicited by unpleasant stimuli. Effects of 5-HTT and COMT genotypes did not affect brain processing of pleasant stimuli. These data indicate that functional brain imaging may be used to assess the interaction of multiple genes on the function of neuronal networks.

Nicotine Dependence Is Characterized by Disordered Reward Processing in a Network Driving Motivation

BACKGROUNDnDrug addiction is characterized by an unhealthy priority for drug consumption with a compulsive, uncontrolled drug-intake pattern due to a disordered motivational system. However, only some individuals become addicted, whereas others maintain regular but controlled drug use. Whether the transition occurs might depend on how individuals process drug relative to nondrug reward.nnnMETHODSnWe applied functional magnetic resonance imaging to measure mesocorticolimbic activity to stimuli predicting monetary or cigarette reward, together with behavioral assessment of subsequent motivation to obtain the respective reward on a trial-by-trial basis, in 21 nicotine-dependent and 21 nondependent, occasional smokers.nnnRESULTSnOccasional smokers showed increased reactivity of the mesocorticolimbic system to stimuli predicting monetary reward relative to cigarette reward and subsequently spent more effort to obtain money. In the group of dependent smokers, we found equivalent anticipatory activity and subsequent instrumental response rates for both reward types. Additionally, anticipatory mesocorticolimbic activation predicted subsequent motivation to obtain reward.nnnCONCLUSIONSnThis imbalance in the incentive salience of drug relative to nondrug reward-predicting cues, in a network that drives motivation to obtain reward, could represent a central mechanism of drug addiction.

The Effects of Catechol O-methyltransferase Genotype on Brain Activation Elicited by Affective Stimuli and Cognitive Tasks

Catechol-O-methyltransferase (COMT) degrades the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. A functional polymorphism in the COMT gene (val158 met) accounts for a four-fold variation in enzyme activity. The low activity met158 allele has been associated with improved working memory, executive functioning, and attentional control, but also with a higher risk of anxiety-related behaviors. In spite of the strong effect of the COMT genotype on enzyme activity, its effects on behavior are moderate, accounting for only 4% of variance in task performance. Studies of individuals with intermediate phenotypes during activities such as task-dependent brain activation, may more sensitively detect gene effects on the brain. A series of studies using functional magnetic resonance imaging (fMRI) assessed the effects of the COMT val158 met genotype on central processing during working memory, attentional control, and emotional tasks. fMRI revealed a more focused response in the prefrontal cortex (PFC) of met158 allele carriers during a working memory task. A comparable effect during the performance of an attentional control task in the cingulate cortex was also observed. These data indicate that met158 allele load is associated with improved processing efficiency in the PFC and cingulate, which might be due to lower prefrontal dopamine (DA) metabolism, higher DA concentrations, and an increased neuronal signal-to-noise ratio during information processing. During performance of an emotional task, reactivity to unpleasant visual stimuli was positively correlated with the number of met158 alleles in the amygdala, as well as in other limbic and paralimbic nodes. This increased limbic reactivity to unpleasant stimuli might be the underlying cause of the lower emotional resilience against negative mood states observed in individuals with a higher met158 allele load. Thus the met158 allele seems to be beneficial during the performance of working memory and attention-related tasks, whereas the val158 allele appears to be advantageous during the processing of aversive emotional stimuli.

Dopamine in amygdala gates limbic processing of aversive stimuli in humans

Dopamine is released under stress and modulates processing of aversive stimuli. We found that dopamine storage capacity in human amygdala, measured with 6-[18F]fluoro-L-DOPA positron emission tomography, was positively correlated with functional magnetic resonance imaging blood oxygen level–dependent signal changes in amygdala and dorsal anterior cingulate cortex that were evoked by aversive stimuli. Furthermore, functional connectivity between these two regions was inversely related to trait anxiety. Our results suggest that individual dopamine storage capacity in amygdala subserves modulation of emotional processing in amygdala and dorsal cingulate, thereby contributing to individual differences in anxious temperament.

Serotonin Transporter Genotype (5-HTTLPR): Effects of Neutral and Undefined Conditions on Amygdala Activation

BACKGROUNDnA polymorphism of the human serotonin transporter gene (SCL6A4) has been associated with serotonin transporter expression and with processing of aversive stimuli in the amygdala. Functional imaging studies show that during the presentation of aversive versus neutral cues, healthy carriers of the short (s) allele showed stronger amygdala activation than long (l) carriers. However, a recent report suggested that this interaction is driven by amygdala deactivation during presentation of neutral stimuli in s carriers.nnnMETHODSnFunctional MRI was used to assess amygdala activation during the presentation of a fixation cross or affectively aversive or neutral visual stimuli in 29 healthy men.nnnRESULTSnAmygdala activation was increased in s carriers during undefined states such as the presentation of a fixation cross compared with emotionally neutral conditions.nnnCONCLUSIONSnThis finding suggests that s carriers show stronger amygdala reactivity to stimuli and contexts that are relatively uncertain, which we propose are stressful.