Why We Like to Drink: A Functional Magnetic Resonance Imaging Study of the Rewarding and Anxiolytic Effects of Alcohol

“Participants also completed the PANAS before and after the scan.”

“Analyses were conducted using Analysis of Functional Neuroimages software (Cox, 1996).”

“The VS, particularly the NAcc, is critical in the reward system of the brain (Robinson and Berridge, 1993; Koob and Nestler, 1997; Everitt and Wolf, 2002), and lesions in this brain region decrease the rewarding effects of many drugs of abuse (Di Chiara, 2000).”

“Behind only tobacco use and obesity, alcohol use is the third most common lifestyle-related cause of death in the United States (Mokdad et al., 2004).”

“Emotional facial expressions activated higher-order visual areas related to emotion, including lingual and superior temporal gyri as well as the affective division of the anterior cingulate, as has been previously reported in studies exploring the effects of emotional stimuli on brain activation (Devinsky et al., 1995…”

“Where might alcohol recruit circuitry that regulates positive affect leading to euphoria? A critical area of interest is the ventral striatum (VS), which is recruited by reward-predictive stimuli (Knutson et al., 2001; Bjork et al., 2004).”

“Emotional facial expressions activated higher-order visual areas related to emotion, including lingual and superior temporal gyri as well as the affective division of the anterior cingulate, as has been previously reported in studies exploring the effects of emotional stimuli on brain activation (Devinsky et al., 1995…”

“This result is consistent with previous findings that recruitment of these regions is enhanced by emotionally valenced visual stimuli (Vuilleumier, 2005).”

“, 2004), and support Koob’s (1992) hypothesis that all drugs of abuse activate the striatum.”

“The amygdala in particular is critical in an attention allocation circuit that is recruited by stimuli that signal the requirement for an immediate behavioral response, such as fight or flight (LeDoux, 2003; Fitzgerald et al., 2006).”

“Similarly, functional magnetic resonance imaging (fMRI) studies have shown striatal activation in response to drugs of abuse such as cocaine (Breiter et al., 1997) and nicotine (Stein et al., 1998).”

“Why We Like to Drink: A Functional Magnetic Resonance”

“…increase in BOLD signal in the striatum may result from the increased firing rate of dopaminergic neurons secondary to the disinhibitory effect mediated through GABAergic interneurons and a decrease in glutamate-related potassium currents in the ventral tegmental area (Pierce and Kumaresan, 2006).”

“Why We Like to Drink: A Functional Magnetic Resonance”

“Regressors of interest were convolved with a gamma-variate function that modeled a prototypical hemodynamic response before inclusion in the regression model (Cohen, 1997).”

“A variety of primary rewards activate this circuit, including fruit juice and water (Berns et al., 2001; O’Doherty et al., 2002; Pagnoni et al., 2002; McClure et al., 2003), as well as secondary rewards such as praise and money (for review, see Knutson and Cooper, 2005).”

“The VS, particularly the NAcc, is critical in the reward system of the brain (Robinson and Berridge, 1993; Koob and Nestler, 1997; Everitt and Wolf, 2002), and lesions in this brain region decrease the rewarding effects of many drugs of abuse (Di Chiara, 2000).”

“All participants reported both stimulation and sedation effects on the BAES during this session.”

“The VS, particularly the NAcc, is critical in the reward system of the brain (Robinson and Berridge, 1993; Koob and Nestler, 1997; Everitt and Wolf, 2002), and lesions in this brain region decrease the rewarding effects of many drugs of abuse (Di Chiara, 2000).”

“Why We Like to Drink: A Functional Magnetic Resonance”

“The VS, particularly the NAcc, is critical in the reward system of the brain (Robinson and Berridge, 1993; Koob and Nestler, 1997; Everitt and Wolf, 2002), and lesions in this brain region decrease the rewarding effects of many drugs of abuse (Di Chiara, 2000).”

“Where might alcohol recruit circuitry that regulates positive affect leading to euphoria? A critical area of interest is the ventral striatum (VS), which is recruited by reward-predictive stimuli (Knutson et al., 2001; Bjork et al., 2004).”

“Accordingly, the mesocorticolimbic reward circuit is important in the development and maintenance of addiction (Koob et al., 1998).”

“Similarly, functional magnetic resonance imaging (fMRI) studies have shown striatal activation in response to drugs of abuse such as cocaine (Breiter et al., 1997) and nicotine (Stein et al., 1998).”

“A variety of primary rewards activate this circuit, including fruit juice and water (Berns et al., 2001; O’Doherty et al., 2002; Pagnoni et al., 2002; McClure et al., 2003), as well as secondary rewards such as praise and money (for review, see Knutson and Cooper, 2005).”

“The amygdala in particular is critical in an attention allocation circuit that is recruited by stimuli that signal the requirement for an immediate behavioral response, such as fight or flight (LeDoux, 2003; Fitzgerald et al., 2006).”

“A variety of primary rewards activate this circuit, including fruit juice and water (Berns et al., 2001; O’Doherty et al., 2002; Pagnoni et al., 2002; McClure et al., 2003), as well as secondary rewards such as praise and money (for review, see Knutson and Cooper, 2005).”

“A recent review of animal pharmacological MRI suggests that NAcc dopamine release increases local BOLD signal via postsynaptic D1 receptor activation (Knutson and Gibbs, 2007).”

“…depending on factors such as the point on the blood alcohol concentration vs time curve, the individual’s drinking history, and the dose of alcohol consumed (Levenson et al., 1980; Lukas et al., 1986; Turkkan et al., 1988; Giancola and Zeichner, 1997; Conrod et al., 2001; King et al., 2002).”

“Consistent with human self-report, animal studies also suggest that alcohol produces a rewarding as well as an anxiolytic effect (Coop et al., 1990; Blanchard et al., 1993; Spanagel et al., 1995; Da Silva et al., 2005).”

“This method has been used successfully in several studies of the pharmacokinetics and pharmacological effects of alcohol in humans (Kwo et al., 1998; Ramchandani et al., 1999, 2001, 2002; Blekher et al., 2002; Morzorati et al., 2002).”

“…depending on factors such as the point on the blood alcohol concentration vs time curve, the individual’s drinking history, and the dose of alcohol consumed (Levenson et al., 1980; Lukas et al., 1986; Turkkan et al., 1988; Giancola and Zeichner, 1997; Conrod et al., 2001; King et al., 2002).”

“Alcohol intoxication increases the incidence of aggression and social risk taking (Giancola and Zeichner, 1997; Corbin and Fromme, 2002; Giancola et al., 2002), perhaps by disrupting the amygdala-mediated differentiation between threatening and nonthreatening stimuli.”

“…handheld breathalyzer (Drager Safety Diagnostics, Irving, TX), to ensure that the BrACs were within 0.01 g% of the target and to enable minor adjustments to the infusion rates to overcome errors in parameter estimation and experimental variability (Ramchandani et al., 1999; O’Connor et al., 2000).”

“tients (Heinz et al., 2007; Salloum et al., 2007), and between”

“This method has been used successfully in several studies of the pharmacokinetics and pharmacological effects of alcohol in humans (Kwo et al., 1998; Ramchandani et al., 1999, 2001, 2002; Blekher et al., 2002; Morzorati et al., 2002).”

“tients (Heinz et al., 2007; Salloum et al., 2007), and between”

“ism (Glahn et al., 2007), in brain regions involved in the process-”

“…depending on factors such as the point on the blood alcohol concentration vs time curve, the individual’s drinking history, and the dose of alcohol consumed (Levenson et al., 1980; Lukas et al., 1986; Turkkan et al., 1988; Giancola and Zeichner, 1997; Conrod et al., 2001; King et al., 2002).”

“…depending on factors such as the point on the blood alcohol concentration vs time curve, the individual’s drinking history, and the dose of alcohol consumed (Levenson et al., 1980; Lukas et al., 1986; Turkkan et al., 1988; Giancola and Zeichner, 1997; Conrod et al., 2001; King et al., 2002).”

“This method has been used successfully in several studies of the pharmacokinetics and pharmacological effects of alcohol in humans (Kwo et al., 1998; Ramchandani et al., 1999, 2001, 2002; Blekher et al., 2002; Morzorati et al., 2002).”

“Alcohol intoxication increases the incidence of aggression and social risk taking (Giancola and Zeichner, 1997; Corbin and Fromme, 2002; Giancola et al., 2002), perhaps by disrupting the amygdala-mediated differentiation between threatening and nonthreatening stimuli.”

“Although there have not yet been fMRI studies of the action of alcohol on reward circuits, positron emission tomography (PET) studies demonstrate increased striatal glucose metabolism or blood flow in response to alcohol (Wang et al., 2000; Boileau et al., 2003; Schreckenberger et al., 2004).”

“…to experimentally alter emotional states while administering alcohol or measuring alcohol intake (Gabel et al., 1980; Stritzke et al., 1996; Curtin et al., 1998; Schroder and Perrine, 2007), but these studies have not demonstrated a specific anxiolytic interaction between alcohol and…”

“Subjective response to alcohol was measured using the Biphasic Alcohol Effects Scale (BAES) (Martin et al., 1993) and the modified Drug Effects Questionnaire (DEQ), (de Wit and McCracken, 1990), which were given before the beginning of the infusion and every 10 –15 min during the infusion.”

“Consistent with human self-report, animal studies also suggest that alcohol produces a rewarding as well as an anxiolytic effect (Coop et al., 1990; Blanchard et al., 1993; Spanagel et al., 1995; Da Silva et al., 2005).”

“Although there have not yet been fMRI studies of the action of alcohol on reward circuits, positron emission tomography (PET) studies demonstrate increased striatal glucose metabolism or blood flow in response to alcohol (Wang et al., 2000; Boileau et al., 2003; Schreckenberger et al., 2004).”

“This method has been used successfully in several studies of the pharmacokinetics and pharmacological effects of alcohol in humans (Kwo et al., 1998; Ramchandani et al., 1999, 2001, 2002; Blekher et al., 2002; Morzorati et al., 2002).”

“A variety of nonimaging human studies have attempted to experimentally alter emotional states while administering alcohol or measuring alcohol intake (Gabel et al., 1980; Stritzke et al., 1996; Curtin et al., 1998; Schroder and Perrine, 2007), but these studies have not demonstrated a specific anxiolytic interaction b…”

“…depending on factors such as the point on the blood alcohol concentration vs time curve, the individual’s drinking history, and the dose of alcohol consumed (Levenson et al., 1980; Lukas et al., 1986; Turkkan et al., 1988; Giancola and Zeichner, 1997; Conrod et al., 2001; King et al., 2002).”

“Consistent with human self-report, animal studies also suggest that alcohol produces a rewarding as well as an anxiolytic effect (Coop et al., 1990; Blanchard et al., 1993; Spanagel et al., 1995; Da Silva et al., 2005).”

“A variety of nonimaging human studies have attempted to experimentally alter emotional states while administering alcohol or measuring alcohol intake (Gabel et al., 1980; Stritzke et al., 1996; Curtin et al., 1998; Schroder and Perrine, 2007), but these studies have not demonstrated a specific anxiolytic interaction b…”

“Consistent with human self-report, animal studies also suggest that alcohol produces a rewarding as well as an anxiolytic effect (Coop et al., 1990; Blanchard et al., 1993; Spanagel et al., 1995; Da Silva et al., 2005).”

“This method has been used successfully in several studies of the pharmacokinetics and pharmacological effects of alcohol in humans (Kwo et al., 1998; Ramchandani et al., 1999, 2001, 2002; Blekher et al., 2002; Morzorati et al., 2002).”

“…variety of nonimaging human studies have attempted to experimentally alter emotional states while administering alcohol or measuring alcohol intake (Gabel et al., 1980; Stritzke et al., 1996; Curtin et al., 1998; Schroder and Perrine, 2007), but these studies have not demonstrated a specific…”

“…depending on factors such as the point on the blood alcohol concentration vs time curve, the individual’s drinking history, and the dose of alcohol consumed (Levenson et al., 1980; Lukas et al., 1986; Turkkan et al., 1988; Giancola and Zeichner, 1997; Conrod et al., 2001; King et al., 2002).”

“…al., 2000; Elliott et al., 2000; Knutson et al., 2003), as well as primary rewards (e.g., fruit juice) (Berns et al., 2001; McClure et al., 2003), social rewards (acquisition of good reputation; Izuma et al., 2008), and drugs of abuse (Breiter et al., 1997; Gilman et al., 2008; Stein et al., 1998).”

“Alcohol takes effect through promoting the reaction of the GABAA receptor [72] and increasing stimulation to the dopamine and opiate receptor [73,74].”

“2), human studies have demonstrated that alcoholic patients exhibit an increased susceptibility to stress not observed in social drinking controls (Gilman and Hommer, 2008; Gilman et al., 2008; Sinha, 2001).”

“First, the nucleus accumbens and amygdala have been implicated in non-drug reward processing (Blood and Zatorre, 2001; Breiter et al., 2001), as well as with the euphoria associated with the rewarding effects of drugs (Breiter et al., 1997; Gálvez-Buccollini et al., 2008; Gilman et al., 2008).”

“2008) and alcohol (Gilman et al. 2008), also attenuate limbic responses to social threat (Gilman et al.”

“Recent evidence also indicates that alcohol taste cue [Filbey et al., 2008] and intravenous injection of alcohol [Gilman et al., 2008] reliably activate brain reward circuits, specifically, mesocortico-striatal structures such as the PFC and ventral striatum (VS) in healthy social drinkers.”

“…(Wallace et al. , 1996 ). fMRI studies have also linked the pleasurable experience during drug intoxication with subcortical striatal function after acute drug administration across several drug classes (Breiter et al. , 1997 ; Stein et al. , 1998 ; Kufahl et al. , 2005 ; Gilman et al. , 2008 ).”

“Acute alcohol is a potent anxiolytic in both humans and rodents (Gilman et al., 2008; Moonat et al., 2011; Pandey et al., 2008a; Peterson et al., 1990), implicating limbic structures such as the extended amygdala in the response to acute alcohol intoxication.”

“Since converging evidence implicates these limbic regions in incentivemotivational processes in drug reward (Breiter et al., 1997; Gilman et al., 2008; Stein et al., 1998), it is tempting to speculate that acute alcohol primes limbic incentive neurocircuitry while suppressing top-down cognitive…”

“(Gilman et al., 2008).”

“Importantly, the present study differed from Gilman et al. (2008) in a number of respects including that the present study (1) used happy faces as the 'control' for the threat condition rather than neutral faces; (2) included a more clinically-relevant subpopulation, i.e., frequent binge social…”

“The self-medication theory suggests that alcohol and other substances may be used to alleviate symptoms of anxiety (Gilman, 2008; Sher, 2005; Viveros et al., 2005).”

“In these studies, the anxiolytic effects of alcohol are well established (Gilman et al., 2008).”

“Alcohol cues elicit reward responses in the brain (Gilman et al., 2008).”

“…(from non-alcoholic controls) in brain function and organization within both top-down and bottom-up networks that mediate inhibitory control of behavior and appetitive drive toward consummatory behavior (Akine et al. 2007; Gilman et al. 2008; Li et al. 2009; Vollstadt-Klein et al. 2010).”

“Recent fMRI work has correlated ventral striatal activation with ratings of intoxication during intravenous alcohol administration.(62) This suggests that an individual’s subjective feeling of intoxication is modulated by increased neuronal activity in the ventral striatum.”

“Recently, it has been postulated that alcohol’s ability to modulate affect may be mediated by attenuation of threat processing in the amygdala (Gilman et al. 2008, 2011; Sripada et al. 2011).”

“While including both genders is a common practice in MRI studies examining the effects of alcohol on the brain (Gilman et al., 2008; Eijk et al., 2013) there may be a differential effect of gender on the patient group.”

“In addition, it may be criticized that activity in reward regions during the evaluation of stimuli with high personal relevance is rather due to unspecific rewarding effects of the food and alcohol stimuli, than their high personal relevance [Gilman et al., 2008; Goldstone et al., 2009; Porubska et al., 2006].”

“…an allostatic view of the MOR system and opioidmediated reward, which is in line with published papers indicating a progressive loss of ventro-striatal-mediated alcohol reward as detected by functional magnetic resonance imaging (Gilman et al., 2008; Gilman et al., 2012; Spagnolo et al., 2014).”

“Our previous work has used the model-based method to obtain a steady-state BrAC exposure (called the alcohol clamp), and examine various aspects of the pharmacokinetics and pharmacodynamics of alcohol (Blekher et al., 2002; Gilman et al., 2008; Kwo et al., 1998; Morzorati et al., 2002; Neumark et al., 2004; O’Connor e…”

“Despite the yet unknown mechanism underlying this impaired risk perception in zebrafish, we can trace a parallel with the effects of alcohol in humans, since people exposed to alcohol present an impaired ability to discriminate threatening from non-threatening cues [31,32].”

“AS, VR, RM, and DW provided critical revision of the manuscript for intellectual content.”

“This profile resembles those of several other drugs of abuse, including alcohol (Gilman et al., 2008), benzodiazepines (Paulus et al., 2005), and +/-3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) (Bedi et al., 2009).”

“Importantly, the dopamine system is rapidly activated after alcohol administration (Gilman et al., 2008; Williams-Hemby and Porrino, 1997), which increases the firing of DA cell bodies in the VTA (Brodie et al., 1990; Okamoto et al., 2006; McDaid et al., 2008) and regulates of the amount of…”

“For example, participants with acute alcohol administration showed reduced right amygdala (Gilman et al., 2008) or bilateral amygdala activation (Sripada et al.”

“…to negative emotional stimuli (Gilman et al. 2008; Sripada et al. 2011), enhanced striatal response to rewarding stimuli (Filbey et al. 2008; Gilman et al. 2008; Seo et al. 2011) and to risky decisionmaking (Gilman et al. 2012), and impaired episodic memory functioning (Soderlund et al.…”

“As blood alcohol levels rise, neurons of the ventral tegmental area (VTA) in the midbrain are activated and release dopamine into numerous target areas including the nucleus accumbens (NAc) and prefrontal cortex (Carboni et al. 2000; Engleman et al. 2000; Weiss & Porrino 2002; Gilman et al. 2008; Ding et al. 2009; How…”

“These initial features are mediated by both the dopaminergic and opioidergic activity within the ventral striatum (Volkow et al., 2003; Gilman et al., 2008; Mitchell et al., 2012).”

“Work by Gilman and colleagues [29] shows that after consuming alcohol, social drinkers have decreased sensitivity in brain regions involved in detecting threats and increased activity in brain regions involved in reward [29].”

“2013) and insula reactivity (Gilman et al. 2008; Padula et al. 2011) while participants view threatening faces.”

“08% also affected limbic activation to emotional faces (Gilman et al., 2008) and to alcoholic drink odors at |0.”

“Previous studies with acute alcohol administration show that alcohol specifically targets the amygdala and amygdala-OFC connectivity (Gilman et al., 2012; Gilman et al., 2008; Sripada et al., 2011; also see Bjork and Gilman, 2014; Gorka et al., 2013), and chronic alcohol use is associated with degeneration of frontal…”

“It has been demonstrated in experimental animal models as well as in humans that alcohol induces mesolimbic dopamine release (Di Chiara and Imperato, 1988a,b; Weiss et al., 1993; Boileau et al., 2003; Gilman et al., 2008).”

“Acute alcohol exposure has been found to reduce anxiety (a behavioral state that is not directly induced by stimuli) and is also known to impair the behavioral responses to fear inducing stimuli [5, 10, 22].”

“The emotion/ stress pathway and the reward/motivation pathways closely interact, and such interactions are involved in emotional cuerelated drinking motivation.(11,12)”

“As in prior studies (e.g., Gilman et al. 2008; 2012), participants underwent an initial alcohol clamp session outside of the scanner.”

“Alcohol has anxiolytic properties, for example reducing visual and limbic system MRI bold responses to fearful faces (Gilman et al. 2008); however, rapid tolerance also develops to alcohol’s anxiolytic effect (Sakharkar et al. 2011).”

“Inclusion criteria were: (1) ages 21–55 years, (2) current DSM-IV alcohol dependence, (3) no major psychiatric disorders, (4) no current use of illicit substances (other than marijuana), verified by toxicology screening, and (5) no DSM-IV abuse or dependence on any illicit substance (including marijuana) in the past 1…”

“Noteworthy is that alcohol induces a euphoric state, relaxation of the mind, and alleviation of stress-and anxiety-like conditions (Gilman et al. 2008).”

“Neuroimaging studies have shown that oral or i.v. alcohol administration can activate the ventral striatum in humans (Boileau et al., 2003; Gilman et al., 2008; Ramchandani et al., 2011; Urban et al., 2010).”

“One of the strongest positively reinforcing effects of alcohol is induction of euphoria (“high”) and feelings of well being (Gilman et al., 2008).”

“This is echoed in a series of studies in which fearful faces produced blunted amygdala activation following exposure to alcohol (Gilman et al., 2008; Gowin et al., 2016).”

“Scans done under alcohol and placebo were analyzed separately, given alcoholinduced differences in activation observed in this sample and other studies (Gilman et al., 2008; Kareken et al., 2010a).”

“…et al, 2005, 2008a, b; Wilson et al, 2005; McBride et al, 2006; Franklin et al, 2007) and alcohol challenge fMRI studies (Bragulat et al, 2008; Gilman et al, 2008) and for subsequent generation of new hypotheses, we report activation results in other brain regions other than the vSTR that…”

“%) in 15 min and maintain that concentration for 20 min (for further details see Gilman et al. 2008).”

“Specifically, this modified DEQ consisted of five items scored by the subject using a 100 mm visual analog scale: feel drug, like drug, like more drug, feel high and feel intoxicated.”

“Studies using the alcohol clamp that provides a steady-state BrAC exposure profile following IV alcohol (Ramchandani et al., 1999a) have been used in studies by Gilman et al., 2008, Ramchandani et al., 2011, Wetherill et al., 2012, Kerfoot et al., 2013, Vatsalya et al., 2014, to name a few.”

“For example, alcohol increased ventral striatum activity during processing of emotional faces in one study (Gilman et al., 2008), but not another (Padula et al.”

“…preencoding administration of several drugs that dampen amygdalar reactivity to emotional images, including both addictive drugs (e.g., alcohol (Gilman et al. 2008; Knowles and Duka 2004), benzodiazepines (Buchanan et al. 2003; Del-Ben et al. 2010; Kamboj and Curran 2006; Paulus et al. 2005))…”