Mesocorticolimbic system reactivity to alcohol use-related visual cues as a function of alcohol sensitivity phenotype: A pilot fMRI study.

Low sensitivity (LS) to alcohol is a risk factor for alcohol use disorder (AUD). Compared to peers with high sensitivity (HS), LS individuals drink more, report more problems, and exhibit potentiated alcohol cue reactivity (ACR). Heightened ACR suggests LS confers AUD risk via incentive sensitization, which is thought to take place in the mesocorticolimbic system. This study examined neural ACR in LS and HS individuals. Young adults (N = 32, M age=20.3) were recruited based on the Alcohol Sensitivity Questionnaire (HS: n = 16; LS: n = 16; 9 females/group). Participants completed an event-related fMRI ACR task. Group LS had higher ACR in left ventrolateral prefrontal cortex than group HS. In group LS, ACR in left caudomedial orbitofrontal cortex or left putamen was low at low alcohol use levels and high at heavier or more problematic alcohol use levels, whereas the opposite was true in group HS. Alcohol use level also was associated with the level of ACR in left substantia nigra among males in group LS. Taken together, results suggest elevated mesocorticolimbic ACR among LS individuals, especially those using alcohol at hazardous levels. Future studies with larger samples are warranted to determine the neurobiological loci underlying LS-based amplified ACR and AUD risk.

Correspondence between the alcohol-P3 event-related potential and alcohol reward phenotypes among young adults.

BACKGROUND: Behavioral economic theory suggests that the value of alcohol depends upon elements of the choice context, such that increasing constraints on alternatives (e.g., price) or increasing the benefits of alcohol (e.g., social context) may result in greater likelihood of heavy drinking. The P3 event-related potential elicited by alcohol-related cues, a proposed marker of incentive salience, may be an electrophysiological parallel for behavioral economic alcohol demand. However, these indices have not been connected in prior research, and studies typically do not disaggregate social influences in the context of alcohol cue reactivity. METHOD: The current study recruited heavy drinking young adults (N = 81) who completed measures of alcohol use and alcohol demand, in addition to a 2 (social/nonsocial) × 2 (alcohol/nonalcohol) visual oddball task to elicit the P3. RESULTS: In multilevel models controlling for demographic characteristics, P3 reactivity was greater to alcohol (p < 0.001) and social (p < 0.001) cues than to nonalcohol and nonsocial cues, but without a significant interaction. Higher alcohol consumption (p = 0.02) and lower elasticity of demand (p = 0.01) were associated with greater P3 response to alcohol than nonalcohol cues. CONCLUSIONS: The results highlight a brain-behavior connection that may be an important marker for alcohol reward across units of analysis and may be sensitive to changes in the economic choice contexts that influence the likelihood of alcohol use.

Predictive utility of the P3 event-related potential (ERP) response to alcohol cues for ecologically assessed alcohol craving and use.

Neural measures of alcohol cue incentive salience have been associated with retrospective reports of riskier alcohol use behaviour and subjective response profiles. This study tested whether the P3 event-related potential (ERP) elicited by alcohol-related cues (ACR-P3) can forecast alcohol use and craving during real-world drinking episodes. Participants (N = 262; Mage = 19.53; 56% female) completed a laboratory task in which they viewed images of everyday objects (Neutral), non-alcohol drinks (NonAlc) and alcohol beverages (Alc) while EEG was recorded and then completed a 21-day ecological momentary assessment (EMA) protocol in which they recorded alcohol craving and consumption. Anthropometrics were used to derive estimated blood alcohol concentration (eBAC) throughout drinking episodes. Multilevel modelling indicated positive associations between P3 amplitudes elicited by all stimuli and within-episode alcohol use measures (e.g., eBAC, cumulative drinks). Focal follow-up analyses indicated a positive association between AlcP3 amplitude and eBAC within episodes: Larger AlcP3 was associated with a steeper rise in eBAC. This association was robust to controlling for the association between NonAlcP3 and eBAC. AlcP3 also was positively associated with episode-level measures (e.g., max drinks, max eBAC). There were no associations between any P3 variables and EMA-based craving measures. Thus, individual differences in neural measures of alcohol cue incentive salience appear to predict the speed and intensity of alcohol consumption but not reports of craving during real-world alcohol use episodes.

Sleep and circadian influences on blood alcohol concentration.

STUDY OBJECTIVES: Anecdotally, adults reach higher levels of subjective intoxication on days they are fatigued or sleep-deprived, but sleep is not typically discussed as a predictor of blood alcohol concentration (BAC) in clinical settings. To inform clinical work and future research, this perspective reviews data examining the impact of sleep (process S) and circadian (process C) factors on indicators of BAC in humans and animal models. METHODS: Literature searches of medical and psychological databases were conducted to identify articles that manipulated sleep/circadian factors and reported effects on indicators of alcohol pharmacology (e.g. BAC, alcohol metabolism). RESULTS: Of the 86 full-text articles reviewed, 21 met inclusion criteria. Studies included manipulations of time of day, circadian phase (evidence for process C), and time in bed (evidence for process S). Evidence for time-of-day effects on alcohol pharmacology was most compelling. Studies also provided evidence for circadian phase effects, but failed to find support for time-in-bed effects. Although results were not uniform across studies, most evidence from human and animal models indicates that peak BACs occur toward the beginning of the biological day, with some studies indicating slower alcohol elimination rates at this time. CONCLUSIONS: Circadian factors likely influence alcohol pharmacokinetics, perhaps due to altered elimination of alcohol from the body. This means that individuals may reach higher BACs if they drink during the morning (when, for most people, circadian alerting is low) versus other times of the day. Alcohol prevention and intervention efforts should highlight sleep/circadian health as a potential contributor to alcohol-related harm.

Alcohol craving in the natural environment: Moderating roles of cue exposure, drinking, and alcohol sensitivity.

Effects of cue exposure and alcohol consumption (e.g., priming doses) on craving for alcohol have been examined in largely separate literature, limiting what is known about their potential interaction. Individuals with low alcohol sensitivity, a known risk factor for alcohol use disorder (AUD), exhibit stronger cue-elicited craving than their higher-sensitivity (HS) peers in both laboratory and real-world contexts. Here, underage drinkers (N = 155) completed a 21-day ecological momentary assessment (EMA) protocol in which they recorded exposure to alcohol cues and levels of craving during both nondrinking and postdrinking moments. Multilevel modeling detected a significant interaction of cue exposure and postdrinking status on craving. Cue-induced craving was increased in postdrinking moments compared to nondrinking moments. Contrary to prediction, cue-elicited increase in craving during nondrinking moments was stronger in participants reporting higher sensitivity to alcohol. In the presence of cues, lower sensitivity was robustly related to craving intensity in the postdrinking state but unrelated to craving during nondrinking moments. Craving during drinking episodes in the natural environment is magnified by the presence of alcohol cues, potentially contributing to the maintenance or acceleration of drinking episodes. Moreover, lower-sensitivity drinkers may be particularly susceptible to the combined effects of cue exposure and postdrinking status on alcohol craving. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Acute sensitization of the P3 event-related potential response to beverage images and the risk for alcohol use disorder.

Previous research suggests the amplitude of the P3 event-related potential (ERP) response reflects the incentive value of the eliciting stimulus, and that individuals with trait-like lower sensitivity (LS) to the acute effects of alcohol, a potent risk factor for alcohol use disorder (AUD), tend to show exaggerated P3 ERP responses to alcohol beverage cues (compared to their peers with higher sensitivity; HS). No prior research has examined trajectories of the cue-elicited P3 response across repeated trials of nonreinforced cue presentations. Characterizing these trajectories can be informative as to potential mechanisms linking LS with increased AUD risk. Here, we tested whether individual differences in alcohol sensitivity are associated with different trial-by-trial trajectories of the P3 elicited by alcohol and nonalcohol reward cues (infrequent oddball/target stimuli) using a large sample of emerging adults (M age = 19.53; N = 287; 55% female; 86% White; 90% right-handed) stratified for alcohol sensitivity. Multilevel models adjusted for age, sex, handedness, and alcohol use indicated that: (i) the P3 response to alcohol and nonalcohol reward cues alike sensitized (i.e., increased) across trials; (ii) across the task, the P3 response to alcohol cues was larger for the LS than the HS phenotype; and (iii) the P3 difference score (alcohol - nonalcohol) was larger for the LS than HS phenotype only across the first half of task. Findings suggest that whereas incentive value attribution may be a mechanism for alcohol cue-triggered attentional biases for both LS and HS individuals, LS individuals more consistently over-attribute incentive value to alcohol cues.

Enhanced conditioned "liking" of novel visual cues paired with alcohol or non-alcohol beverage container images among individuals at higher risk for alcohol use disorder.

RATIONALE/OBJECTIVE: This study used an evaluative conditioning (EC) procedure to assess the affective properties of a CS for ingested drug reward in humans. Specifically, the study tested whether the evaluative response ("liking"/"disliking") to an arbitrary visual stimulus ("CS2," e.g., a purple hexagon) could be changed through pairings with an alcohol or non-alcohol beverage cue ("CS1," e.g., a full wine glass, a juice box), which is ostensibly a conditioned visual predictive stimulus for alcohol or non-alcohol liquid reward, respectively. METHODS: Participants (N = 369, 18-23 years, 66% female, 79% white, 21% reporting no alcohol use ever or in the past year) received 24 CS1 pairings with each CS2. CS2 and CS1 evaluations were assessed pre- and post-conditioning. RESULTS: Alcohol and non-alcohol CS2 "liking" correlated with alcohol use. "Liking" of the alcohol but not non-alcohol CS1 also correlated with alcohol use. Alcohol CS1 "liking" also correlated with alcohol and non-alcohol CS2 'liking," whereas non-alcohol CS1 'liking" correlated with non-alcohol but not alcohol CS2 "liking." CONCLUSIONS: Taken together, findings support the idea that drug-related visual stimuli acquire appetitive (hedonic and/or incentive) properties as a function of individual differences in drug use, which entail individual differences in exposure to the conditioning effects of addictive substances like alcohol. Findings also suggest a link between drug use and the propensity to attribute affective/motivational significance to reward-predictive cues in general.

Friend recollections, and a collection of collaborations with Nadia.

In this selective review article, we showcase our collaborations with our colleague, Dr. Nadia Chaudhri. Dr. Chaudhri was an esteemed colleague and researcher who contributed greatly to our understanding of Pavlovian alcohol conditioning. From 2014 to 2019, we collaborated with Nadia. Here, we reflect on our friendship, the work we did together, and the continued impact on the field.

Behavioral response bias and event-related brain potentials implicate elevated incentive salience attribution to alcohol cues in emerging adults with lower sensitivity to alcohol.

AIMS: This study used a behavioral approach-avoidance task including images of alcoholic beverages to test whether low sensitivity to alcohol (LS) is a phenotypical marker of a dispositional propensity to attribute bottom-up incentive value to naturally conditioned alcohol cues. DESIGN, SETTING AND PARTICIPANTS: Experimental study with a measured individual difference variable at a university psychology laboratory in Missouri, MO, USA. Participants were 178 emerging adults (aged 18-20 years) varying in self-reported sensitivity to alcohol's acute effects. MEASUREMENTS: Participants completed the alcohol approach-avoidance task while behavior (response time; RT) and the electroencephalogram (EEG) were recorded. Stimulus-locked event-related potentials (ERPs) provided indices of integrated (top-down and bottom-up) stimulus incentive value (P3 amplitude) and conflict between top-down task demands and bottom-up response propensities (N450 amplitude). FINDINGS: Linear mixed models showed faster RT for 'alcohol-approach' relative to 'alcohol-avoid' trials for lower-sensitivity (LS) [meanD ± standard errorD (MD ± SED ) = 29.51 ± 9.74 ms, t(328) = 3.03, P = 0.003] but not higher-sensitivity (HS) individuals (MD ± SED = 2.27 ± 9.33 ms, t(328) = 0.243, P = 0.808). There was enhanced N450 amplitude (response conflict) for alcohol-avoid relative to alcohol-approach trials for LS participants (MD ± SED = 0.811 ± 0.198 µV, Z = 4.108, P < 0.001) and enhanced N450 amplitude for alcohol-approach relative to alcohol-avoid for HS participants (MD ± SED = 0.419 ± 0.188 µV, Z = 2.235, P = 0.025). There was also enhanced P3 amplitude for alcohol-approach relative to alcohol-avoid for LS (MD ± SED = 0.825 ± 0.204 µV, Z = 4.045, P < 0.001) but not HS (MD ± SED = 0.013 ± 0.194 µV, Z = 0.068, P = 0.946). CONCLUSIONS: Findings from a human laboratory study appear to support the notion that low sensitivity to alcohol indexes a propensity to attribute bottom-up incentive value to naturally conditioned alcohol cues.

Internal consistency and test-retest reliability of the P3 event-related potential (ERP) elicited by alcoholic and non-alcoholic beverage pictures.

Addiction researchers are interested in the ability of neural signals, like the P3 component of the ERP, to index individual differences in liability factors like motivational reactivity to alcohol/drug cues. The reliability of these measures directly impacts their ability to index individual differences, yet little attention has been paid to their psychometric properties. The present study fills this gap by examining within-session internal consistency reliability (ICR) and between-session test-retest reliability (TRR) of the P3 amplitude elicited by images of alcoholic beverages (Alcohol Cue P3) and non-alcoholic drinks (NADrink Cue P3) as well as the difference between them, which isolates alcohol cue-specific reactivity in the P3 (ACR-P3). Analyses drew on data from a large sample of alcohol-experienced emerging adults (session 1 N = 211, 55% female, aged 18-20 yr; session 2 N = 98, 66% female, aged 19-21 yr). Evaluated against domain-general thresholds, ICR was excellent (M ± SD; r= 0.902 ± 0.030) and TRR was fair (r = 0.706 ± 0.020) for Alcohol Cue P3 and NADrink Cue P3, whereas for ACR-P3, ICR and TRR were poor (r = 0.370 ± 0.071; r = 0.201 ± 0.042). These findings indicate that individual differences in the P3 elicited by cues for ingested liquid rewards are highly reliable and substantially stable over 8-10 months. Individual differences in alcohol cue-specific P3 reactivity were less reliable and less stable. The conditions under which alcohol/drug cue-specific reactivity in neural signals is adequately reliable and stable remain to be discovered.

Acute effect of alcohol on working memory updating.

AIMS: To examine the acute effects of alcohol on working memory (WM) updating, including potential variation across the ascending limb (AL) and descending limb (DL) of the blood alcohol concentration (BAC) time-course. DESIGN: A two-session experiment in which participants were randomly assigned to one of three beverage conditions [alcohol (males: 0.80 g/kg; females: 0.72 g/kg), active placebo (0.04 g/kg) or non-alcohol control (tonic)] and one of two BAC limb testing conditions (AL and DL or DL-only) for the second session, yielding a 3 (beverage) × 2 (time-points tested) × 3 (time-point) mixed factorial design with repeated measures on the latter factor. One of the repeated assessments is 'missing by design' in the DL-only condition. SETTING: A psychology laboratory at the University of Missouri campus in Columbia, MO, USA. PARTICIPANTS: Two hundred thirty-one community-dwelling young adults (51% female; aged 21-34 years) recruited from Columbia, MO, USA, tested between 2011 and 2013. MEASUREMENTS: Latent WM updating performance as indexed by shared variance in accuracy on three WM updating tasks (letter memory, keep track, spatial 2-back) at three time-points. FINDINGS: Multi-group modeling of latent WM updating indicated that performance among participants who consumed placebo or control beverages improved during the second session at time-points corresponding to AL (∆ from baseline in latent mean ± standard error (SE) + 0.5 ± 0.01, P < 0.001) and DL (+ 0.08 ± 0.01, P < 0.001). Alcohol consumption did not impair WM updating (∆ from baseline in latent mean ± SE, at AL: + 0.01 ± 0.01, P = 0.56; at DL: + 0.05 ± 0.01, P < 0.001), but attenuated performance improvements (equality of latent means across beverage groups at AL or DL: Δχ2(1)  ≥ 7.53, P < 0.01). CONCLUSIONS: Acute alcohol-induced impairment in working memory updating may be limited, but dampening of practice effects by alcohol could interfere with the completion of novel, unpracticed tasks.

Transfer of incentive salience from a first-order alcohol cue to a novel second-order alcohol cue among individuals at risk for alcohol use disorder: electrophysiological evidence.

BACKGROUND AND AIMS: In susceptible individuals, cues associated with drug use are theorized to take on incentive-motivational properties, including the ability to reinforce higher-order, drug-related associative learning. This study aimed to test this prediction among people varying in risk for alcohol use disorder. DESIGN, SETTING AND PARTICIPANTS: Repeated-measures experiment with a measured individual difference variable at a University psychology laboratory in Missouri, USA. One hundred and six young adults (96 contributed complete data) were pre-selected to represent the upper and lower quartiles of self-reported sensitivity to alcohol's acute effects. MEASUREMENTS: Participants completed a second-order Pavlovian conditioning paradigm in which an initially neutral visual cue (second-order conditional stimulus; CS2 ) predicted onset of an olfactory cue (first-order conditional stimulus; CS1 ). Olfactory cues were isolated from alcoholic beverages, sweets and non-comestible substances, each presumed to have a natural history of first-order conditioning. Event-related potential responses to the CS2 across its conditioning and extinction, and to the CS1 , provided neurophysiological indices of incentive salience (IS). FINDINGS: The IS of the alcohol CS1 was higher among participants low in alcohol sensitivity (LS), relative to their higher-sensitivity (HS) peers. The IS of the CS2 paired with the alcohol CS1 increased across the CS2 conditioning phase among LS but not HS participants. Also, LS (but not HS) individuals also experienced increases in alcohol craving following alcohol CS1 exposure, and this change was correlated with increases in the IS of the CS2 paired with the alcohol CS1 . CONCLUSIONS: Alcoholic beverage odor, a proximal cue for alcohol consumption, appears to reinforce conditioning of neurophysiological responses to a novel cue among low alcohol sensitivity (LS) individuals but not high alcohol sensitivity individuals, providing the first evidence that the LS phenotype may be associated with differences in the conditioned reinforcing properties of alcohol-related cues. These findings support the idea that the LS phenotype may increase alcohol use disorder risk via susceptibility to incentive salience sensitization.

Acute effects of alcohol on error-elicited negative affect during a cognitive control task.

RATIONALE: Alcohol intoxication can dampen negative affective reactions to stressors. Recently, it has been proposed that these acute anxiolytic effects of alcohol may extend to dampening of negative affective reactions to error commission during cognitive control tasks. Nonetheless, empirical verification of this claim is lacking. OBJECTIVES: Test the acute effect of alcohol on negative affective reactions to errors during an effort-demanding cognitive control task. METHODS: Healthy, young adult social drinkers (N = 96 [49 women], 21-36 years old) were randomly assigned to consume alcohol (0.80 g/kg; n = 33 [15 female]), active placebo (0.04 g/kg; n = 33 [18 women]), or a non-alcoholic control beverage (n = 30 [16 women]) before completing the Eriksen flanker task. Corrugator supercilii (Corr) activation, a psychophysiological index of negative affect, was tracked across the task. Two neurophysiological reactions to errors, the error-related negativity (ERN) and the error positivity (Pe), were also measured. RESULTS: Erroneous actions increased Corr activation in the control and (to a lesser extent) placebo groups, but not in the alcohol group. Error-induced Corr activation was coupled to ERN and Pe in the control, but not in the alcohol and placebo groups. Error-induced Corr activation was not coupled to post-error performance adjustments in any group. CONCLUSIONS: The ability of alcohol to dampen error-related negative affect was verified. It was also shown that placebo alone can disrupt coupling of affective and (neuro)cognitive reactions to errors. Although its behavioral relevance remains to be demonstrated, more attention should be paid to the role of affect in action monitoring and cognitive control processes.

Behavioral, neurobiological, and neurochemical mechanisms of ethanol self-administration: A translational review.

Alcohol use disorder has multiple characteristics including excessive ethanol consumption, impaired control over drinking behaviors, craving and withdrawal symptoms, compulsive seeking behaviors, and is considered a chronic condition. Relapse is common. Determining the neurobiological targets of ethanol and the adaptations induced by chronic ethanol exposure is critical to understanding the clinical manifestation of alcohol use disorders, the mechanisms underlying the various features of the disorder, and for informing medication development. In the present review, we discuss ethanol's interactions with a variety of neurotransmitter systems, summarizing findings from preclinical and translational studies to highlight recent progress in the field. We then describe animal models of ethanol self-administration, emphasizing the value, limitations, and validity of commonly used models. Lastly, we summarize the behavioral changes induced by chronic ethanol self-administration, with an emphasis on cue-elicited behavior, the role of ethanol-related memories, and the emergence of habitual ethanol seeking behavior.

Female drinkers are more sensitive than male drinkers to alcohol-induced heart rate increase.

The present study examined the acute effect of alcohol and its cues on autonomic and cardiovascular physiology, as indexed by changes in heart rate (HR), in a relatively large sample of healthy young adult men and women. Participants (27-31 years old, final N = 145) were administered an alcoholic beverage (n = 88; 52 women) or a placebo beverage (n = 57; 35 women) in a simulated bar. Target breath alcohol concentration (BrAC) was .08 g%. HR was recorded while participants were seated alone during an initial baseline assessment in a lab room; seated with others during preparation and administration of 2 beverages in a simulated bar; and seated alone in the lab room at ascending, peak, and descending BrAC. HR increased over time for participants in both beverage groups during beverage preparation. During beverage consumption, HR decreased over time in those who drank placebo whereas HR increased over time in those who drank alcohol, increasing at a faster rate in women compared to men. HR remained elevated at the ascending, peak, and descending limb assessments only in participants who drank alcohol with HR increasing over time at ascending BrAC in the women but not men. Sex differences in HR under alcohol were not explained by sex differences in body mass index, BrAC, recent alcohol use, or subjective stimulation. Our findings suggest that women may be more sensitive to alcohol-induced increases in HR, especially in environments where alcohol cues are abundant. This may have implications for cardiovascular risks associated with alcohol. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Evidence for incentive salience sensitization as a pathway to alcohol use disorder.

The incentive salience sensitization (ISS) theory of addiction holds that addictive behavior stems from the ability of drugs to progressively sensitize the brain circuitry that mediates attribution of incentive salience (IS) to reward-predictive cues and its behavioral manifestations. In this article, we establish the plausibility of ISS as an etiological pathway to alcohol use disorder (AUD). We provide a comprehensive and critical review of evidence for: (1) the ability of alcohol to sensitize the brain circuitry of IS attribution and expression; and (2) attribution of IS to alcohol-predictive cues and its sensitization in humans and non-human animals. We point out gaps in the literature and how these might be addressed. We also highlight how individuals with different alcohol subjective response phenotypes may differ in susceptibility to ISS as a pathway to AUD. Finally, we discuss important implications of this neuropsychological mechanism in AUD for psychological and pharmacological interventions attempting to attenuate alcohol craving and cue reactivity.

Cue-alcohol associative learning in female rats.

The ability of environmental cues to trigger alcohol-seeking behaviors is believed to facilitate problematic alcohol use. We previously showed that the development of this cue-evoked alcohol approach reflects cue-alcohol learning and memory in the adult male rat; however, we do not know whether the same is true for similarly aged female rats. Consequently, adult Long-Evans female rats were allowed to drink unsweetened alcohol in the home cage (Monday, Wednesday, Friday; 24-h two-bottle choice; 5 weeks) and were subsequently split into two experimental groups: Paired and Unpaired. Groups were matched for ingested doses and alcohol bottle preference across the pre-conditioning home cage period. Both groups were trained in conditioning chambers using a Pavlovian procedure. For the Paired group, the chamber houselight was illuminated to signal access to an alcohol sipper. Houselight onset was yoked for the Unpaired group, but access to the alcohol sipper was scheduled to occur only during the intervening periods (in the absence of light). We found that in the Paired, but not Unpaired group, an alcohol approach reaction was conditioned to houselight illumination, and the level of cue-conditioned reactivity predicted drinking behavior within trials. Groups experienced equivalently low but non-negligible blood alcohol concentrations over the course of conditioning sessions. We conclude that cue-triggered alcohol-seeking behavior in adult female rats reflects associative learning about the relationship between alcohol availability and houselight illumination.

Alcohol-associated antecedent stimuli elicit alcohol seeking in non-dependent rats and may activate the insula.

Alcohol self-administration produces brain and behavior adaptations that facilitate a progressive loss of control over drinking and contribute to relapse. One possible adaptation is the ability of antecedent environmental stimuli that are consistently paired with alcohol to trigger alcohol-seeking behaviors. We previously modeled this adaptation in rats using a Pavlovian conditioning procedure in which illumination of a houselight preceded the presentation of a sipper tube that produced unsweetened alcohol when licked. However, in our previous work we did not demonstrate whether this adaptation represented a consequence of repeated exposure to alcohol or the houselight, or whether it was the consequence of associative learning and memory. Thus, in the present study, we tested the associative basis of alcohol seeking in response to houselight illumination in our task using adult male rats that were not food- or water-deprived and were not dependent on alcohol. Separate groups of rats received houselight illumination that was explicitly paired or unpaired with presentation of the retractable sipper that provided access to unsweetened alcohol. Our primary dependent variable was appetitive alcohol-directed behavior: the frequency of movement toward and interaction with the hole in the wall of the chamber through which the sipper was presented during the period of houselight illumination trial before each sipper presentation. However, we also analyzed consummatory sipper licking behavior and blood ethanol concentration in the same rats. Finally, we explored the brain basis of cue-elicited alcohol seeking using c-Fos immunohistochemistry. Our findings confirmed the associative basis of cue-elicited alcohol seeking in our paradigm and mapped these onto the insular cortex, suggesting a role for this brain region in early stages of brain and behavior adaptation to regular alcohol use.

Correction to: Acute phenylalanine/tyrosine depletion of phasic dopamine in the rat brain.

After publication of this paper, the authors determined an error in the calculation of the norepinephrine standard concentrations for the HPLC calibration curves.

Characterizing conditioned reactivity to sequential alcohol-predictive cues in well-trained rats.

Implicit learning about antecedent stimuli and the unconditional stimulus (US) properties of alcohol may facilitate the progressive loss of control over drinking. To model this learning, Cofresí et al. (2017) developed a procedure in which a discrete, visual conditional stimulus (houselight illumination; CS) predicted the availability of a retractable sipper that rats could lick to receive unsweetened alcohol [Alcoholism: Clinical and Experimental Research, 41, 608-617]. Here we investigated the possibility that houselight illumination, sipper presentation, and oral alcohol receipt might each exert control over alcohol seeking and drinking. We also determined the relationship between ingested dose and blood alcohol concentration, in order to validate the idea that the US is a post-ingestive action of alcohol. Finally, we tested a major prediction from the conditioning account of problematic drinking [Tomie, A., & Sharma, N. (2013). Current Drug Abuse Reviews, 6, 201-219], which is that once learned, responses elicited by a CS will promote drinking. We found that despite having constrained opportunities to drink alcohol during the conditioning procedure, ingested doses produced discriminable blood concentrations that supported cue conditioning. Based on our analysis of the dynamics of cue reactivity in well-trained rats, we found that houselight illumination triggered conditioned approach, sipper presentation evoked licking behavior, and alcohol receipt promoted drinking. Reactivity to these cues, which varied in terms of their temporal proximity to the alcohol US, persisted despite progressive intoxication or satiety. Additionally, rats with the greatest conditioned reactivity to the most distal alcohol cue were also the fastest to initiate drinking and drank the most. Our findings indicate that the post-ingestive effects of alcohol may condition multiple cues simultaneously in adult rats, and these multiple cues help to trigger alcohol seeking and drinking. Moreover, identification and characterization of these cues should be helpful for designing interventions that attenuate the power of these cues over behavior.