Pavlovian Conditioned Stimulus Research Articles

Adolescent alcohol exposure persistently alters orbitofrontal cortical encoding of Pavlovian conditional stimulus components in female rats

Exposure to alcohol during adolescence impacts cortical and limbic brain regions undergoing maturation. In rodent models, long-term effects on behavior and neurophysiology have been described after adolescent intermittent ethanol (AIE), especially in males. We hypothesized that AIE in female rats increases conditional approach to a reward-predictive cue and corresponding neuronal activity in the orbitofrontal cortex (OFC) and nucleus accumbens (NAc). We evaluated behavior and neuronal firing after AIE (5 g/kg intragastric) or water (CON) in adult female rats. Both AIE and CON groups expressed a ST phenotype, and AIE marginally increased sign-tracking (ST) and decreased goal-tracking (GT) metrics. NAc neurons exhibited phasic firing patterns to the conditional stimulus (CS), with no differences between groups. In contrast, neuronal firing in the OFC of AIE animals was greater at CS onset and offset than in CON animals. During reward omission, OFC responses to CS offset normalized to CON levels, but enhanced OFC firing to CS onset persisted in AIE. We suggest that the enhanced OFC neural activity observed in AIE rats to the CS could contribute to behavioral inflexibility. Ultimately, AIE persistently impacts the neurocircuitry of reward-motivated behavior in female rats.

The effects of extinction and an explicitly unpaired treatment on the reinforcing properties of a Pavlovian conditioned stimulus

This series of experiments examined the effects of extinction and an explicitly unpaired treatment on the ability of a conditioned stimulus (CS) to function as a reinforcer. Rats were trained to lever press for food, exposed to pairings of a noise CS and food, and, finally, tested for their willingness to lever press for the CS in the absence of the food. Experiment 1 provided a demonstration of conditioned reinforcement (using controls that were only exposed to unpaired presentations of the CS and food) and showed that it was equivalent after one or four sessions of CS-food pairings. Experiments 2 and 3 showed that, after one session of CS-food pairings, repeated presentations of the CS alone reduced its reinforcing properties; but after four sessions of CS-food pairings, repeated presentations of the CS alone had no effect on these properties. Experiment 4 showed that, after four sessions of CS-food pairings, explicitly unpaired presentations of the CS and food completely undermined conditioned reinforcement. Finally, Experiment 5 provided within-experiment evidence that, after four sessions of CS-food pairings, the reinforcing properties of the CS were disrupted by explicitly unpaired presentations of the CS and food but spared by repeated presentations of the CS alone. Together, these findings indicate that the effectiveness of extinction in undermining the reinforcing properties of a CS depends on its level of conditioning; and that, where extinction fails to disrupt these properties, they are successfully undermined by an explicitly unpaired treatment. They are discussed with respect to findings in the literature on Pavlovian-to-instrumental transfer; and the Rescorla-Wagner model, which anticipates that an explicitly unpaired treatment will be more effective than extinction in reversing the effects of conditioning.

Ethanol-paired conditioned stimulus effects on concurrent reinforced responding for ethanol and food.

The influence of Pavlovian Conditioned Stimuli (CS) on ethanol self-administration and choice between ethanol and an alternative are potentially important. Ethanol-paired CS might increase ethanol self-administration, especially when it has been reduced during recovery, though the selectivity of these increases has been questioned. To date, one study examined the effects of an ethanol-paired CS on ethanol choice and found that the CS increased ethanol-responding more than food-responding when both were in extinction. However, it remains unclear whether ethanol-paired CS increase ethanol-choice that is not in extinction. Here, we examine the effects of an ethanol-paired CS on ethanol-choice when both food- and ethanol-responding are reinforced. Sixteen adult male Lewis rats were trained on a concurrent schedule to respond for ethanol on one lever and for food on the other lever. Ethanol was available under an FR 5 schedule, and food was available under an FR schedule that was adjusted for each rat to earn an equal number of food and ethanol deliveries. Then, 2-min light presentations were paired with an RT 25-sec schedule of ethanol delivery for 10 sessions in the absence of both levers. After this, subjects were placed back on the concurrent schedule for one session, then five sessions with the CS being present or absent on each trial of the concurrent schedule occurred. Rats learned to respond on one lever for ethanol and on the other for food and earned similar numbers of ethanol and food deliveries. During Pavlovian Conditioning, the number of head entries into the head-entry detector was higher in the presence of the CS than in its absence. In the test sessions, rats made more ethanol responses in the presence of the CS than in its absence. However, this effect was small and did not increase the amount of ethanol earned. Thus, ethanol-paired CS could increase ethanol-responding under a choice procedure but did not increase ethanol consumption meaningfully under the studied conditions.

What enables "distraction" to reduce delay discounting for pigeons (Columba livia).

In a successive delay-discounting task, a small reward can be obtained immediately but a larger reward can be obtained if one waits. There is evidence that the larger reward can be obtained more easily if one is "distracted" from obtaining the small reward. It is proposed here that a distractor stimulus may function as a Pavlovian conditioned stimulus (sign tracking) because orienting to it may be directly associated with the larger reinforcer. In the present study with pigeons, we examined two successive procedures: (a) a peck to a red light resulted in one pellet of food, and waiting for the red light to turn off resulted in five pellets (Red-Only). (b) If the pigeon pecked a red light, it received one pellet of food, and if it waited for the red light to turn to green, a peck to the green light resulted in five pellets of food (Red-Green). For both groups, on some trials, a concurrent (distractor) stimulus appeared with the red light but responses to it had no programed consequence. Results indicated that the pigeons in both groups waited for the larger reward more often when the distractor was present than when it was absent and that pigeons in the Red-Only group waited longer than those in the Red-Green group. The results are consistent with the hypothesis that the concurrent stimulus served as a conditioned stimulus for the Red-Only group and as a higher order conditioned stimulus for the Red-Green group. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Neurobehavioral Precursors of Compulsive Cocaine Seeking in Dual Frontostriatal Circuits

BackgroundOnly some individuals who use drugs recreationally eventually develop a substance use disorder, characterized in part by the rigid engagement in drug foraging behavior (drug seeking), which is often maintained in the face of adverse consequences (i.e., is compulsive). The neurobehavioral determinants of this individual vulnerability have not been fully elucidated. MethodsUsing a prospective longitudinal study involving 39 male rats, we combined multidimensional characterization of behavioral traits of vulnerability to stimulant use disorder (impulsivity and stickiness) and resilience (sign tracking and sensation seeking/locomotor reactivity to novelty) with magnetic resonance imaging to identify the structural and functional brain correlates of the later emergence of compulsive drug seeking in drug-naïve subjects. We developed a novel behavioral procedure to investigate the individual tendency to persist in drug-seeking behavior in the face of punishment in a drug-free state in subjects with a prolonged history of cocaine seeking under the control of the conditioned reinforcing properties of a drug-paired Pavlovian conditioned stimulus. ResultsIn drug-naïve rats, the tendency to develop compulsive cocaine seeking was characterized by behavioral stickiness–related functional hypoconnectivity between the prefrontal cortex and posterior dorsomedial striatum in combination with impulsivity-related structural alterations in the infralimbic cortex, anterior insula, and nucleus accumbens. ConclusionsThese findings show that the vulnerability to developing compulsive cocaine-seeking behavior stems from preexisting structural or functional changes in two distinct corticostriatal systems that underlie deficits in impulse control and goal-directed behavior.

A laboratory model of canine search vigilance decrement, II: Noncontingent reward and Pavlovian appetitive stimuli.

Detection dogs have demonstrated reduced performance in operational settings when required to search in an environment where few to no target odors are present. This study's purpose was to increase detection dog accuracy using noncontingent reward (NCR) and Pavlovian stimuli associated with reward. Eighteen dogs were randomly spilt into two groups and received four 40-trial sessions in an operational and training context at 90% odor prevalence (baseline). Following baseline, in the operational context (now at 10% odor prevalence), experimental dogs received an NCR schedule consisting of delivering food rewards at the end of 66% of trials. After the NCR Test, dogs returned to baseline. During baseline, the experimental dogs received 10 days of delayed Pavlovian conditioning to a tone. During the test phase, the conditioned stimulus (tone) was presented to experimental dogs on average every two trials for 30 s in the operational context (now at 10% odor prevalence). Overall, NCR showed a nonsignificant trend for increased responding in the experimental group but tended to increase false alerts; therefore, a permutation of an NCR-like reward schedule may maintain search. The Pavlovian conditioned stimulus didn't decrease timeouts or improve accuracy, but a within-session analysis indicated that the dogs were more likely to time out and less likely to false alert when the tone was on than when it was off.

"Distractor" effects in delay discounting of probability by pigeons.

Impulsive behavior can be measured by performance on a successive delay-discounting task, in which a response to a stimulus provides a small reinforcer sooner (SS), but in the absence of a response, a larger reinforcer later (LL). Previous research suggests that the presence of a concurrent "distractor" stimulus, to which responding has no programed consequence, can result in increased LL reinforcers. In the present experiments, we used differences in the probability of reinforcement between SS and LL (rather than magnitude of reinforcement) and tested the hypothesis that the concurrent stimulus may become a Pavlovian conditioned stimulus. For the Red-Only group, a response to the SS stimulus resulted in a reinforcer with a low probability (SS), whereas the absence of a response resulted in a reinforcer with a high probability (LL). For the Red-Green group, (analogous to the more typical simultaneous choice between an SS and LL stimulus) the absence of a response to the SS stimulus replaced the SS stimulus with the LL stimulus and a response to the LL stimulus resulted in the reinforcer. Thus, for the Red-Green group, the concurrent stimulus should have been less effective because responding to the concurrent stimulus was not immediately followed by the reinforcer. In Experiment 1, the concurrent stimulus was a yellow key-light; in Experiment 2, it was a houselight. In both experiments, the concurrent stimulus was effective in increasing the number of LL reinforcers and the effect was larger for the Red-Only group than for the Red-Green group.

The role of the bed nucleus of the stria terminalis in the motivational control of instrumental action.

We review recent studies assessing the role of the bed nucleus of the stria terminalis (BNST) in the motivational control of instrumental conditioning. This evidence suggests that the BNST and central nucleus of the amygdala (CeA) form a circuit that modulates the ventral tegmental area (VTA) input to the nucleus accumbens core (NAc core) to control the influence of Pavlovian cues on instrumental performance. In support of these claims, we found that activity in the oval region of BNST was increased by instrumental conditioning, as indexed by phosphorylated ERK activity (Experiment 1), but that this increase was not due to exposure to the instrumental contingency or to the instrumental outcome per se (Experiment 2). Instead, BNST activity was most significantly incremented in a test conducted when the instrumental outcome was anticipated but not delivered, suggesting a role for BNST in the motivational effects of anticipated outcomes on instrumental performance. To test this claim, we examined the effect of NMDA-induced cell body lesions of the BNST on general Pavlovian-to-instrumental transfer (Experiment 3). These lesions had no effect on instrumental performance or on conditioned responding during Pavlovian conditioning to either an excitory conditioned stimulus (CS) or a neutral CS (CS0) but significantly attenuated the excitatory effect of the Pavlovian CS on instrumental performance. These data are consistent with the claim that the BNST mediates the general excitatory influence of Pavlovian cues on instrumental performance and suggest BNST activity may be central to CeA-BNST modulation of a VTA-NAc core circuit in incentive motivation.

How common is a common error term? The rules that govern associative learning in sensory preconditioning and second-order conditioning.

In standard (first-order) Pavlovian conditioning protocols, pairings of an initially neutral conditioned stimulus (CS) and a biologically significant unconditioned stimulus (US) result in the formation of a CS-US association. The strength of this association is theoretically regulated by prediction error: specifically, the difference between the total level of conditioning supported by the US and the degree to which it is predicted by all stimuli present (i.e., a common error term). In higher-order conditioning protocols (e.g., sensory preconditioning and second-order conditioning), a Pavlovian CS is used to condition responses to other stimuli with which it is paired. At present, it is unknown whether error-correction processes regulate associative learning in higher-order conditioning and, if so, whether these processes are the same as those that regulate formation of a CS-US association in first-order conditioning. Here we review studies that have provided findings relevant to this question: specifically, studies that have examined blocking and/or inhibitory learning in sensory preconditioning and second-order conditioning. These studies show that: (1) animals can form inhibitory associations between relatively neutral sensory stimuli; (2) the learning that occurs in sensory preconditioning and second-order conditioning can be blocked; and, finally, (3) a first-order CS can block conditioning to a second-order CS, and vice versa. The findings are taken to imply that a common error term regulates associative learning in higher-order conditioning, just as it regulates associative learning in first-order conditioning. They are discussed with respect to the nature of the error signal that underlies conditioning and future work that is needed to advance our understanding of the rules that govern different types of learning.

No significant effect of frequent online sexual behaviour on Pavlovian-to-instrumental transfer (PIT): Implications for compulsive sexual behaviour disorder.

Reward based learning is broadly acknowledged to underpin the development and maintenance of addictive behaviour although the mechanism in sexual compulsivity is less understood. Using a Pavlovian-to-Instrumental Transfer (PIT) task we tested whether the motivational aspect of conditioned Pavlovian conditioned stimulus invigorated instrumental responding in relation to specific compatible monetary rewards. Performance on the task was analysed between two groups of males based on Low (N = 38) and High (N = 41) self-report online sexual behaviour (OSB). Psychometric tests including sexual compulsivity scale and behavioural activation/behavioural inhibition (BIS/BAS) were also administered to determine the relationship between OSB and general reward sensitivity. We show clear evidence of acquisition in the Pavlovian and instrumental conditioning phases. Specific transfer effect was greater in the High-OSB group although the difference compared to the Low-OSB group was non-significant. OSB negatively correlated with both BIS and BAS indicative of introversion and low reward sensitivity. OSB positively correlated with sexual compulsivity although it is unclear whether individuals in the High-OSB group considered their behaviour either excessive or problematic. These findings contribute to the ongoing debate regarding the nature of problematic OSB. Fundamental differences in motivational characteristics and mechanism contributing to compulsive behaviour in relation to high-OSB might indicate incompatibility with behavioural addiction models. PIT was not enhanced in high-OSB by appetitive conditioning, although problematic OSB could stem from failure to inhibit actions. Further research should investigate whether aversive conditioning differentially affects responding in high-OSB individuals, potentially explaining perseverant behaviour despite negative consequences.

Neuroscience: Mechanisms for bridging stimuli in Pavlovian trace conditioning in flies

A recent study revealed neural mechanisms underlying visual trace conditioning in flies. To associate visual stimuli with heat punishment, the activity of visual- and heat-processing circuits was extended into the gap between them. Distractors delivered during the gap disrupted learning, raising the question of the cognitive processes at play.

Dysfunction of goal-directed control in patients with depression and nonsuicidal self-injury.

BackgroundNon‐suicidal self‐injury (NSSI) is a common problem associated with dangerous outcomes. Dysfunction of goal‐directed behavioral control may contribute to NSSI. To test this, we used a novel experimental paradigm (Pavlovian‐to‐Instrumental Transfer, PIT) to test whether patients with NSSI utilize Pavlovian conditioned stimuli (CSs) during goal‐directed control of ongoing behavior.MethodsThirty‐five depressed patients with NSSI (D‐NSSI) and thirty‐four healthy controls performed a PIT task. We measured the influence of positive and negative background CSs on instrumental responses for rewards.ResultsThe results showed that D‐NSSI performed significantly lower PIT than controls, and PIT measures were negatively correlated with NSSI frequency. Furthermore, in a subset of patients exhibiting high levels of compulsivity, PIT positively moderated the relationship between compulsivity and NSSI frequency.ConclusionsThese results indicate that D‐NSSI patients have difficulties in using different CSs to control ongoing behavior in a goal‐directed manner, and the dysfunction of goal‐directed control may contribute to NSSI.

Conditioned inhibition of amphetamine sensitization

Repeated intermittent exposure to psychostimulants, such as amphetamine, leads to a progressive enhancement of the drug’s ability to increase both behavioral and brain neurochemical responses. The expression of these enhancements, known as sensitization, can be regulated by Pavlovian conditioned stimuli. Cues that are associated with drug experience can facilitate sensitization so that it only occurs in the presence of these stimuli (context-specific sensitization). In contrast, cues that are explicitly related to the absence of drugs (conditioned inhibitors) can prevent the expression of sensitization. We hypothesized that disrupting conditioned inhibition would enable amphetamine sensitization in new contexts. Using male Sprague Dawley rats and a two-context amphetamine conditioning procedure, we found that extinguishing amphetamine experience in one environment led to the loss of conditioned inhibition in a separate context. Thus, amphetamine-induced sensitized locomotion, as well as both enhanced dopamine and glutamate neurotransmission in the nucleus accumbens, were observed in a context where the drug was never experienced before. A similar loss of contextual control of sensitization was seen after using baclofen/muscimol microinjections to transiently inhibit the medial prefrontal cortex, basolateral amygdala, or ventral subiculum of the hippocampus. In other words, compared to control infusions, these intracranial injections of GABA-receptor agonists were able to block conditioned inhibitors from preventing the expression of sensitized locomotion. Together, these findings reveal the importance of conditioned inhibitors for regulating addiction-like behavior. The results suggest that dopaminergic and glutamatergic brain circuitry controls the context-specific expression of amphetamine sensitization.

Nigrostriatal dopamine signals sequence-specific action-outcome prediction errors

Dopamine has been suggested to encode cue-reward prediction errors during Pavlovian conditioning, signaling discrepancies between actual versus expected reward predicted by the cues.1-5 While this theory has been widely applied to reinforcement learning concerning instrumental actions, whether dopamine represents action-outcome prediction errors and how it controls sequential behavior remain largely unknown. The vast majority of previous studies examining dopamine responses primarily have used discrete reward-predictive stimuli,1-15 whether Pavlovian conditioned stimuli for which no action is required to earn reward or explicit discriminative stimuli that essentially instruct an animal how and when to respond for reward. Here, by training mice to perform optogenetic intracranial self-stimulation, we examined how self-initiated goal-directed behavior influences nigrostriatal dopamine transmission during single and sequential instrumental actions, in behavioral contexts with minimal overt changes in the animal's external environment. We found that dopamine release evoked by direct optogenetic stimulation was dramatically reduced when delivered as the consequence of the animal's own action, relative to non-contingent passive stimulation. This dopamine suppression generalized to food rewards was specific to the reinforced action, was temporally restricted to counteract the expected outcome, and exhibited sequence-selectivity consistent with hierarchical control of sequential behavior. These findings demonstrate that nigrostriatal dopamine signals sequence-specific prediction errors in action-outcome associations, with fundamental implications for reinforcement learning and instrumental behavior in health and disease.

Dissociable dopaminergic and pavlovian influences in goal-trackers and sign-trackers on a model of compulsive checking in OCD

RationaleChecking is a functional behaviour that provides information to guide behaviour. However, in obsessive-compulsive disorder (OCD), checking may escalate to dysfunctional levels. The processes underpinning the transition from functional to dysfunctional checking are unclear but may be associated with individual differences that support the development of maladaptive behaviour. We examined one such predisposition, sign-tracking to a pavlovian conditioned stimulus, which we previously found associated with dysfunctional checking. How sign-tracking interacts with another treatment with emerging translational validity for OCD-like checking, chronic administration of the dopamine D2 receptor agonist quinpirole, is unknown.ObjectivesWe tested how functional and dysfunctional checking in the rat observing response task (ORT) was affected by chronic quinpirole administration in non-autoshaped controls and autoshaped animals classified as sign-trackers or goal-trackers.MethodsSign-trackers or goal-trackers were trained on the ORT before the effects of chronic quinpirole administration on checking were assessed. Subsequently, the effects on checking of different behavioural challenges, including reward omission and the use of unpredictable reinforcement schedules, were tested.ResultsPrior autoshaping increased checking. Sign-trackers and goal-trackers responded differently to quinpirole sensitization, reward omission and reinforcement uncertainty. Sign-trackers showed greater elevations in dysfunctional checking, particularly during uncertainty. By contrast, goal-trackers predominantly increased functional checking responses, possibly in response to reduced discrimination accuracy in the absence of cues signalling which lever was currently active.ConclusionsThe results are discussed in terms of how pavlovian associations influence behaviour that becomes compulsive in OCD and how this may be dependent on striatal dopamine D2 receptors.

The Basolateral Amygdala to Nucleus Accumbens Core Circuit Mediates the Conditioned Reinforcing Effects of Cocaine-Paired Cues on Cocaine Seeking

BackgroundIndividuals addicted to cocaine spend much of their time foraging for the drug. Pavlovian drug-associated conditioned stimuli exert a major influence on the initiation and maintenance of drug seeking often long into abstinence, especially when presented response-contingently, acting as conditioned reinforcers that bridge delays to drug use. The acquisition of cue-controlled cocaine seeking has been shown to depend on functional interactions between the basolateral amygdala (BLA) and the nucleus accumbens core (NAcC). However, the precise neuronal circuits underlying the acquisition of cue-controlled cocaine-seeking behavior have not been elucidated. MethodsHere, we used a projection-specific Cre-dependent DREADD (designer receptor exclusively activated by designer drugs)-mediated causal approach to test the hypothesis that the direct projections from the BLA to the NAcC are required for the acquisition of cue-controlled cocaine-seeking behavior. ResultsIn Sprague Dawley rats with Cre-mediated expression of the inhibitory DREADD hM4D(Gi) in the NAcC-projecting BLA neurons, treatment with clozapine N-oxide, but not vehicle, selectively prevented the impact of cocaine-associated conditioned reinforcers on cocaine seeking under a second-order schedule of reinforcement. This effect was attributable to the chemogenetic inhibition of the NAcC-projecting BLA neurons, as it was reversible, and it was absent in clozapine N-oxide–treated rats expressing an empty control virus. In contrast, chemogenetic inhibition of the anterior insula, which receives collateral projections from NAcC-projecting BLA neurons, was without effect. ConclusionsThese data demonstrate that the acquisition of cue-controlled cocaine seeking that depends on the conditioned reinforcing effects of cocaine cues requires activity in the direct projections from the BLA to the NAcC.

Intact corticostriatal control of goal-directed action in Alcohol Use Disorder: a Pavlovian-to-instrumental transfer and outcome-devaluation study

Deficits in instrumental, goal-directed control, combined with the influence of drug-associated Pavlovian-conditioned stimuli, are thought to influence the development and maintenance of addiction. However, direct evidence has mainly come from animal studies. We sought to establish whether alcohol use disorder (AUD) is characterized by behavioral or neurobiological deficits in (i) the integration of Pavlovian and instrumental values and (ii) goal-directed control; and (iii) whether duration or severity of AUD is associated with such deficits. The influence of cues predicting food rewards on instrumental action was assessed in a Pavlovian-to-instrumental transfer (PIT) test, measuring both specific and general PIT, and goal-directed behavior in an outcome-devaluation test. Brain activity was measured using functional MRI in 38 abstinent individuals with AUD and 22 matched healthy control individuals (HCs). We found significant specific and general PIT and outcome-devaluation effects across groups indicating goal-directed control, mediated by distinct corticostriatal signals, but no significant differences between individuals with AUD and healthy controls. Bayesian analyses provided substantial-to-strong evidence for the absence of group differences for these effects, or any relationship with duration or severity of AUD. These results suggest intact ability to integrate action-outcome associations on specific and general PIT and goal-directed learning in AUD during abstinence.

Recruitment and disruption of ventral pallidal cue encoding during alcohol seeking.

A critical area of inquiry in the neurobiology of alcohol abuse is the mechanism by which cues gain the ability to elicit alcohol use. Previously, we found that cue-evoked activity in rat ventral pallidum robustly encodes the value of sucrose cues trained under both Pavlovian and instrumental contingencies, despite a stronger relationship between cue-evoked activity and behavioral latency after instrumental training (Richard etal., 2018, Elife, 7, e33107). Here, we assessed: (a) ventral pallidal representations of Pavlovian versus instrumental cues trained with alcohol reward, and (b) the impact of non-associative alcohol exposure on ventral pallidal representations of sucrose cues. Decoding of cue identity based on ventral pallidum firing was blunted for the Pavlovian alcohol cue in comparison to both the instrumental cue trained with alcohol and either cue type trained with sucrose. Further, non-associative alcohol exposure had opposing effects on ventral pallidal encoding of sucrose cues trained on instrumental versus Pavlovian associations, enhancing decoding accuracy for an instrumental discriminative stimulus and reducing decoding accuracy for a Pavlovian conditioned stimulus. These findings suggest that alcohol exposure can drive biased engagement of specific reward-related signals in the ventral pallidum.

Pavlovian-To-Instrumental Transfer and Alcohol Consumption in Young Male Social Drinkers: Behavioral, Neural and Polygenic Correlates

In animals and humans, behavior can be influenced by irrelevant stimuli, a phenomenon called Pavlovian-to-instrumental transfer (PIT). In subjects with substance use disorder, PIT is even enhanced with functional activation in the nucleus accumbens (NAcc) and amygdala. While we observed enhanced behavioral and neural PIT effects in alcohol-dependent subjects, we here aimed to determine whether behavioral PIT is enhanced in young men with high-risk compared to low-risk drinking and subsequently related functional activation in an a-priori region of interest encompassing the NAcc and amygdala and related to polygenic risk for alcohol consumption. A representative sample of 18-year old men (n = 1937) was contacted: 445 were screened, 209 assessed: resulting in 191 valid behavioral, 139 imaging and 157 genetic datasets. None of the subjects fulfilled criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-IV-TextRevision (DSM-IV-TR). We measured how instrumental responding for rewards was influenced by background Pavlovian conditioned stimuli predicting action-independent rewards and losses. Behavioral PIT was enhanced in high-compared to low-risk drinkers (b = 0.09, SE = 0.03, z = 2.7, p < 0.009). Across all subjects, we observed PIT-related neural blood oxygen level-dependent (BOLD) signal in the right amygdala (t = 3.25, pSVC = 0.04, x = 26, y = −6, z = −12), but not in NAcc. The strength of the behavioral PIT effect was positively correlated with polygenic risk for alcohol consumption (rs = 0.17, p = 0.032). We conclude that behavioral PIT and polygenic risk for alcohol consumption might be a biomarker for a subclinical phenotype of risky alcohol consumption, even if no drug-related stimulus is present. The association between behavioral PIT effects and the amygdala might point to habitual processes related to out PIT task. In non-dependent young social drinkers, the amygdala rather than the NAcc is activated during PIT; possible different involvement in association with disease trajectory should be investigated in future studies.

Pairing neutral cues with alcohol intoxication: new findings in executive and attention networks.

Alcohol-associated stimuli capture attention, yet drinkers differ in the precise stimuli that become paired with intoxication. Extending our prior work to examine the influence of alcoholism risk factors, we paired abstract visual stimuli with intravenous alcohol delivered covertly and examined brain responses to these Pavlovian-conditioned stimuli in fMRI when subjects were not intoxicated. Sixty healthy drinkers performed task-irrelevant alcohol conditioning that presented geometric shapes as conditioned stimuli. Shapes were paired with a rapidly rising alcohol limb (conditioned stimulus; CS+) using intravenous alcohol infusion targeting a final peak breath alcohol concentration of 0.045g/dL or saline (CS-) infusion at matched rates. On day 2, subjects performed monetary delay discounting outside the scanner to assess delay tolerance and then underwent event-related fMRI while performing the same task with CS+, CS-, and an irrelevant symbol. CS+ elicited stronger activation than CS- in frontoparietal executive/attention and orbitofrontal reward-associated networks. Risk factors including family history, recent drinking, sex, and age of drinking onset did not relate to the [CS+ > CS-] activation. Delay-tolerant choice and [CS+ > CS-] activation in right inferior parietal cortex were positively related. Networks governing executive attention and reward showed enhanced responses to stimuli experimentally paired with intoxication, with the right parietal cortex implicated in both alcohol cue pairing and intertemporal choice. While different from our previous study results in 14 men, we believe this paradigm in a large sample of male and female drinkers offers novel insights into Pavlovian processes less affected by idiosyncratic drug associations.