Lee Hogarth

The neural basis of drug stimulus processing and craving: an activation likelihood estimation meta-analysis.

BACKGROUND The capacity of drug cues to elicit drug-seeking behavior is believed to play a fundamental role in drug dependence; yet the neurofunctional basis of human drug cue-reactivity is not fully understood. We performed a meta-analysis to identify brain regions that are consistently activated by presentation of drug cues. Studies involving treatment-seeking and nontreatment-seeking substance users were contrasted to determine whether there were consistent differences in the neural response to drug cues between these populations. Finally, to assess the neural basis of craving, consistency across studies in brain regions that show correlated activation with craving was assessed. METHODS Appropriate studies, assessing the effect of drug-related cues or manipulations of drug craving in drug-user populations across the whole brain, were obtained via the PubMed database and literature search. Activation likelihood estimation, a method of quantitative meta-analysis that estimates convergence across experiments by modeling the spatial uncertainty of neuroimaging data, was used to identify consistent regions of activation. RESULTS Cue-related activation was observed in the ventral striatum (across both subgroups), amygdala (in the treatment-seeking subgroup and overall), and orbitofrontal cortex (in the nontreatment-seeking subgroup and overall) but not insula cortex. Although a different pattern of frontal and temporal lobe activation between the subgroups was observed, these differences were not significant. Finally, right amygdala and left middle frontal gyrus activity were positively associated with craving. CONCLUSIONS These results substantiate the key neural substrates underlying reactivity to drug cues and drug craving.

Associative learning mechanisms underpinning the transition from recreational drug use to addiction

Learning theory proposes that drug seeking is a synthesis of multiple controllers. Whereas goal‐directed drug seeking is determined by the anticipated incentive value of the drug, habitual drug seeking is elicited by stimuli that have formed a direct association with the response. Moreover, drug‐paired stimuli can transfer control over separately trained drug seeking responses by retrieving an expectation of the drugs identity (specific transfer) or incentive value (general transfer). This review covers outcome devaluation and transfer of stimulus‐control procedures in humans and animals, which isolate the differential governance of drug seeking by these four controllers following various degrees of contingent and noncontingent drug exposure. The neural mechanisms underpinning these four controllers are also reviewed. These studies suggest that although initial drug seeking is goal‐directed, chronic drug exposure confers a progressive loss of control over action selection by specific outcome representations (impaired outcome devaluation and specific transfer), and a concomitant increase in control over action selection by antecedent stimuli (enhanced habit and general transfer). The prefrontal cortex and mediodorsal thalamus may play a role in this drug‐induced transition to behavioral autonomy.

Parallel goal-directed and habitual control of human drug-seeking: implications for dependence vulnerability.

Dual-process theories of learning and addiction propose that whereas freely elected drug/reward-seeking is goal-directed in being mediated by the expected value of the outcome, cue-elicited drug/reward-seeking is habitual in being elicited directly by antecedent stimuli, without retrieving a representation of outcome value. To substantiate this claim, the current study conducted a human devaluation-transfer procedure in which young adult smokers were first trained on a concurrent choice task to earn tobacco and chocolate points before one outcome was devalued by specific satiety or health warnings against consumption of that outcome. When choice was again tested in extinction, the selective reduction in performance of the action associated with the devalued outcome indicated that choice was controlled by an expectation of outcome value, that is, was goal-directed. Moreover, the presentation of tobacco and chocolate cues enhanced selection of the response associated with that outcome, indicating that transfer was also mediated by the retrieval of the outcome representation. Paradoxically, however, the magnitude of this transfer effect was unaffected by devaluation, indicating that the stimulus retrieved a representation of outcome identity but not current incentive value. Individual differences in tobacco dependence in the young adult sample were associated with tobacco preference in the concurrent choice task but not with the devaluation or transfer effects. These data accord with dual-process theories in suggesting that drug/reward-seeking are mediated by goal-directed and habitual controllers under freely elected and cued conditions, respectively, and that initial uptake of drug use is associated with hyper-valuation of the drug as an outcome of goal-directed drug-seeking rather than with accelerated habit formation.

Repeated ethanol exposure and withdrawal impairs human fear conditioning and depresses long-term potentiation in rat amygdala and hippocampus.

BACKGROUND In rats, repeated episodes of alcohol consumption and withdrawal (RWD) impair fear conditioning to discrete cues. METHODS Fear conditioning was measured in human binge drinkers as the increased startle response in the presence of a CS+ conditioned to aversive white noise. Secondly, the ability of tone CSs, paired with footshock, to induce c-fos expression, a marker of neuronal activity, in limbic structures subserving emotion was studied in rats. Additionally, consequences of RWD on subsequent induction of long term potentiation (LTP) in external capsule/lateral amygdala and Schaffer collateral/hippocampus CA1 pathways were studied in rat brain slices. RESULTS Fear conditioning was impaired in young human binge drinkers. The ability of fear-conditioned CSs to increase c-fos expression in limbic brain areas was reduced following RWD, as was LTP induction. Rats conditioned prior to RWD, following RWD showed generalization of conditioned fear from the tone CS+ to a neutral control stimulus, and a novel tone. CONCLUSIONS Binge-like drinking impairs fear conditioning, reduces LTP, and results in inappropriate generalization of learned fear responses. We propose a mechanism whereby RWD-induced synaptic plasticity reduces capacity for future learning, while allowing unconditioned stimuli access to neuronal pathways underlying conditioned fear.

The role of drug expectancy in the control of human drug seeking.

Human drug seeking may be goal directed in the sense that it is mediated by a mental representation of the drug or habitual in the sense that it is elicited by drug-paired cues directly. To test these 2 accounts, the authors assessed whether a drug-paired stimulus (S+) would transfer control to an independently trained drug-seeking response. Smokers were trained on an instrumental discrimination that established a tobacco S+ in Experiment 1 and a tobacco and a money S+ in Experiment 2 that elicited an expectancy of their respective outcomes. Participants then learned 2 new instrumental responses, 1 for each outcome, in the absence of these stimuli. Finally, in the transfer test, each S+ was found to augment performance of the new instrumental response that was trained with the same outcome. This outcome-specific transfer effect indicates that drug-paired stimuli controlled human drug seeking via a representation or expectation of the drug rather than through a direct stimulus-response association.

Human nicotine conditioning requires explicit contingency knowledge: is addictive behaviour cognitively mediated?

RationaleTwo seemingly contrary theories describe the learning mechanisms that mediate human addictive behaviour. According to the classical incentive theories of addiction, addictive behaviour is motivated by a Pavlovian conditioned appetitive emotional response elicited by drug-paired stimuli. Expectancy theory, on the other hand, argues that addictive behaviour is mediated by an expectancy of the drug imparted by cognitive knowledge of the Pavlovian (predictive) contingency between stimuli (S+) and the drug and of the instrumental (causal) contingency between instrumental behaviour and the drug.Aims and methodThe present paper reviewed human-nicotine-conditioning studies to assess the role of appetitive emotional conditioning and explicit contingency knowledge in mediating addictive behaviour.ResultsThe studies reviewed here provided evidence for both the emotional conditioning and the expectancy accounts. The first source of evidence is that nicotine-paired S+ elicit an appetitive emotional conditioned response (CR), albeit only in participants who expect nicotine. Furthermore, the magnitude of this emotional state is modulated by nicotine deprivation/satiation. However, the causal status of the emotional response in driving other forms of conditioned behaviour remains undemonstrated. The second source of evidence is that other nicotine CRs, including physiological responses, self-administration, attentional bias and subjective craving, are also dependent on participants possessing explicit knowledge of the Pavlovian contingencies arranged in the experiment. In addition, several of the nicotine CRs can be brought about or modified by instructed contingency knowledge, demonstrating the causal status of this knowledge.ConclusionsCollectively, these data suggest that human nicotine conditioned effects are mediated by an explicit expectancy of the drug coupled with an appetitive emotional response that reflects the positive biological value of the drug. The implication of this conclusion is that treatments designed to modify the expected value of the drug may prove effective.

Goal-directed and transfer-cue-elicited drug-seeking are dissociated by pharmacotherapy: evidence for independent additive controllers.

According to contemporary learning theory, drug-seeking behavior reflects the summation of 2 dissociable controllers. Whereas goal-directed drug-seeking is determined by the expected current incentive value of the drug, stimulus-elicited drug-seeking is determined by the expected probability of the drug independently of its current incentive value, and these 2 controllers contribute additively to observed drug-seeking. One applied prediction of this model is that smoking cessation pharmacotherapies selectively attenuate tonic but not cue-elicited craving because they downgrade the expected incentive value of the drug but leave expected probability intact. To test this, the current study examined whether nicotine replacement therapy (NRT) nasal spray would modify goal-directed tobacco choice in a human outcome devaluation procedure, but leave cue-elicited tobacco choice in a Pavlovian to instrumental transfer (PIT) procedure intact. Smokers (N= 96) first underwent concurrent choice training in which 2 responses earned tobacco or chocolate points, respectively. Participants then ingested either NRT nasal spray (1 mg) or chocolate (147 g) to devalue 1 outcome. Concurrent choice was then tested again in extinction to measure goal-directed control of choice, and in a PIT test to measure the extent to which tobacco and chocolate stimuli enhanced choice of the same outcome. It was found that NRT modified tobacco choice in the extinction test but not the extent to which the tobacco stimulus enhanced choice of the tobacco outcome in the PIT test. This dissociation suggests that the propensity to engage in drug-seeking is determined independently by the expected value and probability of the drug, and that pharmacotherapy has partial efficacy because it selectively effects expected drug value.

Attention and expectation in human predictive learning: The role of uncertainty

Three localized, visual pattern stimuli were trained as predictive signals of auditory outcomes. One signal partially predicted an aversive noise in Experiment 1 and a neutral tone in Experiment 2, whereas the other signals consistently predicted either the occurrence or absence of the noise. The expectation of the noise was measured during each signal presentation, and only participants for whom this expectation demonstrated contingency knowledge showed differential attention to the signals. Importantly, when attention was measured by visual fixations, the contingency-aware group attended more to the partially predictive signal than to the consistent predictors in both experiments. This profile of visual attention supports the Pearce and Hall (1980) theory of the role of attention in associative learning.

The associative basis of cue-elicited drug taking in humans

RationaleDrug cues play an important role in motivating human drug taking, lapse and relapse, but the psychological basis of this effect has not been fully specified.MethodTo clarify these mechanisms, the study measured the extent to which pictorial and conditioned tobacco cues enhanced smoking topography in an ad libitum smoking session simultaneously with cue effects on subjective craving, pleasure and anxiety.ResultsBoth cue types increased the number of puffs consumed and craving, but pleasure and anxiety responses were dissociated across cue type. Moreover, cue effects on puff number correlated with effects on craving but not pleasure or anxiety. Finally, whereas overall puff number and craving declined across the two blocks of consumption, consistent with burgeoning satiety, cue enhancement of puff number and craving were both unaffected by satiety.ConclusionsOverall, the data suggest that cue-elicited drug taking in humans is mediated by an expectancy-based associative learning architecture, which paradoxically is autonomous of the current incentive value of the drug.

Acute alcohol impairs human goal-directed action.

There are two forms of motivated behaviour. Goal-directed action is mediated by knowledge of the consequences whereas habitual action is elicited directly by stimuli associated with the action. Alcohol may impair goal-directed control, favouring habit. To evaluate this proposal, participants were administered with 0.4 g/kg of alcohol or placebo before acquiring separate instrumental responses for chocolate and water points. Chocolate was then fed to satiety to devalue this outcome before choice between the two responses was tested in extinction. Any reduction in chocolate choice must be mediated by knowledge of the current incentive value of this outcome, i.e. must be goal-directed. Alcohol attenuated the devaluation effect on choice in extinction, but had no effect on reacquisition performance, the hedonic appraisal of rewards or acquisition of the instrumental contingencies. Acute alcohol impaired goal-directed control of action selection, favouring habit, which may mediate alcohol effects on under-controlled behaviour more broadly.