Steven Glautier

The biological, social and clinical bases of drug addiction : commentary and debate

This article summarizes the main discussions at a meeting on the biological, social and clinical bases of drug addiction focused on contemporary topics in drug dependence. Four main domains are surveyed, reflecting the structure of the meeting: psychological and pharmacological factors; neurobiological substrates; risk factors (including a consideration of vulnerability from an environmental and genetic perspective); and clinical treatment. Among the topics discussed were tolerance, sensitization, withdrawal, craving and relapse; mechanisms of reinforcing actions of drugs at the behavioural, cognitive and neural levels; the role of subjective factors in drug dependence; approaches to the behavioural and molecular genetics of drug dependence; the use of functional neuroimaging; pharmaceutical and psychosocial strategies for treatment; epidemiological and sociological aspects of drug dependence. The survey takes into account the considerable disagreements and controversies arising from the discussions, but also reaches a degree of consensus in certain areas.

Outcome and cue properties modulate blocking

Participants saw a series of situations in which a cue (a light appearing at a certain position) could be followed by an outcome (a drawing of a tank that exploded) and were afterwards asked to rate the likelihood of the outcome in the presence of the cue. In Experiments 1 and 2, the compound cues AT and KL were always followed by the outcome (AT+, KL+). During an elemental phase that either preceded or followed the compound phase, Cue A was also paired with the outcome (A+). Cue T elicited a lower rating than Cues K and L when cues were described as being weapons but not when the cues were said to be indicators. The magnitude of this blocking effect was also influenced by whether the outcome occurred to a maximal or submaximal extent. Experiment 3 replicated the effect of cue instructions on blocking (A+, AT+) but showed that cue instructions had no impact on reduced overshadowing (B-, BT+). The results shed new light on previous findings and support probabilistic contrast models of human contingency judgements.

Dissociation of wanting and liking for alcohol in humans: a test of the incentive-sensitisation theory

RationaleIncentive sensitisation theory (IST) claims that the mechanism of reward is comprised of separate neurobiological systems of wanting and liking, that dependent drug use occurs as a result of sensitisation of the system controlling wanting, and that the two systems can be dissociated.ObjectiveTo test the IST prediction that wanting and liking for alcohol can be dissociated in humans.MethodsMeasures of wanting and liking for alcohol were obtained in three experiments. Experiment 1 examined whether liking for alcohol was associated with levels of wanting, as indexed by self-reported weekly alcohol intake. Experiments 2 and 3 also assessed the association between liking and wanting but in these experiments wanting was also indexed by alcohol consumption in the laboratory. Experiment 2 increased wanting for alcohol using an alcohol priming dose to determine whether liking would be similarly affected. Experiment 3 reduced liking for alcohol by adulterating drinks with Tween to see whether wanting would also be reduced.ResultsLittle evidence for an association between liking and wanting for alcohol was found in Experiments 1–3 but, collapsing across all experiments, a weak positive correlation between liking and wanting was found. However, in Experiment 2, wanting was increased by the alcohol priming dose whereas liking was not and in Experiment 3 liking was reduced without a concurrent reduction in wanting.ConclusionsAlthough correlations between wanting and liking can be observed these results support the contention of the IST that wanting and liking for alcohol can be dissociated in human participants.

The concentration-dependent effects of ethanol on Caenorhabditis elegans behaviour

The effects of ethanol on the brain are concentration dependent. Low concentrations (mM) intoxicate, while greater than 100 mM anaesthetize. Of most relevance to human alcohol addiction are mechanisms of intoxication. Previously, Caenorhabditis elegans has been employed in genetic screens to define effectors of intoxication. Here, we inform interpretation of these studies by providing evidence that ethanol rapidly equilibriates across C. elegans cuticle. Importantly, the effect of ethanol on muscle activity rapidly reaches steady-state, and the concentration-dependence of the effect is very similar in intact animals and exposed muscle. Thus the cuticle does not present an absorption barrier for ethanol, and furthermore the internal concentration is likely to approach that applied externally. Thus, modelling intoxication in C. elegans requires exposure to external ethanol less than 100 mM. Furthermore, the permeability of the cuticle to ethanol enables analysis of precisely controlled concentration-dependent effects of acute, chronic, and episodic ethanol exposure on behaviour.

A Differential Role for Neuropeptides in Acute and Chronic Adaptive Responses to Alcohol: Behavioural and Genetic Analysis in Caenorhabditis elegans

Prolonged alcohol consumption in humans followed by abstinence precipitates a withdrawal syndrome consisting of anxiety, agitation and in severe cases, seizures. Withdrawal is relieved by a low dose of alcohol, a negative reinforcement that contributes to alcohol dependency. This phenomenon of ‘withdrawal relief’ provides evidence of an ethanol-induced adaptation which resets the balance of signalling in neural circuits. We have used this as a criterion to distinguish between direct and indirect ethanol-induced adaptive behavioural responses in C. elegans with the goal of investigating the genetic basis of ethanol-induced neural plasticity. The paradigm employs a ‘food race assay’ which tests sensorimotor performance of animals acutely and chronically treated with ethanol. We describe a multifaceted C. elegans ‘withdrawal syndrome’. One feature, decrease reversal frequency is not relieved by a low dose of ethanol and most likely results from an indirect adaptation to ethanol caused by inhibition of feeding and a food-deprived behavioural state. However another aspect, an aberrant behaviour consisting of spontaneous deep body bends, did show withdrawal relief and therefore we suggest this is the expression of ethanol-induced plasticity. The potassium channel, slo-1, which is a candidate ethanol effector in C. elegans, is not required for the responses described here. However a mutant deficient in neuropeptides, egl-3, is resistant to withdrawal (although it still exhibits acute responses to ethanol). This dependence on neuropeptides does not involve the NPY-like receptor npr-1, previously implicated in C. elegans ethanol withdrawal. Therefore other neuropeptide pathways mediate this effect. These data resonate with mammalian studies which report involvement of a number of neuropeptides in chronic responses to alcohol including corticotrophin-releasing-factor (CRF), opioids, tachykinins as well as NPY. This suggests an evolutionarily conserved role for neuropeptides in ethanol-induced plasticity and opens the way for a genetic analysis of the effects of alcohol on a simple model system.

Spatial separation of target and competitor cues enhances blocking of human causality judgements

Three experiments were carried out. Each required subjects to make judgements about the causal status of cues following a two-stage blocking procedure. In Stage 1 a competitor cue was consistently paired with an outcome, and in Stage 2 the competitor continued to be paired with the outcome but was accompanied by a target cue. It was predicted that causal judgements for the target would be reduced by the presence of the competitor. In Experiments 1 and 2 the blocking procedure was implemented as a computer simulation of a card game during which subjects had to learn which cards produced the best payouts. The cues that subjects used to make their judgement were colours and symbols that appeared on the backs of the cards. When the target and competitor cues appeared on the same card blocking effects did not emerge, but when they appeared as part of different cards blocking effects were found. Thus, spatial separation of target and competitor cues appeared to facilitate blocking. Experiment 3 replicated the blocking result using spatially separated target and competitor cues.

Flavour conditioning and alcohol: a multilevel model of individual differences

Previous research shows that dependent drinkers respond more strongly to alcohol-related cues and suggests that alcohol cue-reactivity may be relevant to understanding dependence liability. However, a significant weakness in many studies is the fact that cue-reactivity is studied without actually conditioning subjects; responses to alcohol-related cues are simply assumed to be conditioned responses. The current report attempts to overcome this weakness by studying alcohol cue-reactivity following a flavour-conditioning procedure. A statistical model of individual differences in cue-reactivity was constructed using previous alcohol exposure, alcohol tolerance, and personality as predictor variables. Although there was no evidence for overall differences in subjective and psychophysiological responses to alcohol and soft-drink paired flavours, there were marked individual differences in responding to the different flavours. The statistical model showed that reward sensitivity (high extroversion, high neuroticism), heavier levels of drinking, and higher levels of tolerance to the intoxicating effects of alcohol were associated with lower levels of skin conductance in the presence of alcohol paired flavours.

Alcohol as an unconditioned stimulus in human classical conditioning

Recent experiments with human subjects have shown that drug cues (e.g. sight of beer or needle and syringe) elicit different responses than do neutral stimuli. However, because conditioning has not been carried out in the majority of cases, it is not clear why drug cues have different response eliciting capacities; associative and non-associative mechanisms may both play a part. In this experiment a counterbalanced differential conditioning procedure was used to isolate the role of associative processes in the development of physiological, behavioural, and subjective conditioned responses to cues for alcohol over the course of repeated conditioning sessions. Twelve healthy volunteers took part in the experiment which involved each subject attending for ten sessions. On physiological measures evidence was found for conditioning of skin conductance and cardiac inter-beat interval responses to cues for alcohol delivery. Over the course of conditioning on behavioural measures of drink consumption there were changes in the rate of consumption and number of sips taken as a function of whether or not the drinks contained alcohol. Finally, on subjective measures, there was a differential change in subjective state in response to alcohol and soft drink expectancy as conditioning progressed.

Asymmetry of generalization decrement in causal learning

Two experiments required volunteers to learn which of various “planes” caused high levels of pollution. Novel test items were then rated as causes of pollution. Items created by adding novel features were rated at the same level as that of the original training items but items created by removing features received reduced ratings. This asymmetry of generalization decrement was not predicted by a well-known configural model of stimulus representation (Pearce, 1987, 1994) but was predicted by a recently proposed model of stimulus representation, the replaced-elements model (Brandon, Vogel, & Wagner, 2000).

Nicotine withdrawal and reward responsivity in a card-sorting task

RationaleAnimal studies have demonstrated decreased reward responsivity during nicotine withdrawal (e.g., Epping-Jordan et al., Nature 393:76–79, 1998) and the Card Arranging Reward Responsivity Objective Test (CARROT) has recently been used to study the effect of nicotine withdrawal on reward responsivity in humans (e.g., Al-Adawi and Powell, Addiction 92:1773–1782, 1997; Powell et al., Biol Psychiatry 51:151–163, 2002). We investigated a suggestion that nicotine withdrawal may have additional reward-related effects apart from the reward responsivity effects already observed.ObjectiveThe objective of this study was to determine whether or not nicotine withdrawal results in slower improvements in performance on a card-sorting task over a series of trials.MethodWe carried out two experiments using a modified version of the CARROT, the mCARROT, to compare the performance of human participants in nicotine withdrawal with those who were satiated.ResultsAlthough withdrawal produced no direct effect on the mCARROT measure of reward responsivity, the overall sorting rate was lower, and the increase in sorting rate across successive trials was slower during nicotine withdrawal than during satiation.ConclusionsThese data indicate that nicotine withdrawal impacted on task performance independently of the introduction of a performance contingent reward, suggesting a novel reward-related effect of nicotine withdrawal.