Joseph R. Troisi

Extinction of cue-evoked drug-seeking relies on degrading hierarchical instrumental expectancies

There has long been need for a behavioural intervention that attenuates cue-evoked drug-seeking, but the optimal method remains obscure. To address this, we report three approaches to extinguish cue-evoked drug-seeking measured in a Pavlovian to instrumental transfer design, in non-treatment seeking adult smokers and alcohol drinkers. The results showed that the ability of a drug stimulus to transfer control over a separately trained drug-seeking response was not affected by the stimulus undergoing Pavlovian extinction training in experiment 1, but was abolished by the stimulus undergoing discriminative extinction training in experiment 2, and was abolished by explicit verbal instructions stating that the stimulus did not signal a more effective response-drug contingency in experiment 3. These data suggest that cue-evoked drug-seeking is mediated by a propositional hierarchical instrumental expectancy that the drug-seeking response is more likely to be rewarded in that stimulus. Methods which degraded this hierarchical expectancy were effective in the laboratory, and so may have therapeutic potential.

Pavlovian-Instrumental Transfer of the Discriminative Stimulus Effects of Nicotine and Ethanol in Rats.

To date, only 1 study has evaluated the impact of a Pavlovian drug conditional stimulus (CS) on operant responding. A within-subject operant 1-lever go/no-go (across sessions) design was used to evaluate the impact of Pavlovian contingencies on the discriminative stimulus effects of nicotine (0.4 mg/kg) and ethanol (800 mg/kg) in male Sprague Dawley rats. Drugs were administered 10 min before each acquisition and test session. One drug predicted sessions of food reinforcement and the other drug predicted sessions of nonreinforcement; stimulus roles were counterbalanced. In Experiment 1 (n = 7), operant lever pressing was initially maintained on a VI-30 s schedule of food reinforcement. This phase was followed by 20 (CS+ vs. CS-) Pavlovian drug discrimination training sessions without the levers present. Two extinction tests revealed significantly more operant lever pressing under the CS+ drug conditions compared to the CS- drug conditions, suggesting evidence for Pavlovian-instrumental transfer. Operant training significantly strengthened stimulus control. In Experiment 2 (n = 7), the drugs functioned as operant drug discriminative stimuli first. Next, the predictive roles of the drug SDs and SΔs were reversed under Pavlovian CS- and CS+ contingencies, respectively. The original stimulus control was significantly undermined but was not reversed. These studies suggest that Pavlovian drug-reinforcer contingencies embedded within the operant 3-term contingency may play a partial role in mediating the discriminative stimulus effects of drugs.

Spontaneous Recovery During, But not Following, Extinction of the Discriminative Stimulus Effects of Nicotine in Rats: Reinstatement of Stimulus Control

Extinction of the discriminative stimulus effects of drugs has received little research attention. Using a one-lever food-reinforcement (VI-1 min) operant procedure with rats (N = 16), the studies reported here assessed extinction, spontaneous recovery, and reinstatement of responding to the discriminative stimulus effects of nicotine. Experiment 1 found evidence for retention of differential responding to IP administrations of nicotine after a 3-month (87 days) delay following acquisition. Experiment 2 compared spontaneous recovery of discriminative control 2 and 4 weeks following extinction. Additionally, the impact of noncontingent reinforcement on discriminative control was evaluated (reinstatement). During extinction training, nicotine (.4 mg/kg) or saline was administered 15 min prior to each 15-min session, as they were during training, but responding was not reinforced under either stimulus condition. Spontaneous recovery (SR) of responding under the SD condition occurred during a session (11th) preceded by two consecutive SΔ sessions. Matched by response rate, 8 rats were randomly assigned to either a 2-week delay group or a 4-week delay group. There was no evidence for SR of discriminated responding to the drugs 2 or 4 weeks following the final extinction session. Between-group comparisons further revealed that SR did not vary as a function of delay following extinction. Reinstatement of stimulus control was observed following 2 brief sessions of noncontingent food delivery (levers retracted and conducted in the absence of the drug cues). These results suggest that the maintenance and extinction of the discriminative stimulus effects of nicotine are temporally stable. Theoretical ideas regarding drug self-administration, craving, and therapy are entertained.

Nicotine vs. ethanol discrimination: extinction and spontaneous recovery of responding.

Studies regarding extinction and spontaneous recovery of the discriminative stimulus effects of drugs are limited. Eight rats were initially trained to discriminate nicotine (0.4 mg/kg) vs. ethanol (800 mg/kg). For four rats, itraperitaneal (IP) administrations of nicotine fifteen minutes prior to fifteen-minute training sessions served as a discriminative stimulus (SD) for predicting food-reinforced lever pressing (VI-1 min). On other sessions ethanol functioned in predicting nonreinforcement (SΔ). The stimulus roles of the drugs were counterbalanced for the remaining four rats. SΔ and SD sessions alternated quasi-randomly with two daily sessions at 1000 and 1400 hours. Discriminative control was not disrupted following ten extinction sessions under a non-drug/saline condition, but was disrupted following extinction sessions under the original training drugs. Instances of spontaneous recovery (SR) occurred throughout extinction under the drug condtions. There was no evidence for SR two weeks following extinction, but partial recovery four weeks following the final extinction phase. Contextual status (context renewal) had neither a restorative or disruptive impact on extiguished or discriminated responding, respectively. Theser results support and extend the limited number of other studies by demonstrating extinction and spontaneous recovery of responding discriminated bytwo distinct drugs. Some theoretical interpretations regarding history effects and training in the context of drug discrimination are entertained.

Extinction of the Discriminative Stimulus Effects of Nicotine with a Devalued Reinforcer: Recovery Following Revaluation

Extinction and recovery of the discriminative stimulus effects of nicotine (0.3 mg/kg) was investigated with a devalued food reinforcer (rats sated). Sixteen rats were trained in a counterbalanced one manipulandum (nose-poke) drug discrimination procedure with the roles of nicotine and saline counterbalanced as SD and SΔ. Discrimination training was maintained and then extinguished with the devalued reinforcer. Devaluation of the reinforcer diminished SD response rates during discrimination training but not discriminative control. Following delays after extinction, recovery of responding occurred with the revalued but not devalued reinforcer. These data demonstrate that (a) discriminative control by nicotine is temporally stable with a devalued reinforcer following acquisition and extinction, (b) revaluation of the reinforcer promotes recovery of discriminative control, and (c) recovery of interoceptive discriminative control by nicotine following extinction is affected by changes in motivation. Theoretical implications regarding drug replacement therapy and cue-exposure therapy are discussed.

Negative mood reverses devaluation of goal-directed drug-seeking favouring an incentive learning account of drug dependence.

BackgroundTwo theories explain how negative mood primes smoking behaviour. The stimulus–response (S-R) account argues that in the negative mood state, smoking is experienced as more reinforcing, establishing a direct (automatic) association between the negative mood state and smoking behaviour. By contrast, the incentive learning account argues that in the negative mood state smoking is expected to be more reinforcing, which integrates with instrumental knowledge of the response required to produce that outcome.ObjectivesOne differential prediction is that whereas the incentive learning account anticipates that negative mood induction could augment a novel tobacco-seeking response in an extinction test, the S-R account could not explain this effect because the extinction test prevents S-R learning by omitting experience of the reinforcer.MethodsTo test this, overnight-deprived daily smokers (n = 44) acquired two instrumental responses for tobacco and chocolate points, respectively, before smoking to satiety. Half then received negative mood induction to raise the expected value of tobacco, opposing satiety, whilst the remainder received positive mood induction. Finally, a choice between tobacco and chocolate was measured in extinction to test whether negative mood could augment tobacco choice, opposing satiety, in the absence of direct experience of tobacco reinforcement.ResultsNegative mood induction not only abolished the devaluation of tobacco choice, but participants with a significant increase in negative mood increased their tobacco choice in extinction, despite satiety.ConclusionsThese findings suggest that negative mood augments drug-seeking by raising the expected value of the drug through incentive learning, rather than through automatic S-R control.

A Hierarchical Instrumental Decision Theory of Nicotine Dependence

It is important to characterize the learning processes governing tobacco-seeking in order to understand how best to treat this behavior. Most drug learning theories have adopted a Pavlovian framework wherein the conditioned response is the main motivational process. We favor instead a hierarchical instrumental decision account, wherein expectations about the instrumental contingency between voluntary tobacco-seeking and the receipt of nicotine reward determines the probability of executing this behavior. To support this view, we review titration and nicotine discrimination research showing that internal signals for deprivation/satiation modulate expectations about the current incentive value of smoking, thereby modulating the propensity of this behavior. We also review research on cue-reactivity which has shown that external smoking cues modulate expectations about the probability of the tobacco-seeking response being effective, thereby modulating the propensity of this behavior. Economic decision theory is then considered to elucidate how expectations about the value and probability of response-nicotine contingency are integrated to form an overall utility estimate for that option for comparison with qualitatively different, nonsubstitute reinforcers, to determine response selection. As an applied test for this hierarchical instrumental decision framework, we consider how well it accounts for individual liability to smoking uptake and perseveration, pharmacotherapy, cue-extinction therapies, and plain packaging. We conclude that the hierarchical instrumental account is successful in reconciling this broad range of phenomenon precisely because it accepts that multiple diverse sources of internal and external information must be integrated to shape the decision to smoke.

Pavlovian Extinction of the Discriminative Stimulus Effects of Nicotine and Ethanol in Rats Varies as a Function of Context

Operant extinction contingencies can undermine the discriminative stimulus effects of drugs. Here, nicotine (0.4 mg/kg) and ethanol (0.8 g/kg) first functioned as either an SD or SD, in SΔ, in a counterbalanced one-lever go/no-go (across sessions) operant drug discrimination procedure. Pavlovian extinction in the training context (levers removed) grossly undermined the response rates and discriminative stimulus functions of nicotine, but not ethanol; presentation of the drugs in the home cage had no impact on stimulus control for either drug but lowered overall response rates. This result was replicated between, and within, groups of rats that differed in the order of extinction phases. These data suggest that stimulus reinforcer relationships play a role in the discriminative stimulus effects of drugs with regard to response rate, but vary pharmacologically and as a function of the context in which extinction occurs.

Acquisition, Extinction, Recovery, and Reversal of Different Response Sequences Under Conditional Control by Nicotine in Rats

ABSTRACT Complex voluntary behaviors occur in sequence. Eight rats were trained in an operant procedure that used nicotine and non-drug (saline) states as interoceptive cues that signaled which of two behavioral sequences led to food reward. The distal and proximal responses in the chain were always maintained on variable interval 30-sec and fixed ratio-1 schedules, respectively, and rate differences between the responses were used as the dependent variable. Extinction and reversal training was conducted. Distal response rates were significantly greater than proximal response rates during training, testing, extinction, and reversal learning. These data suggest that (a) nicotine can establish interoceptive control over different response sequences, and (b) extinction of one response sequence may be state-dependent. The clinical relevance of extinction of complex behavioral repertoires such as drug-seeking and drug-taking behavior that are evoked by specific interoceptive cues is addressed in regard to drug abuse treatment and relapse.

The Pavlovian vs. operant interoceptive stimulus effects of EtOH: Commentary on Besheer, Fisher, & Durant (2012)

Various interoceptive subjective states are correlated with drug taking and contribute to drug abuse and relapse. Besheer, Fisher, and Durant (2012; Vol 46, issue 8, pp. 747–755) note that the interoceptive “subjective” effects of EtOH likely contribute to its abuse, and that systematic evaluation of such subjective effects may be elucidative in this regard. In rats, the two-lever drug discrimination paradigm (Colpaert & Koek, 1995) has been a staple behavioral pharmacological assay for evaluating the interoceptive (i.e., “subjective”) effects of drug states as mediated by various receptor mechanisms. Besheer and colleagues provide data suggesting that a Pavlovian discriminated goal tracking procedure (DGT) may be more expedient for evaluating the interoceptive effects of EtOH compared to the standard twolever operant drug discrimination procedure. They suggested that the DGT could be useful for evaluating “subjective” effects of drugs in developmental longitudinal studies that require measurements within brief critical phases because: a) acquisition of stimulus control occurs more rapidly than in the operant procedure, and b) it is more sensitive to stimulus generalization to differing doses.