Stimuli produced by observing responses make rats' ethanol self-administration more resistant to price increases

Rationale. Observing responses bring sensory receptors into contact with environmental stimuli. In the observing-response procedure, periods in which an operant response (e.g. pressing a lever) is reinforced by drug deliveries alternate with periods in which this response is never reinforced (i.e. extinction). These alternating periods of drug availability versus extinction are not signaled. Observing responses (i.e. presses on a second lever) produce brief stimuli signaling whether drug is available or not for responses on the first lever. Little is known about how parameters of the drug reinforcer affect drug-stimulus observing. Objectives. The effects of changes in the unit price (responses/reinforcer magnitude) of self-administered ethanol on rats' observing were examined. Also, the effects of an observing-response-produced ethanol stimulus on ethanol consumption were examined by comparing consumption during signaled and unsignaled periods of ethanol availability. Methods. Rats self-administered oral ethanol in the observing-response procedure. The unit price of ethanol in the observing-response procedure was increased by increasing the response requirement for ethanol across conditions. Results. Observing and response rates on the ethanol lever increased and then decreased with increases in the unit price of ethanol. However, ethanol-lever responding and ethanol consumption during periods when ethanol was available were less sensitive to increases in price when the observing-response-produced ethanol stimulus was present. Conclusions. Observing varies as an orderly function of unit price of a drug reinforcer, and drug stimuli produced by observing responses can make drug consumption less sensitive to increases in price. This procedure may provide an animal model of both attending to drug stimuli and the resultant effects of these stimuli on drug taking. Electronic Publication     

The observing-response procedure: a novel method to study drug-associated conditioned reinforcement

In this experiment, the observing-response procedure was adapted for use with drug self-administration. Rats' responding for oral ethanol was sometimes reinforced on a random-ratio schedule, whereas at other times it had no effect (i.e., extinction). Behavior producing stimuli associated with the otherwise unsignaled random-ratio and extinction periods (i.e., observing behavior) was acquired and maintained. In a vehicle control condition, both self-administration and observing behavior decreased, but observing decreased less rapidly proportionally to baseline than vehicle consumption. Thus, conditioned reinforcers may have persistent effects that are relatively independent of the current status of the primary reinforcer. The procedure allows long-term study of drug-associated conditioned reinforcement and provides independent indexes of the conditioned reinforcing and discriminative stimulus effects of drug stimuli.     

Ethanol-maintained responding of rats is more resistant to change in a context with added non-drug reinforcement

Alternative non-drug reinforcers reliably decrease drug-maintained responding in self-administration procedures. Studies of the resistance to change of food-maintained behavior, however, have found that responding in the presence of a stimulus associated with an alternative reinforcer is more resistant to disruption. This increase in persistence occurs despite lower response rates when the alternative reinforcer is present. The present experiment examined if, in addition to decreasing response rates, an alternative non-drug reinforcer also increases the persistence of drug-maintained responding. Rats self-administered oral ethanol in a multiple schedule of reinforcement in which responding was reinforced in two components signaled by different stimuli. In one component, response-independent food was delivered in addition to the earned ethanol. The effects of the alternative food reinforcer on response rates and resistance to extinction in the two components were examined. As in previous experiments on the resistance to change of food-maintained operant behavior, response rates were lower, but more resistant to extinction in the presence of the stimulus associated with the alternative reinforcer. These findings suggest that all the reinforcers obtained in a context in which drugs are consumed may contribute to the persistence of drug seeking in that context. This increase in persistence may occur even if the alternative reinforcers interfere with drug seeking.     

Resistance to change of alcohol self-administration: effects of alcohol-delivery rate on disruption by extinction and naltrexone

A common finding in resistance to change research with food-maintained operant behavior is that the persistence of behavior depends on the rate of reinforcement delivered in the context in which the behavior occurs. The present experiment evaluated the effects of rate of response-dependent alcohol delivery on the resistance to change of rats' alcohol self-administration in the face of disruption produced by extinction and a range of doses of naltrexone (1.0, 3.0, 10.0 mg/kg, subcutaneous). Rats responded for a 10% alcohol solution in a multiple schedule of reinforcement arranging a higher rate of alcohol delivery (variable interval 15 s) in the presence of one stimulus and a lower rate of alcohol delivery (variable interval 45 s) in the presence of another stimulus. Baseline response rates and resistance to extinction were higher in the presence of the stimulus associated with higher rates of alcohol delivery. This finding is consistent with studies of the resistance to change of food-maintained behavior. The rate of alcohol delivered in the components, however, did not systematically affect resistance to disruption by naltrexone. One interpretation of this finding from the perspective of behavioral momentum theory is that naltrexone may decrease the impact of alcohol-associated stimuli on the persistence of drinking by reducing sensitivity to the relative reinforcement conditions arranged in the presence of different stimuli.     

Effects of a context shift and multiple context extinction on reactivity to alcohol cues

Cue exposure treatment (CET) attempts to reduce the influence of conditioned substance cues on addictive behavior via extinction, but has received only modest empirical support in clinical trials. This may be because extinction learning appears to be context dependent and a change in context may result in a return of conditioned responding (i.e., renewal), although this has received only limited empirical examination. The current study used a 4-session laboratory analogue of CET to examine whether a change in context following 3 sessions of alcohol cue exposure with response prevention would result in renewal of conditioned responding. In addition, this study examined whether conducting extinction in multiple contexts would attenuate renewal of conditioned responding. In one-way between-subjects design, 73 heavy drinkers (71% men) were randomized to 3 conditions: (a) single context extinction (extinction to alcohol cues in the same context for 3 sessions followed by a context shift at the fourth session), (b) multiple context extinction (extinction to alcohol cues in different contexts each day for all 4 sessions), and (c) pseudoextinction control condition (exposure to neutral cues in the same context for 3 sessions followed by exposure to alcohol cues at the fourth session). The results revealed the predicted cue reactivity and extinction effects, but the hypotheses that a context shift would generate renewed cue reactivity and that multiple contexts would enhance extinction were not supported. Methodological aspects of the study and the need for parametric data on the context dependency of extinction to alcohol cues are discussed.     

Reinstatement of alcohol-seeking behavior by drug-associated discriminative stimuli after prolonged extinction in the rat.

Clinical observations suggest that stimuli associated with the availability or consumption of ethanol can evoke subjective feelings of craving and trigger episodes of relapse in abstinent alcoholics. To study the motivational significance of alcohol-related environmental cues experimentally, the effects of discriminative stimuli previously predictive of alcohol availability on the reinstatement of ethanol-seeking behavior were examined. Wistar rats were trained to lever-press for 10% (w/v) ethanol or water in the presence of distinct auditory cues. The rats were then subjected to an extinction phase where lever presses had no scheduled consequences. After extinction, the animals were exposed to the respective auditory cues without the availability of ethanol or water. Neither the ethanol (SA+) nor water-associated (SA-) auditory cue increased responding over extinction levels. In contrast, subsequent presentation of an olfactory cue associated with ethanol (SO+), but not a water-associated (SO-) cue significantly reinstated lever pressing behavior in the absence of the primary reinforcer. Moreover, responding elicited by the concurrent presentation of the SO+ and SA+ was selectively attenuated by the opiate antagonist naltrexone (0.25 mg/kg; s.c.). The results suggest that ethanol-associated cues can reinstate extinguished ethanol-seeking behavior in rats, but that the efficacy of these stimuli may be modality-specific. In addition, the present procedures may be useful for studying neurobiological mechanisms of alcohol-seeking behavior and relapse.     

Effects of response cost and unit dose on alcohol self-administration in moderate drinkers

Alcohol self-administration by nonhumans and alcoholic humans decreases as the response requirement to obtain the drug increases. Also, increases in dose or concentration of alcohol, increase consumption up to a maximum in these populations, after which further increases in dose decrease intake. In the present study, the effects of response cost and dose on alcohol self-administration were investigated in moderate drinkers (12-45 drinks/week). Three male volunteers self-administered alcohol (commercial beer) during 2h sessions twice weekly. Alcohol was available under a fixed-ratio (FR) schedule of reinforcement. Response requirement (FR100-1600) and dose (2 and 4oz of beer) were varied separately across sessions using a within-subjects design. As response cost increased, consumption and overall rates of responding generally changed in an inverted U-shaped manner. Maximal consumption was observed at the 4oz dose. These orderly relations between response cost, dose and alcohol self-administration extend prior findings in nonhumans and alcoholics to moderate drinkers. Such consistencies support a position that a common set of variables control alcohol self-administration across these populations.     

Preference for saccharin-sweetened alcohol relative to isocaloric sucrose

 This experiment tested the reinforcing efficacy of a saccharin-sweetened alcohol solution relative to an isocaloric sucrose drink in rats. One dipper served 10% alcohol plus 0.25% saccharin, and a second, concurrently available, dipper served 14.2% sucrose. During the course of the experiment, access to the two drinks was challenged by increasing the schedule requirement (variable-interval) that determined when a lever press would operate the dipper. There were two main findings. First, the rats continued to consume significant amounts of alcohol despite access to the isocaloric sucrose solution. Second, schedule-requirement increases that decreased sucrose-reinforced responding failed to decrease saccharin-sweetened alcohol reinforced responding. These results extend and replicate earlier findings from studies in which alcohol was mixed with sucrose, and the alcohol mixtures held a caloric advantage over the competing sucrose solutions. The experiment also included controls for differences in baseline response rates and for the influence of saccharin on preference. In the baseline response-rate control conditions, the two reinforcers were 10% sucrose and a mixture of 10% sucrose-plus-quinine. The results showed that the persistence of sweetened-alcohol reinforced responding could not be explained by differences in baseline response rates or the reinforcing properties of saccharin. Rather, the findings were consistent with the idea that the rats were defending baseline levels of alcohol-plus-saccharin consumption. Received: 15 June 1996 / Final version: 13 August 1996     

Observing responses maintained by stimuli associated with cocaine or remifentanil reinforcement in rhesus monkeys

Abstract Rationale. The stimuli associated with drug reinforcement may be particularly relevant to drug abuse and relapse. Objectives. The study measured behavior maintained by conditioned reinforcing stimuli in an observing response procedure. Methods. The experiment was conducted with rhesus monkeys in three stages: 1) discriminative control was established by reinforcing responding on one lever with either intravenous cocaine or remifentanil in the presence of one stimulus and extinguishing the response in the presence of another stimulus, 2) discriminative control was suspended by not presenting the stimuli, and 3) a final stage was implemented wherein the stimuli from the first stage were presented only when one or more responses were made on a second (observing) lever. Results. Under FR1 conditions, observing responses were maintained at low rates, but increased markedly when the response requirement was increased. Conclusions. The procedure maintained observing responses quite well and may be useful to an analysis of conditioned reinforcement based on drug reinforcement. Electronic Publication     

Compound Stimulus Presentation and the Norepinephrine Reuptake Inhibitor Atomoxetine Enhance Long-Term Extinction of Cocaine-Seeking Behavior

Drug abstinence is frequently compromised when addicted individuals are re-exposed to environmental stimuli previously associated with drug use. Research with human addicts and in animal models has demonstrated that extinction learning (non-reinforced cue-exposure) can reduce the capacity of such stimuli to induce relapse, yet extinction therapies have limited long-term success under real-world conditions (Bouton, 2002; O''Brien, 2008). We hypothesized that enhancing extinction would reduce the later ability of drug-predictive cues to precipitate drug-seeking behavior. We, therefore, tested whether compound stimulus presentation and pharmacological treatments that augment noradrenergic activity (atomoxetine; norepinephrine reuptake inhibitor) during extinction training would facilitate the extinction of drug-seeking behaviors, thus reducing relapse. Rats were trained that the presentation of a discrete cue signaled that a lever press response would result in cocaine reinforcement. Rats were subsequently extinguished and spontaneous recovery of drug-seeking behavior following presentation of previously drug-predictive cues was tested 4 weeks later. We find that compound stimulus presentations or pharmacologically increasing noradrenergic activity during extinction training results in less future recovery of responding, whereas propranolol treatment reduced the benefit seen with compound stimulus presentation. These data may have important implications for understanding the biological basis of extinction learning, as well as for improving the outcome of extinction-based therapies.     

Effects of acute alcohol consumption on the perception of eye gaze direction

Alcohol consumption is associated with increases in aggressive behaviour, but the mechanisms underlying this relationship are poorly understood. One mechanism by which alcohol consumption may influence behaviour is via alterations in the processing of social cues such as gaze. We investigated the effects of acute alcohol consumption on the perception of gaze, using a task in which participants determined whether a stimulus face was looking towards or away from them. Gaze direction varied across trials, allowing calculation of a threshold at which participants considered gaze to switch from direct to averted. Target faces varied in both sex and attractiveness. Thirty social drinkers attended three randomized experimental sessions. At each session, participants consumed 0.0, 0.2 or 0.4 g/kg alcohol, and completed the gaze perception task. A significant three-way interaction involving target sex, participant sex and alcohol dose indicated that alcohol increased the cone of gaze for females viewing male targets (i.e. females were biased towards making a direct gaze judgement), but decreased the cone of gaze for males viewing male targets. Our data indicate that alcohol consumption influences gaze perception, but that these effects vary across sex of both stimulus and rater. These effects may have important implications for alcohol-related violence.     

Environmental stimuli promote the acquisition of nicotine self-administration in rats

RATIONALE: Environmental stimuli associated with drugs of abuse are believed to play a major role in the motivation to take drugs, drug dependence, and relapse. Previous work from this laboratory demonstrated that the response-contingent presentation of drug-related, visual cues was at least as important as nicotine in the maintenance, extinction and reacquisition of self-administration in experienced rats. OBJECTIVES: In the present research, we asked whether these same visual cues are effective in promoting the acquisition of operant responding in drug naive rats. METHODS: Male Sprague-Dawley rats were tested for self-administration of IV nicotine (0.03 mg/kg, free base) in 1-h daily sessions when infusions were or were not paired with two lighting events: a 1-s cue light, followed by a 1-min period during which the chamber light was turned off and responding was not reinforced. RESULTS: Rats tested with cues plus nicotine rapidly acquired self-administration and increased their lever pressing rates as the schedule progressed from FR1 to FR5. Without cues, the rate of nicotine self-administration was low and no adjustments were made in response to increasing schedule demands. While one of the stimuli, turning off the chamber light, was shown to have primary reinforcing properties, its association with nicotine produced a synergistic enhancement of lever pressing. Acquisition of operant responding was also enhanced, but to a lesser extent, by a previously neutral compound stimulus, i.e. the nicotine-paired cue light presented with a 1-s tone. CONCLUSIONS: These results illustrate a powerful interaction between environmental stimuli and nicotine in the acquisition of operant responding and indicate that both intrinsically reinforcing and previously neutral cues can participate in this effect.     

The CRF<Subscript>1</Subscript> receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats

Rationale and objectives Yohimbine is an alpha-2 adrenoreceptor antagonist that provokes stress- and anxiety-like responses in both humans and laboratory animals. In rats, yohimbine increases operant alcohol self-administration and reinstates alcohol seeking. In this study, we assess whether these effects of yohimbine are attenuated by systemic injections of the corticotrotropin-releasing factor 1 (CRF₁) receptor antagonist antalarmin. Materials and methods In Exp. 1, we trained rats to lever press for alcohol solutions (12% w/v, 1 h/day) over several weeks; during training, the response requirement was increased from a fixed-ratio-1 (FR-1) to a fixed-ratio-3 (FR-3) reinforcement schedule. We then tested the effect of antalarmin (10 or 20 mg/kg) on yohimbine (1.25 mg/kg)-induced increases in operant alcohol self-administration (FR-3 reinforcement schedule). Subsequently, we assessed the effect of antalarmin on yohimbine-induced increases in plasma corticosterone levels in the previously self-administering rats. In Exp. 2, we trained the rats to self-administer alcohol as in Exp. 1, and after extinction of the alcohol-reinforced lever responding over 13 days, we tested antalarmin’s effect on yohimbine-induced reinstatement of alcohol seeking. Results Yohimbine increased operant alcohol self-administration and reinstated alcohol seeking after extinction. These effects of yohimbine were attenuated by antalarmin. Antalarmin injections in the absence of yohimbine had no effect on either operant alcohol self-administration or extinction responding. Antalarmin had no effect on yohimbine-induced corticosterone release in alcohol-experienced rats. Conclusions These results suggest that extrahypothalamic CRF₁ receptors are involved in the effect of yohimbine on operant alcohol self-administration and on relapse to alcohol seeking and support the notion that CRF₁ receptor antagonists should be considered in alcohol addiction treatment.     

Stimulus conditioned to foot-shock stress reinstates alcohol-seeking behavior in an animal model of relapse

Rationale. Stress and conditioned responses to drug cues have been implicated as critical factors in relapse to drug use. In the animal literature, both the conditioned effects of drug-related stimuli and the unconditioned effects of foot-shock stress have been well documented to reinstate extinguished drug-seeking behavior. What has remained largely unexplored, however, is the significance of stimuli conditioned to foot-shock stress for the resumption of drug seeking. Additionally, although relapse is often the result of several risk factors acting in combination, the possibility that interactions among risk factors such as conditioned stress and drug cues may intensify drug-seeking behavior has received little experimental attention. Objectives. The purpose of this study was to examine the individual and interactive effects of a stimulus conditioned to foot-shock stress (STRESS CS) and a stimulus conditioned to ethanol reward (EtOH CS) on the reinstatement of ethanol-seeking behavior following extinction. Methods. Male Wistar rats were trained to orally self-administer 10% ethanol on a fixed-ratio 3 schedule of reinforcement. The EtOH CS was established by response-contingently pairing 0.5 s illumination of a white cue light with each reinforced response. The STRESS CS was established by pairing a continuous white noise (70 dB) with intermittent foot shock (10 min; 0.5 mA; 0.5 s on; mean off period of 40 s). Ethanol dependence was induced by an ethanol vapor-inhalation procedure. After ethanol-maintained instrumental responding was extinguished by withholding ethanol and the EtOH CS, reinstatement tests were conducted. Results. Both exposure to the STRESS CS and response-contingent presentation of the EtOH CS reinstated extinguished responding at the previously active, ethanol-paired lever without further ethanol availability. When response-contingent availability of the EtOH CS was preceded by exposure to the STRESS CS, interactive effects of these stimuli on responding were observed. However, both the individual and interactive effects of the STRESS CS and the EtOH CS reached statistical significance only in rats with a history of ethanol dependence but not in ethanol-nondependent rats. Conclusions. The results confirm that both conditioned stress and ethanol cues elicit ethanol-seeking behavior and, more importantly, that these stimuli produce interactive effects resulting in an increased ethanol-seeking response. The findings also indicate that susceptibility to ethanol seeking induced by conditioned stress and alcohol cues depends significantly on the history of prior alcohol exposure.     

Reactivity to alcohol cues and induced moods in alcoholics

It has been theorized that respondent conditioning processes in part underlie desire for alcohol and thus contribute to relapse after alcoholism treatment. One implication of this theory is that the relevant conditioned responses could be eliminated by respondent extinction, in which the alcoholic patient is exposed to alcohol-related stimuli while being prevented from consuming alcohol. However, exteroceptive cues such as the sight and smell of alcoholic beverages are not always sufficient to elicit desire for alcohol. In view of this, it has been suggested that interoceptive cues, such as mood states, may also play a role in eliciting desire for alcohol. To test this, eight alcoholic subjects were induced to experience negative or neutral moods on four separate days, and then exposed to the sight and smell of their favorite alcoholic drink, and to a neutral stimulus (seltzer water), in a within-subjects design. Results from this work indicate that: (a) negative moods can be reliably induced in the laboratory as confirmed by subjects' reports; (b) exposure to alcohol cues had no effect on desire for alcohol while subjects were in a relaxed, neutral mood state; (c) the presence of negative mood states alone appeared to be sufficient to elicit desire for alcohol in some subjects, regardless of whether alcohol or water was presented. These data argue that negative mood states may cue desire for alcohol independent of other cues. The data also suggest that reactivity to alcohol cues may be substantially reduced by relaxation.     

Effects of chlorpromazine on food-maintained and observing behavior

Pigeons were trained to peck each of two response keys. Periods during which pecks on one key (the food key) produced access to grain according to a random-ratio 80 schedule alternated irregularly with periods during which food-key responses had no scheduled consequences (extinction). Both keys remained amber unless a random-ratio 8-response requirement on the second key (the observing key) was met. Completion of the observing-response requirement darkened the observing key and illuminated the food key either red or green for 15 s, depending on whether food could be obtained by pecking the food key. Food-key response rate was high and constant when food could be obtained (and the key was illuminated red). Observing-key response rate was somewhat lower but also constant when the observing key was amber, and near zero otherwise. Increasing doses of chlorpromazine (0.03–17.0 mg/kg, IM) decreased food-key response rate, but sometimes increased observing-key response rate. Additionally, larger doses were required to decrease response rate on the observing key. The differential effect of chlorpromazine upon the two performances may have been due to differences in reinforcer type (conditioned versus unconditioned) or other aspects of reinforcement.     

Predicting relapse to cocaine-seeking behavior: a multiple regression approach

Recovery of previously extinguished responding to stimuli paired with the administration of drugs of abuse is becoming a widely utilized animal model of relapse to drug-seeking behaviors. While this approach is useful for identifying factors such as conditioned stimuli that are associated with drug-seeking, it has not directly identified behaviors that might predict susceptibility to relapse. In this study, rats were initially screened for locomotor activity in response to a novel environment. Rats were then trained to self-administer cocaine. A stimulus light and tone were paired with each infusion of cocaine. After 14 days of self-administration (maintenance) rats underwent 7 days of extinction trials (extinction phase 1), in which responding yielded neither cocaine nor the presentation of the conditioned stimulus. After extinction phase 1, rats responded for presentations of the compound stimulus in the absence of cocaine (test day 1). Rats then underwent 3 more days of extinction (extinction phase 2). After extinction phase 2, rats were once again allowed to self-administer cocaine (test day 2) and received presentations of the compound stimulus. Hierarchical regression equations, utilizing data from locomotor screening and the average responding during maintenance and extinction phases 1 and 2, were then constructed in order to predict the magnitude of responding on test days 1 and 2. A model utilizing locomotor activity, maintenance responding and extinction phase 1 responding accounted for over 76% of the variance associated with responding on test day 1, with extinction phase 1 as best predictor. A further model indicated that locomotor activity was the best predictor of propensity to self-administer cocaine on test day 2. These regression models provide a novel approach to determining factors that may predict relapse to drug-seeking behaviors.     

Effects of alcohol on inhibitory processes

Earlier work has shown that alcohol may have disinhibiting effects on behaviour. Two studies tested the effects of a moderate dose of alcohol (0.6 g/kg) versus placebo on tasks that evaluate inhibitory processes related to alcohol stimuli, in moderate-to-heavy social drinkers (student population). An inhibition of interference task, the Stroop task (ST; study 1), and an inhibition of a prepotent response task, the go/no-go task (GNG; study 2), were used. The effects of alcohol on working memory function were also examined. Participants preloaded with alcohol made more errors on the colour and alcohol ST than those preloaded with placebo. In the GNG task, responding to alcohol-related pictures was slower than responding to neutral pictures. When participants were required to switch responding from neutral to alcohol-related go stimuli, responding became slower; however, responding to alcohol go stimuli became faster as time progressed; no effect of alcohol was found. Alcohol had no effect, compared with placebo, on the working memory tasks. Therefore, a moderate dose of alcohol had restricted effects on inhibitory processes: only interference inhibition measured in the ST was affected. Although the data obtained with the GNG task did not show an effect of alcohol on response inhibition, increased latency of response in the presence of alcohol-related stimuli compared with neutral stimuli indicates that alcohol stimuli are more salient to social drinkers, attracting a greater amount of attention.     

Outcome specificity in deepened extinction may limit treatment feasibility: Co-presentation of a food cue interferes with extinction of cue-elicited cocaine seeking

Background

We previously showed that presenting two cocaine cues simultaneously during extinction deepens the extinction of cue-elicited cocaine seeking (Kearns et al., 2012). The present study investigated whether compounding a non-drug appetitive cue with a cocaine cue would similarly deepen extinction.

Methods

In Experiment 1, tone and click were each first established as discriminative stimuli for cocaine-reinforced responding and light was a cue for food-reinforced responding. In an initial extinction phase, all stimuli were presented individually. Then, during an additional compound extinction session, rats received 8 presentations of one of the cocaine cues (counterbalanced over subjects) simultaneously with light and 8 presentations of the other cue alone. A spontaneous recovery test was used to evaluate the effectiveness of the extinction treatments. Experiment 2 was performed under conditions designed to match those of Experiment 1, except food was the reinforcer in tone and click instead of cocaine.

Results

In Experiment 1, the cocaine cue compounded with the food cue during extinction controlled greater spontaneous recovery of cocaine seeking than the cocaine cue always presented alone. In contrast, Experiment 2 demonstrated deepened extinction of responding to a food cue when both compounded cues were food cues.

Conclusions

Results suggest that deepened extinction depends on the compound presentation of cues associated with the same reinforcer. Compound presentation of cues associated with different reinforcers could lead to an enhancement of responding. Care is urged in attempts to deepen the extinction of cue-elicited drug seeking by compounding drug cues with non-drug cues.     

Time-dependent changes in alcohol-seeking behaviour during abstinence.

Exposure of alcohol addicts to alcohol-related environmental cues may elicit alcohol-seeking behaviour even after protracted abstinence. The purpose of the present study was to assess time-dependent changes in alcohol-seeking behaviour in rats trained to respond for alcohol. The rats were re-exposed to alcohol-associated stimuli after 1, 28 or 56 days of withdrawal. During the re-exposure session, the rats were first allowed to respond in extinction. Then, reinstatement of alcohol-seeking behaviour was evoked by a complex of discrete alcohol-associated cues (auditory and light cues combined with taste and smell of alcohol). Extinction behaviour depended on abstinence duration with maximal responding after 28-day abstinence. Reinstatement of alcohol-seeking behaviour evoked by the discrete cues was highest after 56-day abstinence. No correlations were found between individual alcohol intakes, extinction behaviour and cue-induced reinstatement. These results suggest that: (i) alcohol-seeking behaviour may become more intense after long-term imposed abstinence; (ii) alcohol self-administration, extinction behaviour, and reinstatement of alcohol-seeking behaviour may be regulated by separate neural mechanisms.