Withdrawal Cues Research Articles

Effects of acute distress and tobacco cues on tobacco demand

IntroductionCigarette demand, or relative value, can be assessed via analysis of performance on a hypothetical behavioral economic cigarette purchase task (CPT). Substance purchase tasks are highly amenable to manipulation, namely, external stimuli, instructional changes, or acute stressors. In this regard, the current secondary analysis evaluates the role a novel, computerized stress induction paradigm, the Contextual-Frustration Intolerance Typing Task (C-FiTT), plays in eliciting varying levels of stress and resulting demand. MethodDaily smokers (n = 484) completed the C-FiTT wherein they were randomly assigned to one of five distress conditions: combination of task difficulty (low or high difficulty) with neutral or withdrawal cues, and a neutral control group. Tobacco demand was assessed immediately following the distress task using the hypothetical CPT. ResultsThe C-FiTT distress-induction task significantly increased key cigarette demand indices, including price at maximum expenditure (Pmax) and first price where consumption was suppressed to zero (breakpoint). Moreover, demand increased with severity of C-FiTT condition, with the high-difficulty condition resulting in significantly higher breakpoint and Pmax, compared to other conditions. C-FiTT condition was not related to a significant increase in Omax, intensity, or elasticity. DiscussionThe novel C-FiTT paradigm produced comparable effects on tobacco demand relative to in vivo withdrawal induction, indicating that the C-FiTT is a viable procedure by which to influence demand. Reduction of internal and external stressors may be effective in lowering motivation for tobacco. These results highlight the importance of state distress in tobacco demand, and offer a potential avenue for intervention.

The effects of sequential attention shifts within visual working memory.

Previous studies have shown conflicting data as to whether it is possible to sequentially shift spatial attention among visual working memory (VWM) representations. The present study investigated this issue by asynchronously presenting attentional cues during the retention interval of a change detection task. In particular, we focused on two types of sequential attention shifts: (1) orienting attention to one location, and then withdrawing attention from it, and (2) switching the focus of attention from one location to another. In Experiment 1, a withdrawal cue was presented after a spatial retro-cue to measure the effect of withdrawing attention. The withdrawal cue significantly reduced the cost of invalid spatial cues, but surprisingly, did not attenuate the benefit of valid spatial cues. This indicates that the withdrawal cue only triggered the activation of facilitative components but not inhibitory components of attention. In Experiment 2, two spatial retro-cues were presented successively to examine the effect of switching the focus of attention. We observed equivalent benefits of the first and second spatial cues, suggesting that participants were able to reorient attention from one location to another within VWM, and the reallocation of attention did not attenuate memory at the first-cued location. In Experiment 3, we found that reducing the validity of the preceding spatial cue did lead to a significant reduction in its benefit. However, performance was still better at first-cued locations than at uncued and neutral locations, indicating that the first cue benefit might have been preserved both partially under automatic control and partially under voluntary control. Our findings revealed new properties of dynamic attentional control in VWM maintenance.

Emergence of Dormant Conditioned Incentive Approach by Conditioned Withdrawal in Nicotine Addiction

Nicotine is one of the determinants for the development of persistent smoking, and this maladaptive behavior is characterized by many symptoms, including withdrawal and nicotine seeking. The process by which withdrawal affects nicotine seeking is poorly understood. The impact of a withdrawal-associated cue on nicotine (.2 mg/kg)-conditioned place preference was assessed in male C57BL/6J mice (n = 8-17/group). To establish a cue selectively associated with withdrawal distinct from those associated with nicotine, a tone was paired with withdrawal in their home cages; mice were chronically exposed to nicotine (200 μg/mL for 15 days) from drinking water in their home cages and received the nicotinic acetylcholine receptor antagonist mecamylamine (2.5 mg/kg) to precipitate withdrawal in the presence of a tone. The effect of the withdrawal-associated tone on nicotine-conditioned place preference was then evaluated in the place-conditioning apparatus after a delay, when nicotine-conditioned place preference spontaneously disappeared. A cue associated with precipitated withdrawal reactivated the dormant effect of nicotine-associated cues on conditioned place preference. This effect occurred during continuous exposure to nicotine but not during abstinence. A conditioned withdrawal cue could directly amplify the incentive properties of cues associated with nicotine. This observation extends the contemporary incentive account of the role of withdrawal in addiction to cue-cue interaction.

Withdrawal, tolerance, and sensitization to dopamine mediated interoceptive cues in rats trained on a three-lever drug-discrimination task

In the present experiment rats were trained on a three-lever, drug-discrimination task to discriminate the cues associated with 0.30 mg/kg of the indirect dopamine (DA) agonist, amphetamine (AMPH), saline (SAL), and 0.03 mg/kg of the DA, D 2 receptor antagonist, haloperidol (HAL). Choice behavior determined from tests on 0.30 and 0.15 mg/kg AMPH, SAL 0.03 and 0.015 mg/kg HAL provided a behavioral baseline presumed to represent changes along a continuum of DA mediated, interoceptive cues. Results from separate groups tested on 0.30 and 0.15 mg/kg AMPH, SAL, 0.03 and 0.015 mg/kg HAL, 24 h post-treatment with an acute 7.5 mg/kg dose of AMPH, showed rapid tolerance and withdrawal to the AMPH cue and sensitization to the HAL cue. The same tests 24 h following treatment with 1.0 mg/kg HAL showed rapid tolerance to the HAL cue, sensitization to the AMPH cue, but not AMPH-like withdrawal cues. Analysis of the results showed that tolerance to the AMPH and HAL cues reflected neuroadaptive baseline shifts and not weaker cue properties. These findings are consistent with predictions from opponent process theory of motivation and provide an animal model to study the motivational consequences that aversive symptoms of AMPH withdrawal such as dysphoria and anhedonia can have on drug-taking behavior.

Role of withdrawal in reinstatement of morphine-conditioned place preference

Relapse is a major characteristic of drug addiction and the primary problem in treating drug abuse. Based on the negative reinforcement view of addiction, in which the motivation to take drugs is thought to result from the desire to avoid the aversive effect of drug withdrawal, it has been theorized that withdrawal symptoms play a major role in the maintenance of and relapse to drug taking. However, the role of withdrawal in relapse has not yet been systemically investigated in the reinstatement model. Using a conditioned place preference (CPP) paradigm, we examined the role of different morphine withdrawal states (spontaneous withdrawal, naloxone-precipitated withdrawal, and conditioned withdrawal) in relapse to drug seeking. Rats alternately received morphine (10 mg/kg, s.c.) and saline for 8 days to acquire the CPP. The morphine CPP disappeared after a 2-week extinction phase of saline-paired training. Rats were then chronically administered morphine to induce physical dependence. The different withdrawal states were induced and their roles in the reinstatement of extinguished CPP were assessed. During conditioned withdrawal, trunk blood samples were taken and the corticosterone level was measured by radioimmunoassay. To examine the role of corticotropin-releasing factor (CRF) receptor antagonist on conditioned-withdrawal-induced reinstatement of CPP, different doses of alpha-helical CRF (0.1 and 1 mug, i.c.v.) were administered 30 min prior to the CPP testing. The results show that morphine spontaneous withdrawal and naloxone-precipitated morphine withdrawal were ineffective in reinstatement morphine CPP. However, the withdrawal cues significantly elicited the reinstatement of CPP and increased corticosterone level. Moreover, pretreatment with the CRF receptor antagonist alpha-helical CRF (1 mug, i.c.v.) significantly attenuated the effects of withdrawal cues on reinstatement of CPP and corticosterone levels. These findings demonstrate that the cues associated with previous drug withdrawal play a major role in drug relapse and that activation of the CRF receptor is involved in conditioned-withdrawal-induced reinstatement. The present study suggests that CRF receptor antagonists might be of value in the treatment and prevention of relapse to drug seeking after long-term abstinence.

Evidence for bidirectional cues as a function of time following treatment with amphetamine: implications for understanding tolerance and withdrawal

Rationale Previous drug-discrimination studies have focused on characterizing the cue properties associated with amphetamine's (AMPH) primary effect. Results from recent experiments indicate that equally prominent cues are associated with AMPH withdrawal. Objectives The purpose of the present study was to investigate the extent to which AMPH-induced withdrawal cues, opposite to those associated with AMPH's primary effect are observed. Methods Since dopamine (DA) has been implicated in mediating the AMPH cue, rats were trained to discriminate between 0.25 mg/kg AMPH, an indirect DA agonist, and 0.033 mg/kg haloperidol (HAL), a DA antagonist at the D2 receptor site. Training doses were chosen so that rats responded about equally on both levers when tested on saline (SAL) providing a behavioral baseline sensitive to assessing AMPH-related bidirectional changes in cue state. Following acquisition of the discrimination, rats were tested for choice of responding on the AMPH and HAL levers at intervals from 6 to 72 h following treatment with a single dose of 3.0 mg/AMPH. Also, in order to investigate the relationship between withdrawal and tolerance to AMPH's cue properties, AMPH dose–response curves were determined 24 h following treatment with SAL, 1.5 and 3.0 mg/kg AMPH. Results At short intervals after treatment with 3.0 mg/kg AMPH, rats responded primarily on the AMPH lever followed by a shift to predominant responding on the HAL lever 16–30 h post-treatment, before returning to predrug levels. Treatment with 1.5 and 3.0 mg/kg AMPH produced parallel dose–response curve shifts to the right. Conclusions Following a single dose of AMPH, robust cues associated with AMPH withdrawal were observed that lasted approximately three times longer than the cues associated with the drug's primary effects. Furthermore, results from the tolerance tests indicate that tolerance reflects a baseline shift rather than a loss in drug efficacy.

Characterizing withdrawal in rats following repeated drug administration using an amphetamine-vehicle-haloperidol drug discrimination.

Previous research using an amphetamine (AM)-haloperidol (HA) drug- drug discrimination task has shown that predominant responding on the HA-appropriate lever occurs 24 h after a single or multiple administrations of 10 mg/kg AM. Conversely, rebound responding on the AM-appropriate lever occurs following single or multiple administrations of 1 mg/kg HA. HA-appropriate responding was also observed 24 h following a single injection of AM using a three-lever, AM-vehicle-HA discrimination task. However, a single administration of HA did not produce robust rebound responding on the AM-appropriate lever. The present studies seek to clarify the discrepancy between responding following HA in the two- and three-choice tasks. Experiment 1 examined the extent of rebound responding that could be achieved following ten daily administrations of either 10 mg/kg AM or 1 mg/kg HA. Experiment 2 explored potential differences between the two- and three-choice tasks in characterizing the post-HA cue. Animals were trained to discriminate 0.35 mg/kg AM, vehicle, and 0.033 mg/kg HA. In experiment 1, animals received ten daily injections of 10 mg/kg AM, vehicle, or 1 mg/kg HA, and were tested 24 h after the final injection, and again 8, 15, and 22 days post-treatment. In experiment 2, animals were retrained and then treated daily with either vehicle or 1.0 mg/kg HA for 10 days, and then tested 24 h after the final injection, and again 5 and 11 days post-treatment, with either all three levers or with only the AM- and HA-appropriate levers available. In experiment 1, multiple injections of AM produced robust HA lever responding, which is consistent with results from previous studies that used the two-choice, AM-HA discrimination task. However, multiple injections of HA did not produce predominant responding on the AM-appropriate lever. In experiment 2, animals treated with either vehicle or HA responded predominantly on the vehicle-appropriate lever when tested with all three levers present. When tested with the vehicle lever removed, however, animals treated with vehicle responded predominantly on the HA-appropriate lever, whereas those treated with HA responded predominantly on the AM-appropriate lever. These results suggest that the two-choice and three-choice task used here differ in how the post-HA withdrawal cue is characterized. This finding emphasizes the importance of knowing the relative locations of the agonist-, vehicle-, and antagonist-produced cues on the interoceptive stimulus continuum established by discrimination training.

What is learned during opiate withdrawal conditioning? Evidence for a cue avoidance model

How conditioned opiate withdrawal gives rise to avoidance behaviour was examined using a defensive burying procedure in rats made dependent with a morphine pellet. The subjects underwent withdrawal precipitated by naloxone (0.1 mg/kg, SC) on two or three occasions in a box containing only a small object. When exposed to the object in the presence of sawdust one or more days later, the subjects avoided contact and buried this object, i.e., pushed and piled the sawdust against it. The behaviour was seen only when withdrawal had been paired with the object, which was the case even with a choice of objects on the test. Approach but no burying was seen in nondependent animals when the object was paired with 1 mg/kg morphine. Burying, therefore, was concluded to be a defensive response elicited in rats by an object specifically paired with precipitated opiate withdrawal. Consideration of burying and other defensive responses reported to be elicited by cues of withdrawal (conditioned place and taste aversion, and suppression), with respect to the behavioural demands of these responses and the test conditions needed to see them, suggested that a goal of avoidance may be a primary event encoded in a withdrawal cue, as is known for predictors of nonpharmacological noxious events (e.g., shock).