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Addiction Biology

CLINICAL STUDY

doi:10.1111/adb.12140

Incubation of alcohol craving during abstinence in patients with alcohol dependence Peng Li1,2*, Ping Wu2*, Xue Xin3, Yun-Li Fan4, Gui-Bin Wang5, Fan Wang4, Meng-Ying Ma4, Ming-Ming Xue3, Yi-Xiao Luo1,2, Fu-De Yang4, Yan-Ping Bao2, Jie Shi2, Hong-Qiang Sun1 & Lin Lu1,2 Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, Ministry of Health1 and National Institute on Drug Dependence, Peking University, China2, Department of Physiology, Basic Medical College, Inner Mongolia Medical University, China3, Department of Alcohol and Drug Dependence, Beijing Hui-Long-Guan Hospital, Peking University, China4, Institute of Material Medical, Chinese Academy of Medical Sciences and Peking Union Medical College, China5

ABSTRACT Time-dependent increases in cue-induced nicotine and methamphetamine craving during abstinence were recently reported in human drug-dependent individuals. In the present study, we sought to determine whether this ‘incubation of craving’ phenomenon also occurs in alcoholics. Four groups of 80 inpatient adult male alcoholics were assessed in a single session (between-group design) for cue-induced alcohol craving at 7, 14, 30 and 60 days of abstinence. Another group that included 19 patients was repeatedly tested for cue-induced alcohol craving at the same abstinence days as above. Other psychological and physiological measures were assessed at the four abstinence timepoints. Cue-induced alcohol craving measured with visual analogue scales was the highest at 60 days of abstinence both between and within groups. However, heart rate, blood pressure and skin conductance responses did not differ between abstinent groups. These results provide evidence of the incubation of alcohol craving in humans, extending previous reports with smokers and methamphetamine addicts. Keywords

Alcohol dependence, craving, incubation, physiological reaction.

Correspondence to: Lin Lu, Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health, Ministry of Health, and National Institute on Drug Dependence, Peking University, 51, Hua Yuan Bei Road, Haidian District, Beijing 100191, China. E-mail: [email protected]; Hong-Qiang Sun, Institute of Mental Health/Peking University Sixth Hospital, and Key Laboratory of Mental Health, Ministry of Health, Peking University, 51, Hua Yuan Bei Road, Haidian District, Beijing 100191, China. E-mail: [email protected]

INTRODUCTION Alcohol dependence is a chronic relapsing disease that contributes to significant global disease burden (Rehm et al. 2009). Relapse to alcohol use is a major clinical problem in the treatment of alcohol dependence, with a rate as high as 60–80 percent within 1 year (Barrick & Connors 2002; Jaffe 2002). Furthermore, the relapse rate of alcoholism is still 45 percent at 3-year follow-up (Bottlender & Soyka 2005). Passive exposure to drug-associated environmental cues may elicit relapse to drug use in human addicts after weeks or months of abstinence (Drummond, Cooper & Glautier 1990; George et al. 2001; Shi et al. 2008). However, the factors that underlie time-delayed relapse are poorly understood. Increased craving induced by

drug-related cues is believed to play a fundamental role in this process (Shi et al. 2009). Previous studies have shown that drug-related cues can evoke robust subjective craving and physiological responses (Carter & Tiffany 1999). Animal studies have indicated that protracted abstinence does not eliminate cue-induced drug-seeking behavior assessed by several established procedures, including extinction (Ciccocioppo, Angeletti & Weiss 2001; Shalev et al. 2001; Hollander & Carelli 2007) and cue-induced reinstatement (Grimm et al. 2001; Bienkowski et al. 2004; Abdolahi et al. 2010). Investigators have identified the ‘incubation’ phenomenon in rodents, in which time-dependent increases in cueinduced craving for cocaine (Grimm et al. 2001; Lu et al. 2004), heroin (Shalev et al. 2001), methamphetamine (Shepard et al. 2004), morphine (Li et al. 2008), nicotine

*The first two authors contributed equally to this work. © 2014 Society for the Study of Addiction

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(Abdolahi et al. 2010), alcohol (Bienkowski et al. 2004; Weerts et al. 2006) and sucrose (Uejima et al. 2007) occur after withdrawal, assessed by drug selfadministration and conditioned place preference. Recently, Bedi et al. (2011) reported the incubation of cue-induced cigarette craving during abstinence in human smokers. Our recent study in methamphetamine abusers also found that cue-induced craving increased until 3 months of abstinence (Wang et al. 2013). Although preclinical studies have found that cue-induced alcohol craving time dependently increased after withdrawal, this phenomenon has not yet been shown in alcoholic subjects (Bienkowski et al. 2004). Therefore, we sought to determine whether the ‘incubation’ of drug craving generalizes to alcoholism.

MATERIALS AND METHODS Participants The study was approved by the Ethics Committee of Beijing Hui-Long-Guan Hospital, Beijing, China. All of the patients were male inpatients, aged 18–60 years and recruited from Beijing Hui-Long-Guan Hospital. The subjects provided written informed consent after a full explanation of the experimental protocol. Before enrollment, it took 1–2 days for the participants to undergo a rigorous screening that involved a medical history interview and physical examination. The patients with abuse of other drugs (excluding alcohol and nicotine), diagnosed by selfreport or positive urine testing at the recruitment screening, a current or past history of disorders included in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) axis I (American Psychiatric Association 2000), and other serious physical diseases (e.g. respiratory disorders and cardiovascular disease) were excluded. The diagnosis of alcohol dependence was made according to the DSM-IV. The subjects received financial compensation at the end of the experiment. A total of 110 participants were enrolled and randomly assigned to five groups using a random number table, which was generated by SPSS software 20.0 (IBM, Armonk, NY, USA). Of 110 participants enrolled, 99 were included in the final dataset for statistical analysis (see Supporting Information Fig. S1). The subjects in group 1 (n = 17), group 2 (n = 20), group 3 (n = 23) and group 4 (n = 20) were exposed to alcohol-associated stimuli and underwent alcohol craving test on abstinent days 7, 14, 30 or 60 after withdrawal from alcohol use, respectively. The subjects in group 5 (n = 19) went through repeated cue sessions on abstinent days 7, 14, 30 and 60 after withdrawal from alcohol use for withinsubject comparison. The last drink of all the subjects was © 2014 Society for the Study of Addiction

on the day before admission. The time of last drink was reported by themselves and their relatives who accompanied the patients to the hospital. Usually, the treatment period was 1–3 months, so all the patients were required to stay 1–3 months in the hospital on admission. In fact, the average length of stay in hospital was 62.82 ± 34.62 days in this study, without significant difference between groups (F4, 94 = 1.134, P = 0.345), which thus excluded the bias caused by variations in the length of stay. During the period of hospitalization, the subjects had no access to alcohol. Breath alcohol testing was used to verify continued abstinence. Basic demographics and drinking history were assessed using the Montreal Cognitive Assessment (MoCA, Beijing version; Nasreddine et al. 2005), Self-Rating Anxiety Scale (SAS; Zung 1971), Self-Rating Depression Scale (SDS; Zung 1965) and Michigan Alcohol Screening Test (MAST; Selzer 1971). Additionally, withdrawal symptoms were assessed using the Alcohol Withdrawal Syndrome (AWS) scale (Wetterling et al. 1997) at the beginning of each cue session. In addition, all the subjects underwent detoxification and rehabilitation in the inpatient unit. The benzodiazepines were used for the treatment of alcohol withdrawal symptoms, such as diazepam and oxazepam. Additionally, all the patients received antipsychotic medication, and the majority of them received quetiapine (n = 62). There was no significant difference between the five groups in the percentage of subjects who used antipsychotic medication, and in the dose and duration of antipsychotic medication administered. Cue sessions During the cue sessions, neutral and alcohol-related cues were presented to the subjects in a fixed order, in which the neutral cues were always presented prior to the alcohol cues to avoid carry-over effects of the alcohol cues (Monti et al. 1987). The cue exposure sessions included visual and olfactory stimuli (Schacht, Anton & Myrick 2013). The visual stimuli included a set of 30 neutral pictures (natural scenery) and 30 alcohol-related color photographs (e.g. beer, liquor and drinking settings) that were obtained from the Internet. All of the visual stimuli were standardized with regard to brightness and color using Photoshop 5.0 (Adobe Systems Incorporated, San Jose, CA, USA) and resized to 12 × 12 cm. The olfactory stimuli included water and the subjects’ favorite alcoholic beverages used in our prior study (Sun et al. 2012). The participants first viewed 30 neutral pictures while holding, but not drinking, a glass of water for 3 minutes in the neutral cue session, followed by a 30-minute rest period, during which the subjects were asked to do nothing. The alcohol cue session began when heart rate (Croissant et al. 2006) and blood pressure (BP) recovered to normal levels after a 30-minute rest period. In this Addiction Biology, 20, 513–522

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session, the participants viewed 30 alcohol-related photographs while holding, but not drinking, a glass of liquor or beer that they usually drank. Heart rate, BP, skin conductance responses (SCRs) and subjective measures were collected before and after the presentation of each cue. Subjective measures were assessed using a visual analogue scale (VAS) of craving, depression and anxiety (George et al. 2001) and the Alcohol Urge Questionnaire (AUQ; Bohn, Krahn & Staehler 1995). After cue-exposure sessions, all subjects were given a relaxation script.

cate how strongly they currently agree or disagree with each item using a scale from 1 (strongly disagree) to 7 (strongly agree).

Psychological and physical assessments

Heart rate, BP and skin conductance

MoCA

Heart rate and BP were monitored using an automated BP monitor (HEM-4021, OMRON Healthcare Product Development Co., Ltd., Dalian, Liaoning, China). Skin conductance was recorded using a pair of silver–silver chloride electrodes with sodium chloride gel placed on the distal phalanges of digits 2 and 3 of the left hand. We monitored HR, systolic BP (SBP), diastolic BP (DBP) and SCRs at the beginning and immediately before and after neutral cue and alcohol-related cue exposure.

The MoCA, Beijing version, was translated from the original English version (Nasreddine et al. 2005). The test is available at the official website (http://www.MoCAtest .org; accessed November 3, 2013). The MoCA examines seven cognitive domains, including visuospatial/ executive function, naming, attention, abstraction, language, delayed memory and orientation. Each correct answer or operation receives one point. SAS The SAS was used to quantify a patient’s level of anxiety (Zung 1971) on enrollment as a baseline measure. It is a 20-item, self-report assessment. Each question is scored on a scale of 1–4, based on the following responses: ‘a little of the time’, ‘some of the time’, ‘a good part of the time’ and ‘most of the time’. SDS The SDS is a short self-administered questionnaire that quantified the depressed status of a patient (Zung 1965) on enrollment as a baseline measure. The scale has 20 items, and each question is scored on a scale from ‘little or none of the time’ (1) to ‘most of the time’ (4).

AWS The AWS scale included a total of 10 items that assessed the level of withdrawal. The score for each item ranged from 0 (none) to 7 (extreme), with the exception of ‘orientation’. The total score is 67 points (Wetterling et al. 1997).

Statistical analysis All of the data were analyzed using SPSS software 20.0 (IBM). Only outcome measures that were sensitive to alcohol-related cues were included in the main analysis. ANOVA followed by the Student–Newman–Keuls least significant difference test was used to analyze group differences in the demographic and clinical data and baseline craving. Change scores for cue-induced craving, HR, SBP, DBP and SCRs were also analyzed using ANOVAs, with alcohol and neutral cues analyzed separately (Bedi et al. 2011). In group 5, repeated-measure ANOVA, with time (7, 14, 30 and 60 days) as the within-subject factor, was conducted to determine the effect of abstinence time on changes in craving (Bedi et al. 2011). Post hoc analyses were performed when group differences were significant in the ANOVA (P < 0.05).

MAST The MAST is a 24-item questionnaire that evaluates the degree of alcohol dependence (Selzer 1971).

RESULTS Demographic and clinical data

VAS Alcohol craving, depression and anxiety data were collected using a VAS, which is a continuous scale from 0 (‘not at all’) to 100 (‘extremely high’; George et al. 2001). AUQ The AUQ is an eight-question measure of drinking urges (Bohn et al. 1995). The participants were asked to indi© 2014 Society for the Study of Addiction

The demographic and clinical data of all of the subjects are shown in Table 1. All of the groups were matched with regard to age, years of education, alcohol drinking history, hospital stay, MAST score and the number of cigarettes smoked per day. Moreover, MoCA score, SAS score and SDS score did not differ between the four singlecue groups. Furthermore, nine subjects in the group with the within-group design completed the cue sessions on abstinence days 7, 14 and 30, but did not participate in Addiction Biology, 20, 513–522

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Table 1 Demographic and clinical features of the participants in each group.

Characteristic Age (years) Education (years) Age of first exposure (years) Duration (years) Hospital stay (days) MAST score Cigarettes per day MoCA score SAS score SDS score

Group 1 7 days n = 17 Mean (SD)

Group 2 14 days n = 20 Mean (SD)

Group 3 30 days n = 23 Mean (SD)

Group 4 60 days n = 20 Mean (SD)

Group 5 Repeated condition n = 19 Mean (SD) F (d.f.)

44.29 (7.35) 11.53 (2.65) 19.82 (5.50)

48.15 (6.11) 10.20 (3.51) 19.10 (5.52)

46.83 (9.54) 10.22 (2.11) 18.74 (3.67)

48.05 (6.62) 10.75 (2.69) 20.25 (5.78)

44.16 (9.11) 11.63 (3.25) 20.00 (5.56)

9.12 (4.51) 54.3 (30.22) 13.53 (4.13) 16.00 (9.06) 22.47 (2.90) 40.12 (7.29) 40.53 (8.61)

11.80 (5.80) 57.20 (52.53) 13.05 (2.52) 20.40 (7.58) 21.40 (4.51) 36.40 (7.26) 42.78 (7.31)

9.15 (8.06) 60.43 (22.57) 12.24 (3.98) 17.75 (9.47) 22.40 (4.55) 41.04 (9.02) 39.00 (9.58)

9.67 (6.39) 7.84 (6.63) 75.60 (20.01) 65.74 (33.74) 10.95 (3.59) 13.16 (4.17) 18.16 (3.58) 19.00 (10.55) 22.39 (5.03) 37.32 (7.20) 41.42 (9.96)

P-value

1.16 (4,94) 0.34 1.13 (4,94) 0.35 0.31 (4,94) 0.87 0.99 (4,89) 1.13 (4,94) 1.43 (4,91) 0.61 (4,88) 0.27 (3,73) 1.65 (3,75) 0.62 (3,73)

0.42 0.35 0.23 0.66 0.85 0.19 0.60

d.f. = degrees of freedom; MAST = Michigan Alcohol Screening Test; MoCA = Montreal Cognitive Assessment (Beijing version); SAS = Self-Rating Anxiety Scale; SD = standard deviation; SDS = Self-Rating Depression Scale.

the cue session on abstinence day 60 because they were discharged from the hospital.

P > 0.05; DBP: F3, 74 = 0.27, P > 0.05) and SCRs (F3, 76 = 1.14, P > 0.05), did not differ (Fig. 3).

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The ANOVA revealed significant between-group differences in craving ratings (F3, 76 = 3.23, P < 0.05; Fig. 1a), and maximal responding to the alcohol cues was observed in the 60-day group. The alcohol cue-induced VAS score was higher in the 60-day group than in the 7-day group (P < 0.01). However, no difference in change scores on the AUQ (F3, 76 = 0.63, P > 0.05; Fig. 1b), anxiety (F3, 76 = 0.43, P > 0.05; Fig. 1c) or depression (F3, 76 = 1.25, P > 0.05; Fig. 1d) was found between groups. Additionally, no between-group difference in VAS change scores were found in responding to the neutral cues (F3, 76 = 0.06, P > 0.05; Fig. 1a).

In the within-group design, although the length of abstinence did not affect cue-induced AUQ scores (F3, 36 = 1.17, P > 0.05; Fig. 1f), anxiety (F3, 36 = 0.51, P > 0.05; Fig. 1g) or depression (F3, 36 = 1.55, P > 0.05; Fig. 1h), a significant effect on VAS score was found (F3, 36 = 3.59, P < 0.05; Fig. 1e), with more pronounced cue responses on day 60 than on day 7 (P < 0.05). Baseline craving The VAS and AUQ scores were not significantly different in the within-group design (VAS: F3, 36 = 1.90, P > 0.05; AUQ: F3, 36 = 0.31, P > 0.05; Fig. 2c and d).

Baseline craving Drinking craving at different abstinence timepoints before neutral cue presentation is shown in Fig. 2. The ANOVA indicated that the baseline craving, indicated by either the VAS or AUQ, did not change with abstinence (VAS: F3, 76 = 0.15, P > 0.05; AUQ: F3, 76 = 0.27, P > 0.05; Fig. 2a and b).

Heart rate, BP and skin conductance The ANOVA revealed no significant difference in HR (F3, 36 = 2.45, P > 0.05), BP (SBP: F3, 36 = 0.22, P > 0.05; DBP: F3, 36 = 0.66, P > 0.05) or SCRs (F3, 36 = 1.05, P > 0.05; Fig. 3). Withdrawal symptoms

Heart rate, BP and skin conductance The ANOVA indicated that the effects of length of abstinence on cue-induced physiological measures, including HR (F3, 76 = 0.26, P > 0.05), BP (SBP: F3, 76 = 0.09, © 2014 Society for the Study of Addiction

Withdrawal symptoms assessed by the AWS scale progressively decreased with abstinence in both the betweengroup (F3, 76 = 4.78, P < 0.01; Fig. 4a) and within-group (F3, 36 = 3.04, P < 0.05; Fig. 4b) design. A significant Addiction Biology, 20, 513–522

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DISCUSSION The present study investigated the time course of cueinduced craving in alcoholism. We found that cueinduced craving in alcohol addicts did not decline but rather increased with an increased abstinence period up to 60 days, reflected by VAS scores in both the between- and within-group designs, although withdrawal symptoms

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© 2014 Society for the Study of Addiction

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Figure 1 Effects of exposure to alcoholrelated and neutral cues on self-reported craving with abstinence time. Left column: single-cue conditions [group 1 (7-day abstinence): n = 17; group 2 (14-day abstinence): n = 20; group 3 (30-day abstinence): n = 23; group 4 (60-day abstinence): n = 20]. Right column: repeated cue condition (group 5: n = 19). (a, e) Visual analogue scale (VAS) craving score in response to cues. (b, f) Alcohol Urge Questionnaire Scale (AUQ) total score in response to cues. (c, g) VAS anxiety score in response to cues. (d, h) VAS depression score in response to cues. *P < 0.05, significant difference from group 1 (7-day abstinence). The data are expressed as group means (±SE)

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gradually decreased over time. However, HR, BP, SCRs, anxiety and depression did not change with withdrawal time after alcohol cue exposure. The baseline levels of craving also did not change. During the past decade, the ‘incubation’ phenomenon has been identified in both animal and human studies, in which time-dependent increases in cue-induced craving were observed after prolonged withdrawal. This phenomenon was supposed to be the underlying factor for timedelayed relapse. Drug cue-induced increases in craving in the laboratory have been reported to predict future drug relapse risk in heroin and cocaine addicts (Seo et al. Addiction Biology, 20, 513–522

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2013; Sinha 2013), suggesting that the risk for relapse may increase with an increased length of abstinence in alcohol-dependent individuals. We found that alcohol-related cues induced a timedependent increase in craving, which is consistent with previous findings of incubation in both animal and human studies. In a rat operant oral alcohol selfadministration model, alcohol-seeking behavior evoked by alcohol-associated cues reached a maximal level after 8 weeks of withdrawal (Bienkowski et al. 2004). Moreover, Bedi et al. (2011) provided initial evidence of the incubation of cue-induced cigarette craving up to 35 days in human smokers who were paid to abstain, in which incidental cue exposure was unavoidable. Therefore, we conducted the present study in patients who lived in an inpatient setting where incidental drug cue exposure was minimized. This could overcome the extinction of the conditioned response to alcohol cues. Additionally, our previous study in methamphetamine abusers found the incubation of cue-induced craving up to 3 months in a cross-sectional study at an addiction rehabilitation center (Wang et al. 2013). These results may provide more solid evidence for identifying incubation of drug craving in human. However, incubation was evident in some but not all self-reported measures. The possible reason for this is that alcoholics have a significantly smaller craving effect size in craving self-reports (Carter & Tiffany 1999). Additionally, physiological reactions, such as HR, BP and SCRs, in abstinent drug abusers did not differ between the different © 2014 Society for the Study of Addiction

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Figure 2 Effects of length of abstinence on baseline craving. Left column: single-cue conditions [group 1 (7-day abstinence): n = 17; group 2 (14-day abstinence): n = 20; group 3 (30-day abstinence): n = 23; group 4 (60-day abstinence): n = 20]. Right column: repeated cue condition (group 5: n = 19). (a, c) Visual analogue scale (VAS) craving score at baseline. (b, d) Alcohol Urge Questionnaire Scale (AUQ) total score at baseline. The data are expressed as group means (±SE)

abstinent groups. The possible reasons for differences in self-reported craving and physiological responses are still unclear. These physiological processes that supposedly reflect cue reactivity also contain a great deal of noise and are most likely engaged by many functions that are unrelated to drug cue manipulations (Carter & Tiffany 1999). The baseline levels of craving in the present study did not change with withdrawal time, which is inconsistent with the results of the two incubation studies in humans cited above (Bedi et al. 2011; Wang et al. 2013), probably because the participants were hospitalized and received medical treatment (e.g. quetiapine), which may make the craving for alcohol relatively stable when the patient is not exposed to alcohol-related cues. Previous studies have shown that quetiapine reduces alcohol craving and prevents relapse (Croissant et al. 2006; Ray et al. 2011) while recently a meta-analysis suggests that antipsychotics including quetiapine do not reduce drinking or craving in patients with primary alcohol dependence (Kishi et al. 2013). Although whether quetiapine can reduce craving is controversial and we cannot rule out the effects of antipsychotics on alcohol craving in the present study, there is no evidence showing that quetiapine may increase alcohol craving after all, suggesting that the incubation of alcohol craving is quite robust. Furthermore, the incubation of alcohol craving is completely different from ‘alcohol deprivation effect (ADE)’, a relapse episode occurring in human alcoholics. ADE is a transient increase in alcohol intake above Addiction Biology, 20, 513–522

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baseline values when re-exposure to alcohol following a period of alcohol deprivation (Sinclair & Senter 1967); it has been observed repeatedly in various laboratory animals (Kornet, Goosen & Van Ree 1990; Heyser, Schulteis & Koob 1997; Agabio et al. 2000; Tambour, Brown & Crabbe 2008). The increase in alcohol intake is short lasting and returns to baseline levels within 1–3 days, although the ADE can be observed after a long deprivation period (Heyser et al. 1997; Agabio et al. 2000). However, the incubation phenomenon is identified as time-dependent increases in cue-induced craving (Grimm © 2014 Society for the Study of Addiction

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Figure 3 Effects of exposure to alcohol and neutral cues on heart rate, blood pressure and skin conductance responses with abstinence time. Left column: singlecue conditions [group 1 (7-day abstinence): n = 17; group 2 (14-day abstinence): n = 20; group 3 (30-day abstinence): n = 23; group 4 (60-day abstinence): n = 20]. Right column: repeated cue condition (group 5: n = 19). (a, e) Heart rate (HR) response to cues. (b, f) Systolic blood pressure (SBP) response to cues. (c, g) Diastolic blood pressure (DBP) response to cues. (d, h) Skin conductance response (SCR) to cues. The data are expressed as group means (±SE)

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et al. 2001). In the present study, we found that the magnitude of cue-induced drinking craving increased with abstinence period up to 60 days. This means that the incubation phenomenon is relatively long lasting. In addition, the ADE could only be observed with access to alcohol while the incubation of craving exists without exposure to alcohol, which allows us to understand the craving states of alcoholics with little risk of relapse. The mechanism that underlies the incubation of drug craving in humans is still unclear. Previous animal studies suggest that the incubation of drug craving may Addiction Biology, 20, 513–522

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be mediated by neuronal activity and synaptic plasticity within several brain areas, such as the nucleus accumbens (Conrad et al. 2008; Loweth, Tseng & Wolf 2014), medial prefrontal cortex (Koya et al. 2009), orbitofrontal cortex (Fanous et al. 2012) and central nucleus of the amygdala (CeA; Lu et al. 2005; Li et al. 2008). Neuroimaging studies revealed that cue-induced craving was correlated with activation of the amygdala after short term (

Incubation of alcohol craving during abstinence in patients with alcohol dependence.

Time-dependent increases in cue-induced nicotine and methamphetamine craving during abstinence were recently reported in human drug-dependent individu...
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