Addiction Relapse Research Articles

Investigation of Factors Affecting on Relapse of Addiction in Substance Abuse Patients Referred to Narcotics Anonymous Population

Investigation of Factors Affecting on Relapse of Addiction in Substance Abuse Patients Referred to Narcotics Anonymous Population

Accelerated repetitive transcranial magnetic stimulation does not influence grey matter volumes in regions related to alcohol relapse: An open-label exploratory study

The application of repetitive transcranial magnetic stimulation (rTMS) to prevent relapse in alcohol addiction is currently being evaluated. However, how rTMS may influence the related brain processes is far from clear. Here we wanted to investigate whether baseline grey matter volume (GMV) can predict relapse and whether 15 accelerated high-frequency (HF)- rTMS sessions may influence GMV in areas related to relapse. Voxel-based morphometric (VBM) measurements were used to compare baseline GMV of 22 detoxified, hospitalized, alcohol-dependent patients with 22 age and gender matched healthy control subjects. Only patients received 15 accelerated HF-rTMS sessions at the right dorsolateral prefrontal cortex (DLPFC) followed by VBM measurements. Relapse rates were assessed four weeks after the end of the stimulation protocol. At baseline, alcohol-dependent patients overall showed less GMV in diffuse brain areas compared to healthy controls. Relapsers compared to abstainers displayed larger GMV decreases, especially in brain midline structures, insular, hippocampal, and amygdalar areas. Accelerated HF-rTMS treatment had no significant effect on GMV in alcohol-dependent patients, regardless of the relapse state. Although an accelerated HF-rTMS treatment protocol did not influence GMV in alcohol-dependent patients, baseline GMV predicted future relapse.

Spiritual Influence Towards Relapse in Opioid Addicts in Therapy

Introduction: Substance abuse is both a social and public health problem with a substantial burden to society. Opioid dependence results in unemployment, crimes, family disruption, and transmission of diseases. In Malaysia, methadone maintenance therapy (MMT) has been introduced as a harm reduction method. However, relapse during treatment remains an issue to be resolved that hinders successful outcome in the therapy. Spirituality in the treatment of substance abuse disorders has yet to be fully explored. This study aims to examine how MMT clients who relapsed perceive spiritual deficits as an influence and association of spiritual practice with relapse. Methods: This is a cross-sectional study done from June-July 2016. All MMT clients undergoing therapy at 3 treatment centers in Terengganu, Malaysia who fulfilled the inclusion and exclusion criteria and consented were included in the study. A semi-structured questionnaire was filled via face to face interview and spiritual practice was assessed using Hatta Islamic Religiosity Scale. 121 questionnaires were assessed and data was analyzed using SPSS version 22 for quantitative data. Results: All respondents were males of Malay race and Islamic religion. Current relapse, defined as any episode of intake of opioid for the past one month after a period of abstinence was 34%. Only three out of 42 clients who relapsed had some spirituality theme in their perceived cause of their relapse. However, a significant majority of those relapsed had a spiritual practice score of less than the mean practice score. Conclusion: Relapse in opioid addiction remains high in those receiving MMT in Terengganu, Malaysia. Spirituality may have a subconscious influence towards relapse in addiction in MMT clients. Further effort should be taken to inculcate spirituality intervention effective to prevent relapse which may contribute towards achieving a more successful therapy outcomes.

Assessment the Causes of Substance Abuse “Related Relapse among Patients with Addiction in Baghdad City

Background: One of the most problems that face the health workers in addiction units is the relapse of addict patient after a period of treatment. No studies are conducted about the addiction relapse in Iraq.Aims of study: The current study aims to assess the causative factors affecting the substance abuse-related relapse. And find out the relationship between the demographic characteristics and the cause of relapse.Methodology: A descriptive study was conducted from November 15th 2015 to April 15th 2016 on addict patient in Baghdad City. Purposive (non-probability) samples of 65 relapsed addicts who are inpatient in Ibn-Rushd Psychiatric Teaching Hospital and the Psychiatric unit of Baghdad Teaching Hospital who had undergone treatment for substance dependency and they had at least one episode of relapse during the period of addiction. The study uses the self-administrated questionnaire. The data has been analyzed by using the descriptive statistics (Frequencies, Percentages, Means and Standard Deviations (SD)) and the inferential statistics (Chi-square to find out the relationships between the causes of the relapse and the socio-demographic characteristics of addicts).Results: the findings of the current study revealed that all relapsed patients are males with age ranged from 18 years to more than 50 years. The age of onset of substance abuse ranged from 9 years to more than 29 years. Most of addict patients were relapsed during the first six months after treatment. The highest percentage of the addict patients was addicted to alcohol. The results indicated that the main causes of relapse were the feeling of urgent desire for abuse, the availability of the substance and lack of knowledge about the risk to return to addiction and the tension of family relations. There is no significant relationship between the age and occupation of addict patients and the cause of relapse. There is a significant relationship between monthly income and cause of relapse.Conclusions: the study concluded that the feeling of urgent desire for abuse, the availability of the substance, lack of knowledge about the risk to return to addiction and the tension of family relations are the main cause of relapse. There is a significant relationship between monthly income and cause of relapse. There is no significant relationship between the age and occupation of addict patients and the cause of relapse.Recommendations: the study recommended that the treatment programs should be focusing on teaching the clients how to cope with the relapse and control the feeling of craving for substance abuse.

Reinstatement of Drug-seeking in Mice Using the Conditioned Place Preference Paradigm.

The present protocol describes the Conditioned Place Preference (CPP) as a model of relapse in drug addiction. In this model, animals are first trained to acquire a conditioned place preference in a drug-paired compartment, and after the post-conditioning test, they perform several sessions to extinguish the established preference. The CPP permits the evaluation of the conditioned rewarding effects of drugs related to environmental cues. Then, the extinguished CPP can be robustly reinstated by the non-contingent administration of a priming dose of the drug, and by exposure to stressful stimuli. Both methods will be explained here. When the animal reinitiates the behavioral response, a reinstatement of the conditioned reward is considered to have taken place. The main advantages of this protocol are that it is non-invasive, inexpensive, and simple with good validity criteria. In addition, it allows the study of different environmental manipulations, such as stress or diet, which can modulate relapse into drug seeking behaviors. However, one limitation is that if the researcher aims to explore the motivation and primary reinforcing effects of the drug, it should be complemented with self-administration procedures, as they involve operant responses of animals.

(-)-Stepholidine reduces cue-induced reinstatement of cocaine seeking and cocaine self-administration in rats

BackgroundDopamine receptors are implicated in cocaine reward and seeking. We hypothesize that (-)-stepholidine, a dopamine D1/D2/D3 multi-receptor agent, would be effective in reducing cocaine reward and seeking in an animal model. We investigated the effects of (-)-stepholidine in cue-induced reinstatement of cocaine seeking and cocaine self-administration (reward). MethodsCue-induced reinstatement experiment: Rats were trained to press a lever reinforced by cocaine (1 mg/kg/injection) for 15 consecutive daily sessions, after which the response was extinguished by withholding cocaine and cocaine-paired cues (light and pump activation). This was followed by a cue-induced reinstatement test where subjects were exposed to two cocaine cue presentations and presses on the active lever produced cues. Subjects were treated with one of four (-)-stepholidine doses prior to the reinstatement test. Cocaine self-administration (reward) experiment: Rats were trained to self-administer cocaine under a progressive ratio schedule of reinforcement. After stable breakpoints were established, rats were injected with four doses of (-)-stepholidine prior to testing; each dose was injected prior to a separate test session with no-treatment sessions intervening to re-establish break points. Results(-)-Stepholidine significantly reduced cue-induced reinstatement of cocaine seeking in a dose-related manner. Additionally, (-)-stepholidine significantly reduced break points for cocaine reward. (-)-Stepholidine did not significantly affect locomotor activity. Conclusions(-)-Stepholidine reduces cue-induced reinstatement of cocaine seeking and cocaine reward, suggesting that it may be useful in treating relapse in cocaine addiction.

Glucocorticoid receptor gene variants and lower expression of NR3C1 are associated with cocaine use.

Animal and cross-sectional human studies suggest that chronic cocaine use is associated with altered responsivity of the hypothalamic-pituitary-adrenal axis to stress. Moreover, increased susceptibility to stress has been proposed as an important factor for development, maintenance and relapse of cocaine addiction. As the glucocorticoid receptor gene (NR3C1) mediates genomic effects of the stress hormone cortisol, we investigated NR3C1 expression and the association of NR3C1 genotypes with cocaine use, addiction and comorbid psychiatric symptoms in 126 chronic cocaine users and 98 stimulant-naïve healthy controls. A comprehensive psychiatric assessment was performed including severity of depressive symptoms and current psychological distress. Whole blood NR3C1 mRNA levels were determined and six NR3C1 polymorphisms (rs10482605, rs41423247, rs10052957, rs6189, rs56149945 and rs6198) were genotyped. Compared to controls, cocaine users showed significantly lower NR3C1 expression (P<0.001), which was not affected by NR3C1 genotypes. In controls, rs41423247 [P<0.01, false discovery rate (FDR)-corrected], haplotype 2 and haplotype 3 (both P<0.05, FDR-corrected) were associated with altered NR3C1 gene expression. Haplotype 3 (including minor alleles of rs10052957 and rs41423247) was associated with an increased risk for cocaine addiction (odds ratio=2.74, P<0.05, uncorrected). Moreover, addicted cocaine users carrying haplotype 3 showed higher depression scores (P<0.01, FDR-corrected) than noncarriers. Considering possible confounding effects of alcohol and/or depression, we conclude that chronic cocaine use is associated with lower NR3C1 gene expression suggesting possible direct effects of the drug on the biological adaptation of stress-related genes. Finally, we postulate that haplotype 3 of NR3C1 might serve as a potential risk factor for stimulant addiction and associated psychiatric symptoms.

Superiority of Buprenorphine over Suboxone in Preventing Addiction Relapse in Opioid Addicts under Maintenance Therapy: A Double-Blind Clinical Trial

Background: In maintenance therapy for opioid addiction, to reduce the risk of buprenorphine (BUP) abuse, the combination of BUP and naloxone (NX) has been developed and is commercially available as suboxone (BUP/NX). This study was designed to compare addiction relapse frequency in patients receiving BUP and BUP/NX as maintenance therapy. Methods: In this double-blind clinical trial with cross over design, 100 opioid abusers were randomly assigned to two treatment groups to receive either BUP or BUP/NX. After three months, without a time-out period, subjects undertook treatment with the other drug. The subjects were screened weekly for urinary morphine. Results: In each of the study arms, when the patients were given BUP/NX, the number of relapses was significantly higher compared to when they received BUP (0.13±0.24 vs. 0.04±0.09, P = 0.001). If participants� age was taken into account, the number of relapses was significantly higher when BUP/NX was given in age groups of 31 to 40 years and over 50 years (P < 0.05). The length of addiction had also a significant impact on the number of relapses, i.e., patients with over 10-year history of addiction had higher number of relapses if they were given BUP/NX compared with BUP (P < 0.05). Conclusion:BUP seems to be more effective than BUP/NX in preventing addiction relapse in opioid abusers under maintenance treatment.

Hopelessness Scores and Urine Tests in Patients With Methadone Maintenance Therapy

Background: Feelings of hopelessness could be a potential sign of relapse in opiate addiction. Objectives: We investigated statistical relationship of self-reports of hopelessness by patients in methadone maintenance treatment (MMT) to concurrent drug abuse. Patients and Methods: Fifty-two MMT outpatients (34 men, 18 women, mean age 33.6, SD = 9.7) completed the Beck Hopelessness Scale (BHS) to describe how they felt within the last 7 days. Results of urine screening tests for opiates, cocaine, oxycodone, and benzodiazepines were also recorded for the last 7 days. Results: 67.3% of the patients scored within the normal BHS range (scores 14). On urine tests, 23.1% of the patients tested positive for opiates at least once in the last 7 days, 19.2 % for cocaine, and 17.3% for oxycodone. These three urine tests were neither significantly correlated (P > 0.05) with hopelessness scores, nor with gender or age. Only 4 patients tested positive for benzodiazepines (7.7 %). Conclusions: Mild to moderate reports of hopelessness among MMT patients were unrelated to their concurrent abuse of opiates, cocaine, and oxycodone.

Protein Translation in the Nucleus Accumbens Is Dysregulated during Cocaine Withdrawal and Required for Expression of Incubation of Cocaine Craving.

Exposure to drug-associated cues can induce drug craving and relapse in abstinent addicts. Cue-induced craving that progressively intensifies ("incubates") during withdrawal from cocaine has been observed in both rats and humans. Building on recent evidence that aberrant protein translation underlies incubation-related adaptations in the NAc, we used male rats to test the hypothesis that translation is dysregulated during cocaine withdrawal and/or when rats express incubated cocaine craving. We found that intra-NAc infusion of anisomycin, a general protein translation inhibitor, or rapamycin, an inhibitor of mammalian target of rapamycin, reduced the expression of incubated cocaine craving, consistent with previous results showing that inhibition of translation in slices normalized the adaptations that maintain incubation. We then examined signaling pathways involved in protein translation using NAc synaptoneurosomes prepared after >47 d of withdrawal from cocaine or saline self-administration, or after withdrawal plus a cue-induced seeking test. The most robust changes were observed following seeking tests. Most notably, we found that eukaryotic elongation factor 2 (eEF2) and eukaryotic initiation factor 2α (eIF2α) are dephosphorylated when cocaine rats undergo a cue-induced seeking test; both effects are consistent with increased translation during the test. Blocking eIF2α dephosphorylation and thereby restoring its inhibitory influence on translation, via intra-NAc injection of Sal003 just before the test, substantially reduced cocaine seeking. These results are consistent with dysregulation of protein translation in the NAc during cocaine withdrawal, enabling cocaine cues to elicit an aberrant increase in translation that is required for the expression of incubated cocaine craving.SIGNIFICANCE STATEMENT Cue-induced cocaine craving progressively intensifies (incubates) during withdrawal in both humans and rats. This may contribute to persistent vulnerability to relapse. We previously demonstrated a role for protein translation in synaptic adaptations in the NAc closely linked to incubation. Here, we tested the hypothesis that translation is dysregulated during cocaine withdrawal, and this contributes to incubated craving. Analysis of signaling pathways regulating translation suggested that translation is enhanced when "incubated" rats undergo a cue-induced seeking test. Furthermore, intra-NAc infusions of drugs that inhibit protein translation through different mechanisms reduced expression of incubated cue-induced cocaine seeking. These results demonstrate that the expression of incubation depends on an acute increase in translation that may result from dysregulation of several pathways.

Predictors of craving and substance use among patients with alcohol, tobacco, cannabis or opiate addictions: Commonalities and specificities across substances

IntroductionCraving has been proposed as a major contributor to addiction relapse and the influence of mood on craving and substance use has been extensively documented. However, information is lacking concerning the extent to which the magnitude of these effects may vary according to different types of substances. The aim of the present study was to compare the prospective links between emotions, craving and substance use in four groups of patients beginning treatment for alcohol, tobacco, cannabis, or opiate addiction. MethodsEcological Momentary Assessment (EMA) was used over a two-week period. Data were analyzed using hierarchical linear modeling (HLM). Results159 participants were recruited (67.3% male; M = 36.7 years). The average response rate to the EMA assessments was 83.1%. The findings confirmed the strong predictive role of craving intensity on substance use reported at the next assessment of the day among the alcohol (γ = 0.224; p = .018), tobacco (γ = 0.133; p = .013) and cannabis groups (γ = 0.266; p = .019), but not for opiates (γ = 0.098; p = .142). Craving intensity was itself predicted by greater anxious mood (γ = 0.108; p = 0,029) and event negativity (γ = 0.107; p = .003) among tobacco patients, lower sad mood among cannabis patients (γ = −0.248; p = 0,002), and lower event negativity among opiate patients (γ = −0.201; p = .002). ConclusionWhile these results support the benefit of targeting craving in addiction treatment regardless of substance type, the substance-specific emotional risk factors for craving identified in this study may provide important insights for the development of personalized treatment strategies.

Intervention Effect of Repetitive TMS on Behavioral Adjustment After Error Commission in Long-Term Methamphetamine Addicts: Evidence From a Two-Choice Oddball Task.

Behavioral adjustment plays an important role in the treatment and relapse of drug addiction. Nonetheless, few studies have examined behavioral adjustment and its plasticity following error commission in methamphetamine (METH) dependence, which is detrimental to human health. Thus, we investigated the behavioral adjustment performance following error commission in long-term METH addicts and how it varied with the application of repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC). Twenty-nine male long-term METH addicts (for>3years) were randomly assigned to high-frequency (10Hz, n=15) or sham (n=14) rTMS of the left DLPFC during a two-choice oddball task. Twenty-six age-matched, healthy male adults participated in the two-choice oddball task pretest to establish normal performance for comparison. The results showed that 10Hz rTMS over the left DLPFC significantly decreased the post-error slowing effect in response times of METH addicts. In addition, the 10Hz rTMS intervention remarkably reduced the reaction times during post-error trials but not post-correct trials. While the 10Hz rTMS group showed a more pronounced post-error slowing effect than the healthy participants during the pretest, the post-error slowing effect in the posttest of this sample was similar to that in the healthy participants. These results suggest that high-frequency rTMS over the left DLPFC is a useful protocol for the improvement of behavioral adjustment after error commission in long-term METH addicts.

β-Arrestin-biased β-adrenergic signaling promotes extinction learning of cocaine reward memory.

Extinction learning of cocaine-associated contextual cues can help prevent cocaine addicts from relapsing. Pharmacological manipulation of β-adrenergic receptor (β-AR) during extinction learning is being developed as a potential strategy to treat drug addiction. We demonstrated that the extinction learning of cocaine-associated memory was mediated by β-arrestin2-biased but not heterotrimeric guanine nucleotide-binding protein (G protein)-dependent β-adrenergic signaling. We found that administration of the nonbiased β-AR antagonist propranolol, but not the G protein-biased β-AR antagonist carvedilol, blocked extinction learning of cocaine-conditioned place preference and the associated ERK activation in the infralimbic prefrontal cortex. Overexpression of β-arrestin2 in the infralimbic prefrontal cortex promoted extinction learning, which was blocked by propranolol. Knockout of β-arrestin2 in the infralimbic prefrontal cortex, specifically in excitatory neurons, impaired extinction learning of cocaine-conditioned place preference, which was not rescued by carvedilol. β-Arrestin2 signaling in infralimbic excitatory neurons was also required for the extinction learning in the cocaine self-administration model. Our results suggest that β-arrestin-biased β-adrenergic signaling in the infralimbic prefrontal cortex regulates extinction learning of cocaine-associated memories and could be therapeutically targeted to treat addiction.

Associated Factors for Relapse in Opioid Addicts undergoing Therapy

Substance abuse is both a social and public health problem with a substantial burden to society. Opioid dependence results in unemployment, crimes, family disruption, and transmission of diseases. In Malaysia, Methadone Maintanence Therapy (MMT) has been introduced as a harm-reduction method. However, relapse during treatment remains an issue to be resolved that hinders successful outcome in the therapy. This study aims to determine the prevalence of relapse in opioid addicts undergoing MMT and its associated potential risk factors. This is a cross-sectional study done from June-July 2016. All patients with MMT in primary care therapy centres in Kuala Nerus district, Terengganu, Malaysia who fulfilled the inclusion and exclusion criteria was included. A semi-structured questionnaire was filled via face-to-face interview and reference to the case records was done. 122 questionnaires were assessed. All respondents were males of Malay race. Mean age was 36.2. Mean duration in MMT was 1.4 years. Current relapse, defined as any episode of intake of heroine for the past one month after a period of abstinence was 34.4%. The significant factors found in our study for relapse were: the patients’ goal for treatment (p<0.001), status of parents prior to addiction (p<0.038), duration of therapy (p<0.001), and taking of amphetamine during therapy (p<0.013), respectively. Relapse in opioid addiction remains high in those receiving MMT. Clients need to be properly educated regarding reasonable goals for treatment, which may contribute towards achieving more successful therapy outcomes.

The relationship between self mutilative behavior, suicide attempt history and impulsivity and some clinical variables in male opiate-dependent patients

Objective: The aim of this study is to investigate the relationship between self-mutilative behavior (SMB), suicide attempt history (SAH) and impulsivity which is known to play an important role in the etiology, duration, course of treatment, and relapse of addiction in male patients with opiate use disorder. Methods: Ninety five inpatient people diagnosed with opiate use disorder were included in the study. There were three groups according to their clinical findings: Group 1 included the patients with SMB and SAH, Group 2 included the patients with only SMB and Group 3 included the patients showing none of these behaviors. The Sociodemographic Form, Barratt Impulsivity Scale-11 (BIS-11), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) were administered. Results: In terms of age there was a significant difference between the Group 1 and Group 3, to be lower in Group 1. There was a significant difference between Group 1 and Group 3 in terms of job status to be higher in Group 3. There was a significant difference between Group 1 and Group 2 and 3 in terms of childhood abuse history. There was a significant difference between Group 1 and Group 3, and between Group 1 and Group 2 to be higher in Group 1 In terms of BDI and BAI scores. There was a significant difference between Group 3 and Group 1 in terms of BIS-11 motor and motor impulsivity subscores to be higher in Group 1; thus there was no difference between Group 2 and Group 1 and 3. There was a significant difference between Group 1 and Group 2 to be higher in Group 1 in terms of self-control. There were no differences in terms of age, job status, childhood abuse history, BDI, BAI and BIS-11 scores between Group 2 and Group 3. Conclusion: Suicide attempt and SMB include impulsivity in etiology, make treatment difficult and is effective on relapse. However, psychotherapeutic approaches considering that SMB alone is not associated with significant impulsivity and increased depression and anxiety, and that the association of SAH and SMB is associated with increased impulsivity and increased anxiety and depression, may improve treatment success in opiate use disorder.

Grafting a Safeguard against Cocaine Abuse

Drug addiction is a brain disease characterized by compulsive drug-seeking and taking and a high likelihood of relapse when exposed to drugs or drugassociated cues, even long after abstention [1]. Relapse is the major challenge for the treatment of drug addiction in humans. Cocaine is a widely abused drug that causes significant morbidity and mortality. There are currently no FDA-approved medications for reducing cocaine use or treating relapse in cocaine addicts. Moreover, there are no interventions for the acute emergencies that result from cocaine overdose. A novel skin stem cell-based gene therapy has recently been described to be effective in reducing core features of cocaine abuse in laboratory mice [2], offering hope of producing the first medication for treating cocaine abuse, and adding a new tool for treating drug abuse and co-abuse.

Stress and Addiction: When a Robust Stress Response Indicates Resiliency.

Stress reactivity research has traditionally focused on the idea that exaggerated responses to stress may have adverse effects on health. Accumulating evidence suggests that attenuated responses to stress and delayed recovery may also be problematic. This review focuses on the role of the stress response of the hypothalamic-pituitary-adrenocortical axis, the endogenous opioid system, and the cardiovascular system in hypertension, pain perception, and addictive behaviors. Results from multiple methods of assessment and stress paradigms conducted in our laboratory over the past two decades are integrated with research from other investigators and with existing theories. Research indicates that exaggerated biological and physiological responses to stress and attenuated pain perception are associated with hypertension and risk for cardiovascular diseases. This research complements work linking reduced stress responses with enhanced pain sensitivity and discomfort. Multiple studies have also demonstrated that an attenuated stress response is linked to exacerbation of withdrawal symptoms and relapse in nicotine addiction. Evidence indicates important moderators (i.e., sex, personality traits, and early life adversity) and hypothalamic-pituitary-adrenocortical- and endogenous opioid system-related mechanisms in the altered response to stress. I integrate these findings in a conceptual model emphasizing that robust stress responses in the context of addiction and relapse should be considered as a marker of resiliency. A blunted stress response may indicate long-term physiological dysregulation that could usher harmful consequences for cardiovascular disease, pain perception, and addictive disorders. The impact of dysregulation is influenced by multiple individual and situational factors that should be considered in evaluating the clinical significance of stress response dysregulation.

Drug Addicts: Psychosocial Factor Contributing to Relapse

This article present about relapse among drug addicts in rehabilitation center. In Malaysia, many drug addicts relapse to drug use after discharged from successful treatment at rehabilitation center. Various effort and the authorities involved in assisting the National Anti-Drug Agency (NADA) efforts to cure and treat drug addicts. This article aims to examine the factors that affect relapse among drug addicts. Therefore, this article will discuss aspects of psychosocial factors including self-efficacy, family support, friends support and community support. Psychosocial factors, such as aspects of self-efficacy, family support, friends support and community support, had significant relationships with relapse. Psychological factors are also vital to design adequate treatment strategies. Thus, this article evaluating psychosocial factor as main factors that influenced the relapse addictions tendency amongst addicts.

Muscarinic receptors in the nucleus accumbens shell play different roles in context-induced or morphine-challenged expression of behavioral sensitization in rats

Both drug-related cues and drug priming are the main factors that induce relapse of drug addiction. Previous research has reported that blockade of the muscarinic receptors could significantly depress addictive behavior, suggesting that the muscarinic receptors might be involved in drug use and relapse behavior. The nucleus accumbens (NAc), especially the shell of the NAc, where the muscarinic receptors are expressed, is critical for craving and relapse. This study investigated the effects of microinfusion of the muscarinic receptor antagonist scopolamine into the NAc shell on context- and morphine-induced expression of behavioral sensitization. Behavioral sensitization was established by exposure to 5mg/kg morphine once daily for five consecutive days. Expression of behavioral sensitization was induced by saline challenge or 5mg/kg morphine challenge. The results showed that: (a) the muscarinic receptor antagonist scopolamine (10.8μg/rat) microinjected into the NAc shell blocked expression of conditional sensitization; (b) acetylcholinesterase inhibitor huperzine-A (0.5 and 0.1μg/rat), but not scopolamine (10.8μg/rat), microinjected into the NAc shell blocked morphine-induced expression of sensitization; and (c) pre-infusion of scopolamine (10.8μg/rat) reversed the inhibitory effect of huperzine-A (0.5μg/rat) on morphine-induced sensitization. Our findings suggest that muscarinic receptors in the NAc shell play different roles in context-induced and morphine-challenged expression of behavioral sensitization.

Cue-induced reinstatement of alcohol-seeking behavior is associated with increased CaMKII T286 phosphorylation in the reward pathway of mice

Cue-induced reinstatement of alcohol-seeking is a hallmark behavioral pathology of addiction. Evidence suggests that reinstatement (e.g., relapse), may be regulated by cell signaling systems that underlie neuroplasticity. A variety of plasticity events require activation of calcium calmodulin-dependent protein kinase II (CaMKII) in components of the reward pathway, such as the nucleus accumbens and amygdala. We sought to determine if cue-induced reinstatement of alcohol-seeking behavior is associated with changes in the activation state (e.g., phosphorylation) of CaMKII-T286. Male C57BL/6J mice (n=14) were trained to lever press on a fixed-ratio-4 schedule of sweetened alcohol (2% sucrose+9% EtOH) reinforcement. After 14-d of extinction (no cues or reinforcers), mice underwent a response-contingent reinstatement (n=7) vs. an additional day of extinction (n=7). Brains were removed immediately after the test and processed for evaluation of pCaMKII-T286 immunoreactivity (IR). Number of pCaMKII-T286 positive cells/mm2 was quantified from coronal brain sections using Bioquant Image Analysis software. Mice emitted significantly more responses on the alcohol vs. the inactive lever throughout the baseline phase with average alcohol intake of 1.1±0.03g/kg/1-h. During extinction, responses on the alcohol lever decreased to inactive lever levels by day 7. Significant cue-induced reinstatement of alcohol-seeking was observed during a single test with no effects on the inactive lever. Reinstatement was associated with increased pCaMKII-T286 IR specifically in amygdala (LA and BLA), nucleus accumbens (AcbSh), lateral septum, mediodorsal thalamus, and piriform cortex as compared to extinction control. Brain regions showing no change included the dorsal striatum, medial septum, cingulate cortex, habenula, paraventricular thalamus, and ventral hypothalamus. These results show response contingent cue-induced reinstatement of alcohol-seeking behavior is associated with selective increases in pCaMKII-T286 in specific reward- and memory-related brain regions of male C57BL/6J mice. Primary molecular mechanisms of associative learning and memory may regulate relapse in alcohol addiction.