Long Periods Of Abstinence Research Articles

Targeting Neuroplasticity in Substance Use Disorders: Implications for Therapeutics.

The last two decades have witnessed substantial advances in identifying synaptic plasticity responsible for behavioral changes in animal models of substance use disorder. We have learned the most about cocaine-induced plasticity in the nucleus accumbens and its relationship to cocaine seeking, so that is the focus in this review. Synaptic plasticity pointing to potential therapeutic targets has been identified mainly using two drug self-administration models: extinction-reinstatement and abstinence models. A relationship between cocaine seeking and potentiated AMPAR transmission in nucleus accumbens is indicated by both models. In particular, an atypical subpopulation-Ca2+-permeable or CP-AMPARs-mediates cue-induced seeking that persists even after long periods of abstinence, modeling the persistent vulnerability to relapse that represents a major challenge in treating substance use disorder. We review strategies to reverse CP-AMPAR plasticity; strategies targeting other components of excitatory synapses, including dysregulated glutamate uptake and release; and behavioral interventions that can be augmented by harnessing synaptic plasticity.

Sex-specific behavioral and thalamo-accumbal circuit adaptations after oxycodone abstinence.

Opioid use disorder is marked by a progressive change in the motivation to administer the drug even in the presence of negative consequences. After long periods of abstinence, the urge to return to taking the drug intensifies over time, known as incubation of craving. Conditioned responses to drug-related stimuli, can acquire motivational properties and exert control over motivated behaviors leading to relapse. Although, preclinical data suggest that the behavioral expression of opioid use is similar between male and female rodents, we do not have conclusive results on sex differences on craving and relapse across abstinence periods. Here, we investigated the effects of abstinence from oxycodone self-administration on neurotransmission in the paraventricular thalamus (PVT) to nucleus accumbens shell (NAcSh) pathway in male and female rats. Using optogenetics and ex vivo electrophysiology, we assessed synaptic strength and glutamate release probability in this pathway, as well as NAcSh medium spiny neurons (MSN) intrinsic excitability, in slices from rats which were subjected to either 1 (acute) or 14 (prolonged) days of forced abstinence after self-administration. Our results revealed no sex differences in oxycodone self-administration or somatic withdrawal symptoms following acute abstinence. However, we found a sex-specific enhancement in cue-induced relapse after prolonged, but not acute, abstinence from oxycodone self-administration, with females exhibiting higher relapse rates. Notably, prolonged abstinence led to similar increases in synaptic strength at PVT-NAcSh inputs compared to saline controls in both sexes, which was not observed after acute abstinence. Thus, prolonged abstinence results in a time-dependent increase in PVT-NAcSh synaptic strength and sex-specific effects on cue-induced relapse rates. These findings suggest that prolonged abstinence leads to significant synaptic changes, contributing to heightened relapse vulnerability, highlighting the need for targeted therapeutic strategies in opioid use disorder.

The selective D3Receptor antagonist VK4-116 reverses loss of insight caused by self-administration of cocaine in rats

Chronic psychostimulant use causes long-lasting changes to neural and cognitive function that persist after long periods of abstinence. As cocaine users transition from drug use to abstinence, a parallel transition from hyperactivity to hypoactivity has been found in orbitofrontal-striatal glucose metabolism and striatal D2/D3-receptor activity. Targeting these changes pharmacologically, using highly selective dopamine D3-receptor (D3R) antagonists and partial agonists, has shown promise in reducing drug-taking, and attenuating relapse in animal models of cocaine and opioid use disorder. However, much less attention has been paid to treating the loss of insight, operationalized as the inability to infer likely outcomes, associated with chronic psychostimulant use. Here we tested the selective D3R antagonist VK4-116 as a treatment for this loss in rats with a prior history of cocaine use. Male and female rats were first trained to self-administer cocaine or a sucrose liquid for 2 weeks. After 4 weeks of abstinence, performance was assessed using a sensory preconditioning (SPC) learning paradigm. Rats were given VK4-116 (15 mg/kg, i.p.) or vehicle 30 min prior to each SPC training session, thus creating four drug-treatment groups: sucrose-vehicle, sucrose-VK4-116, cocaine-vehicle, cocaine-VK4-116. The control groups (sucrose-vehicle, sucrose-VK4-116) showed normal sensory preconditioning, whereas cocaine use (cocaine-vehicle) selectively disrupted responding to the preconditioned cue, an effect that was reversed in the cocaine-VK4-116 group, which demonstrating responding to the preconditioned cue at levels comparable to controls. These preclinical findings demonstrate that highly selective dopamine D3R antagonists, particularly VK4-116, can reverse the long-term negative behavioral consequences of cocaine use.

Aberrant functional brain network organization is associated with relapse during 1-year follow-up in alcohol-dependent patients.

Alcohol dependence (AD) is a debilitating disease associated with high relapse rates even after long periods of abstinence. Thus, elucidating neurobiological substrates of relapse risk is fundamental for the development of novel targeted interventions that could promote long-lasting abstinence. In the present study, we analysed resting-state functional magnetic resonance imaging (rsfMRI) data from a sample of recently detoxified patients with AD (n = 93) who were followed up for 12 months after rsfMRI assessment. Specifically, we employed graph theoretic analyses to compare functional brain network topology and functional connectivity between future relapsers (REL, n = 59), future abstainers (ABS, n = 28) and age- and gender-matched controls (CON, n = 83). Our results suggest increased whole-brain network segregation, decreased global network integration and overall blunted connectivity strength in REL compared with CON. Conversely, we found evidence for a comparable network architecture in ABS relative to CON. At the nodal level, REL exhibited decreased integration and decoupling between multiple brain systems compared with CON, encompassing regions associated with higher-order executive functions, sensory and reward processing. Among patients with AD, increased coupling between nodes implicated in reward valuation and salience attribution constitutes a particular risk factor for future relapse. Importantly, aberrant network organization in REL was consistently associated with shorter abstinence duration during follow-up, portending to a putative neural signature of relapse risk in AD. Future research should further evaluate the potential diagnostic value of the identified changes in network topology and functional connectivity for relapse prediction at the individual subject level.

Blockade of orexin receptors in the infralimbic cortex prevents stress-induced reinstatement of alcohol-seeking behaviour in alcohol-dependent rats.

A major problem managing alcohol use disorder is the high vulnerability to relapse, even after long periods of abstinence. Chronic alcohol use dysregulates stress responsivity, rendering this system hyporesponsive and making individuals vulnerable to relapse. Orexin (hypocretin) plays a role in diverse physiological processes, including stress. Orexin neurons in the hypothalamus, project to the infralimbic cortex. This study asked does infralimbic cortex orexin transmission play a significant role in stress-induced reinstatement of alcohol-seeking behaviour in alcohol-dependent rats. Male and female rats were trained to self-administer 10% alcohol (3 weeks) and then made dependent via chronic intermittent alcohol vapour exposure. Following extinction (5 days·week-1 at 8 h abstinence for 10 sessions), rats received an intra- infralimbic cortex microinfusion of the OX1/2 antagonist TCS 1102 (15 μg/0.5 μl per side) and then tested for footshock stress-induced reinstatement of alcohol seeking. In a separate cohort, orexin regulation of infralimbic cortex neuronal activity at the time of reinstatement was investigated using ex vivo electrophysiology. TCS 1102 prevented reinstatement in dependent animals only. Moreover, Hcrtr mRNA expression in the hypothalamus and Hcrtr1/2 in the infralimbic cortex increased in alcohol-dependent animals at the time of testing. Dependence dampened basal orexin/OX receptor influence over infralimbic cortex GABAergic synapses (using TCS 1102) allow for greater stimulated orexin effects. Infralimbic cortex transmission is implicate in stress-induced reinstatement of alcohol-seeking behaviour in subjects with a history of alcohol dependence and show maladaptive recruitment of infralimbic cortex transmission by alcohol dependence.

The conceptual basis of addiction memory, allostasis and dual processes, and the classical therapy of addiction.

In recent years, research has yielded new information regarding the impact of intense, long-term alcohol consumption on the development of permanent changes in the central nervous system. The present study examines the mechanisms related to the existence of addiction memory, sensitization and allostasis. A dual-process model was also created, which analyses the role of conscious and automatic mechanisms in the functioning of addicts. The aim of the article is to present these mechanisms and to consider the implications of their existence for the course of therapy. The mechanisms analysed shed new light on some of the negative phenomena occurring during and after therapy, such as frequent abstinence after treatment, switching addictions, and returning to drinking after a long period of abstinence. The existence of these mechanisms should also change the character of addiction therapy, which has so far focused mainly on conscious aspects and ignored the existence of automatic ones. Attempts are already being made to implement the dual-process model in addiction therapy. A better understanding of the mechanisms resulting from the dual-process model can significantly influence perspectives regarding functioning in addiction and the course of therapy. These processes merit further research, as do possible therapeutic interventions based on them.

Repeated Cycles of Binge-Like Ethanol Exposure Induces Neurobehavioral Changes During Short- and Long-Term Withdrawal in Adolescent Female Rats.

Alcohol consumption is spread worldwide and can lead to an abuse profile associated with severe health problems. Adolescents are more susceptible to addiction and usually consume ethanol in a binge drinking pattern. This form of consumption can lead to cognitive and emotional disorders, however scarce studies have focused on long-term hazardous effects following withdrawal periods after binge drinking in adolescents. Thus, the present study aims at investigating whether behavioral and cognitive changes persist until mid and late adulthood. Female Wistar rats (9-10 animals/group) received intragastric administration of four cycles of ethanol binge-like pattern (3.0 g/kg/day, 20% w/v; 3 days-on/4 days-off) from 35th to 58th days old, followed withdrawal checkpoints 1 day, 30 days, and 60 days. At each checkpoint period, behavioral tests of open field, object recognition test, elevated plus maze, and forced swimming test were performed, and blood and hippocampus were collected for oxidative biochemistry and brain-derived neurotrophic factor (BDNF) levels analysis, respectively. The results demonstrated that adolescent rats exposed to binge drinking displayed anxiogenic- and depressive-like phenotype in early and midadulthood, however, anxiety-like profile persisted until late adulthood. Similarly, short-term memory was impaired in all withdrawal periods analysed, including late adult life. These behavioral data were associated with oxidative damage in midadulthood but not BDNF alterations. Taken together, the present work highlights the long-lasting emotional and cognitive alterations induced by ethanol binge drinking during adolescence, even after a long period of abstinence, which might impact adult life.

Investigating discriminative stimulus modulation of opioid seeking after conflict-induced abstinence in sign- and goal-tracking rats.

Discriminative stimuli (DS) are cues that predict reward availability. DS are resistant to extinction and motivate drug seeking even after long periods of abstinence. Previous studies have demonstrated that sign-tracking (ST) and goal-tracking (GT) differences in Pavlovian approach predict distinct cue-modulated vulnerabilities to cocaine reinstatement. GT rats show heightened reinstatement to contextual and DS, while ST rats show heightened reinstatement to discrete stimuli. Here we examine whether DS modulate reinstatement after electric barrier-induced abstinence and whether tracking-related relapse vulnerabilities generalize to opioid relapse. We examine whether DS-modulated reinstatement to fentanyl seeking persists in the presence of reduced adverse consequences after electric barrier-induced abstinence. We also examine whether tracking differences predict the magnitude of DS-modulated reinstatement of fentanyl seeking after electric barrier-induced abstinence. We used Pavlovian lever autoshaping (PLA) training to determine sign-, goal-, and intermediate tracking groups in male and female Sprague Dawley rats. We then trained rats in a DS model of intermittent fentanyl self-administration, and extinguished drug seeking by imposing an electric barrier of increasing intensity. We then measured the level of DS-modulated reinstatement in the presence of a reduced electric barrier intensity. We report that DS strongly modulate fentanyl seeking after electric barrier-induced abstinence. DS-modulation of fentanyl acquisition, electric barrier-induced abstinence, and reinstatement was similar for sign- and goal-tracking groups. Discriminative stimuli powerfully motivate opioid seeking, despite continued aversive consequences. Pavlovian approach differences do not predict the level of DS-modulated reinstatement to fentanyl seeking after conflict-induced abstinence.

A Conditioned Place Preference for Heroin Is Signaled by Increased Dopamine and Direct Pathway Activity and Decreased Indirect Pathway Activity in the Nucleus Accumbens.

Repeated pairing of a drug with a neutral stimulus, such as a cue or context, leads to the attribution of the drug's reinforcing properties to that stimulus, and exposure to that stimulus in the absence of the drug can elicit drug-seeking. A principal role for the NAc in the response to drug-associated stimuli has been well documented. Direct and indirect pathway medium spiny neurons (dMSNs and iMSNs) have been shown to bidirectionally regulate cue-induced heroin-seeking in rats expressing addiction-like phenotypes, and a shift in NAc activity toward the direct pathway has been shown in mice following cocaine conditioned place preference (CPP). However, how NAc signaling guides heroin CPP, and whether heroin alters the balance of signaling between dMSNs and iMSNs, remains unknown. Moreover, the role of NAc dopamine signaling in heroin reinforcement is unclear. Here, we integrate fiber photometry for in vivo monitoring of dopamine and dMSN/iMSN calcium activity with a heroin CPP procedure in rats to begin to address these questions. We identify a sensitization-like response to heroin in the NAc, with prominent iMSN activity during initial heroin exposure and prominent dMSN activity following repeated heroin exposure. We demonstrate a ramp in dopamine activity, dMSN activation, and iMSN inactivation preceding entry into a heroin-paired context, and a decrease in dopamine activity, dMSN inactivation, and iMSN activation preceding exit from a heroin-paired context. Finally, we show that buprenorphine is sufficient to prevent the development of heroin CPP and reduce Fos activation in the NAc after conditioning. Together, these data support the hypothesis that an imbalance in NAc activity contributes to the development of drug-cue associations that can drive addiction processes.SIGNIFICANCE STATEMENT The attribution of the reinforcing effects of drugs to neutral stimuli (e.g., cues and contexts) contributes to the long-standing nature of addiction, as re-exposure to drug-associated stimuli can reinstate drug-seeking and -taking even after long periods of abstinence. The NAc has an established role in encoding the value of drug-associated stimuli, and dopamine release into the NAc is known to modulate the reinforcing effects of drugs, including heroin. Using fiber photometry, we show that entering a heroin-paired context is driven by dopamine signaling and NAc direct pathway activation, whereas exiting a heroin-paired context is driven by NAc indirect pathway activation. This study provides further insight into the role of NAc microcircuitry in encoding the reinforcing properties of heroin.

New Access Routes to Undertreated Populations; How Do Problem Substance Users Recruited from an Unemployment Office Differ from Detoxification Treatment Inpatients?

Background: Only a minority of subjects with substance use disorders (SUDs) are in addiction-specific treatment (treatment gap). Co-operation between an unemployment office and a psychiatric hospital was established for the assessment and counseling of long-term unemployed clients with SUD. We aim at validating whether such a treatment gap exists in that group, and whether clients from an unemployment office differed from a matched group of inpatient detoxification patients with regard to socio-economic characteristics, substance use and treatment history, and the prevalence of mental disorders Methods: Unemployment office clients (n = 166) with an SUD were assessed using a standardized sociodemographic and clinical interview. They were compared with 83 inpatients from a local detoxification ward, matched for age, sex, and primary addictive disorder (matching ratio 2:1). Results: Most (75.9%) subjects were males, with an average age of 36.7 years. The SUDs mostly related to alcohol (63.9%) and cannabis (27.7%). Although most unemployment office clients had a long SUD history, only half of them had ever been in addiction-specific treatment during their lifetime, and only one in four during the last year. There were no statistically significant differences between the groups regarding age at onset of problematic substance use, the proportion of migrants, and prevalence of comorbid mental disorders. The unemployment office sample showed lower levels of education (p < 0.001), job experience (p = 0.009), and current employment rates (p < 0.001). Conversely, inpatients showed lower rates of imprisonment (p < 0.001), more inpatient detoxification episodes (p < 0.03); and longer abstinence periods (p < 0.005). Conclusions: There was a lifetime and recent treatment gap in the group of long-term unemployed subjects with alcohol and cannabis dependence. The markedly lower educational attainment, chronic employment problems and higher degree of legal conflicts in the client group, as compared with patients in detoxification treatment, might require specific access and treatment options. The co-operation between the psychiatric unit and the unemployment office facilitated access to that group.

Epigenetic Landscape of Methamphetamine Use Disorder.

The persistence of the addiction phenotype in methamphetamine use disorder (MUD) suggests the potential presence of epigenetic changes and potential structural adaptations that may drive the manifestations of MUD in humans. In the present review, we discuss the evidence that documents the fact that methamphetamine exposure can cause changes in epigenetic modifications, including histone acetylation and methylation, as well as DNA methylation and hydroxymethylation in a complex manner that need to be fully dissected. Nevertheless, our work has demonstrated the existence of correlations between behavioral changes and epigenetic alterations during methamphetamine self-administration. We found that prolonged methamphetamine self-administration and contingent footshocks resulted in rats with compulsive drug-taking and abstinent phenotypes. In addition, rats that reduce their methamphetamine intake in the presence of punishment showed increased DNA hydroxymethylation in genes encoding potassium channels in their nucleus accumbens. Moreover, altered DNA hydroxymethylation in those genes led to an increase in their mRNA expression. Additional studies revealed decreased mRNA expression of histone deacetylases associated with increased histone acetylation and induced gene expression in the dorsal striatum. These changes were associated with a reduction in methamphetamine intake in response to contingent footshocks. More research is necessary in order to further dissect how pharmacological or genetic manipulations of identified epigenetic alterations and expression of potassium channels can impact methamphetamine-taking behaviors or relapse to methamphetamine-taking after long periods of abstinence. Investigations that use discovery approaches, such as whole-genome sequencing after chromatin immunoprecipitation, should accelerate our efforts to develop epigenetic therapeutic approaches against MUD.

Mitochondrial function influences expression of methamphetamine-induced behavioral sensitization

Repeated methamphetamine use leads to long lasting brain and behavioral changes in humans and laboratory rats. These changes have high energy requirements, implicating a role for mitochondria. We explored whether mitochondrial function underpins behaviors that occur in rats months after stopping methamphetamine self-administration. Accordingly, rats self-administered intravenous methamphetamine for 3 h/day for 14 days. The mitochondrial toxin rotenone was administered as (1 mg/kg/day for 6 days) via an osmotic minipump starting at 0, 14 or 28 days of abstinence abstinence. On abstinence day 61, expression of methamphetamine-induced behavioral sensitization was obtained with an acute methamphetamine challenge in rotenone-free rats. Rotenone impeded the expression of sensitization, with the most robust effects obtained with later abstinence exposure. These findings verified that self-titration of moderate methamphetamine doses results in behavioral (and thus brain) changes that can be revealed months after exposure termination, and that the meth-initiated processes progressed during abstinence so that longer abstinence periods were more susceptible to the consequences of exposure to a mitochondrial toxin.

Solitary Nitric Oxide Signaling Mediates Mild Stress-Induced Anxiety and Norepinephrine Release in the Bed Nucleus of the Stria Terminalis during Protracted Ethanol Withdrawal.

Ethanol withdrawal (EtOHW) alters the pattern of neurohormonal and behavioral response toward internal and external stimuli, which mediates relapse to alcohol use even after a long period of abstinence. Increased noradrenergic signaling from the nucleus tractus solitarius (NTS) to the bed nucleus of the stria terminalis (BNST) during EtOHW underlies withdrawal-induced anxiety, while nitric oxide synthase (NOS) inhibitors injected into the periaqueductal area attenuate EtOHW-induced anxiety. Therefore, this study investigated the involvement of NOS within the NTS in anxiety and increased norepinephrine (NE) release in the BNST during protracted EtOHW in rats exposed to a mild stress. Rats were intraperitoneally administered 3 g/kg/day EtOH for 21 days followed by 28 days of withdrawal, and on the 28th day of withdrawal, the rats were subjected to restraint stress for 7 minutes. The elevated plus maze test was employed to evaluate anxiety-like behavior in rats, and in vivo microdialysis was used to measure the extracellular NE level in the BNST. In elevated plus maze tests, EtOHW rats but not EtOH-naive rats exhibited anxiety-like behavior when challenged with 7-minute mild restraint stress, which was, respectively, mitigated by prior intra-NTS infusion of the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME), or selective neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI). Each of these agents also decreased the plasma corticosterone levels in EtOHW rats. In in vivo microdialysis, prior intra-NTS infusion of carboxy-PTIO, L-NAME, or 7-NI attenuated the mild stress-induced NE release in the BNST of EtOHW rats. Additionally, EtOHW rats showed increased solitary nNOS gene and protein expression. Moreover, the anxiolytic effect of intra-NTS administration of 7-NI was abolished by subsequent intra-NTS administration of sodium nitroprusside. These results suggest that elevation of solitary nitric oxide signaling derived from nNOS mediates stress-precipitated anxiety and norepinephrine release in the BNST during protracted EtOHW.

Glucagon-like peptide-1 receptor agonist, liraglutide, reduces heroin self-administration and drug-induced reinstatement of heroin-seeking behaviour in rats.

Drug addiction is a chronic brain disease characterized by the uncontrolled use of a substance. Due to its relapsing nature, addiction is difficult to treat, as individuals can relapse following even long periods of abstinence and, it is during this time, that they are most vulnerable to overdose. In America, opioid overdose has been increasing for decades, making finding new treatments to help patients remain abstinent and prevent overdose deaths imperative. Recently, glucagon-like peptide-1 (GLP-1) receptor agonists have shown promise in reducing motivated behaviours for drugs of abuse. In this study, we test the effectiveness of the GLP-1 analogue, liraglutide (LIR), in reducing heroin addiction-like behaviour, and the potential side effects associated with the treatment. We show that daily treatment with LIR (0.1 mg/kg sc) increases the latency to take heroin, reduces heroin self-administration, prevents escalation of heroin self-administration and reduces drug-induced reinstatement of heroin-seeking behaviour in rats. A 1-h pretreatment time, however, was too short to reduce cue-induced seeking in our study. Moreover, we showed that, while LIR (0.1, 0.3, 0.6 and 1.0 mg/kg sc) supported conditioned taste avoidance of a LIR-paired saccharin cue, it did not elicit intake of the antiemetic kaolin in heroin-naïve or heroin-experienced rats. Further, 0.1 mg/kg LIR did not produce great disruptions in food intake or body weight. Overall, the data show that LIR is effective in reducing heroin taking and heroin seeking at doses that do not cause malaise and have a modest effect on food intake and body weight gain.

Influence of gender and education on cocaine users in an outpatient cohort in Spain

Gender significantly influences sociodemographic, medical, psychiatric and addiction variables in cocaine outpatients. Educational level may be a protective factor showing less severe addictive disorders, longer abstinence periods, and better cognitive performance. The aim was to estimate gender-based differences and the influence of educational level on the clinical variables associated with cocaine use disorder (CUD). A total of 300 cocaine-consuming patients undergoing treatments were recruited and assessed using the Psychiatric Research Interview for Substance and Mental Diseases according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Women developed CUD later but exhibited more consumption of anxiolytics, prevalence of anxiety disorders, eating disorders, and major depressive disorders. Alcohol and cannabis use disorders were more frequent in men. A predictive model was created and identified three psychiatric variables with good prognosis for distinguishing between women and men. Principal component analysis helped to describe the different profile types of men and women who had sought treatment. Low educational levels seemed to be a risk factor for the onset, development, and duration of CUD in both genders. Women and men exhibited different clinical characteristics that should be taken into account when designing therapeutic policies. The educational level plays a protective/risk role in the onset, development and progression of CUD, thus prolonging the years of compulsory education and implementing cognitive rehabilitation programmes could be useful.

Comparative assessment of outcomes of smoking cessation therapies and role of free medications in successful long-term abstinence.

INTRODUCTIONLong-term outcomes of smoking cessation treatments are crucial to optimize standards of cessation services, which are known to prevent excess morbidity and mortality. This study aimed to evaluate long-term outcomes of a smoking cessation program, to compare the success rates of interventions, to assess relapse rates after quitting, and to determine the duration until relapse.METHODSPatients admitted for smoking cessation between 2010–2018 were contacted to evaluate short- and long-term treatment outcomes. The patients were asked whether they were currently smoking, and whether they quit after smoking cessation treatment and the duration of abstinence.RESULTSThe study included 579 patients (341 males) with a mean age of 50±12 years. The median time from the date of visit to the smoking cessation clinic to analysis was 5 years (range: 2–10). Of the patient, 436 used medications, including varenicline, bupropion, and nicotine replacement therapy (NRT). The overall quit rate was 31.8% by the primary intervention (varenicline: 45.5%, bupropion: 38.2%, NRT: 33%, psychosocial support: 4.2%), and quit rate was similar in the intervention groups (p=0.073). In the long-term, the quit rates were 19.6, 22.5, 25.9, and 21.7%, respectively (p=0.405). About 9% of the patients failed to quit smoking initially but succeeded for a while after the first intervention at the cessation clinic. The relapse rate after initial cessation was 19%. The longest period of abstinence was in patients using NRT (14±17 months), followed by the patients using varenicline (9.5±12.7 months) and bupropion (8.2±14.8 months).CONCLUSIONSBoth short- and long-term quit rates with varenicline, bupropion, and NRT, were similar. The long-term quit rates among patients who did not use medication and received psychosocial support initially were comparable to those who used a smoking cessation drug.

Paradoxical changes in brain reward status during oxycodone self-administration in a novel test of the negative reinforcement hypothesis.

The extra medical use of, and addiction to, prescription opioid analgesics is a growing health problem. To characterize how prescription opioid abuse develops, this study investigated the affective consequences of escalating prescription opioid use using intracranial self-stimulation (ICSS) reward and oxycodone intravenous self-administration (IVSA) models. Male Wistar rats were given access to oxycodone IVSA (0.15 mg·kg-1 per infusion, i.v.) in short-access (ShA; 1 h) or long-access (LgA; 12 h) sessions for five sessions per week followed by intermittent 60-h discontinuations from drug access, a novel explicit test of the negative reinforcement hypothesis. Separate groups were first trained in the ICSS procedure and then in oxycodone IVSA in 11-h LgA sessions. Rats given LgA to oxycodone escalated their responding more than ShA rats, with further significant increases observed following each 60-h discontinuation. Presession brain reward thresholds increased with sequential daily LgA IVSA sessions, consistent with a growing negative affective state consequent to successive daily intoxication/abstinence cycles. A 1-h oxycodone IVSA interval was sufficient to normalize these elevated reward thresholds, as was, paradoxically, a 60-h weekend abstinence. The increase in ICSS thresholds was attenuated in a group treated with the long-acting κ-opioid antagonist norbinaltorphimine prior to IVSA training. Changes in brain reward function during escalation of oxycodone self-administration are driven by an interplay between κ-opioid receptor-mediated negative affective state associated with escalated oxycodone intake and dynamic restoration of brain reward status during longer periods of abstinence.

Feasibility and Preliminary Efficacy of a Community-Based Addiction Rehabilitation Electronic System in Substance Use Disorder: Pilot Randomized Controlled Trial.

BackgroundDrug use disorder has high potential for relapse and imposes an enormous burden on public health in China. Since the promulgation of the Anti-drug law in 2008, community-based rehabilitation has become the primary approach to treat drug addiction. However, multiple problems occurred in the implementation process, leading to a low detoxification rate in the community. Mobile health (mHealth) serves as a promising tool to improve the effectiveness and efficiency of community-based rehabilitation. Community-based addiction rehabilitation electronic system (CAREs) is an interactive system for drug users and their assigned social workers.ObjectiveThe study aimed to examine the feasibility and preliminary efficacy of CAREs in community-based rehabilitation from the perspective of drug users and social workers in Shanghai, China.MethodsIn this pilot randomized controlled trial, 40 participants were recruited from the community in Shanghai from January to May 2019. Participants randomized to the intervention group (n=20) received CAREs + community-based rehabilitation, while participants in the control group (n=20) received community-based rehabilitation only for 6 months. CAREs provided education, assessment, and SOS (support) functions for drug users. The assigned social workers provided service and monitored drug use behavior as usual except that the social workers in the intervention group could access the webpage end to obtain drug users’ information and fit their routine workflow into CAREs. The primary outcome was the feasibility of CAREs, reflected in the overall proportion and frequency of CAREs features used in both app and webpage end. The secondary outcomes were the effectiveness of CAREs, including the percentage of drug-positive samples, longest period of abstinence, contact times with social workers, and the change of Addiction Severity Index (ASI) from baseline to the 6-month follow-up.ResultsThe number of participants logged in to the app ranged from 7 to 20 per week, and CAREs had relatively high levels of continued patient use. Drug users preferred assessment and education features in the app end while their social workers showed high levels of use in urine results record and viewing assessment results on the webpage end. After the 6-month intervention, 3.3% (17/520) of samples in the intervention group and 7.5% (39/520) in the control group were drug-positive (F=4.358, P=.04). No significant differences were noted between the control and intervention groups in terms of longest duration of abstinence, number of contact times and ASI composite scores.ConclusionsThe study preliminarily demonstrated that with relatively good feasibility and acceptability, CAREs may improve the effectiveness and efficiency of the community-based rehabilitation, which provided instruction for further improvement of the system.Trial RegistrationClinicalTrials.gov NCT03451344; https://clinicaltrials.gov/ct2/show/NCT03451344International Registered Report Identifier (IRRID)RR2-10.3389/fpsyt.2018.00556

The molecular neurobiology and neuropathology of opioid use disorder.

The number of people diagnosed with opioid use disorder has skyrocketed as a consequence of the opioid epidemic and the increased prescribing of opioid drugs for chronic pain relief. Opioid use disorder is characterized by loss of control of drug taking, continued drug use in the presence of adverse consequences, and repeated relapses to drug taking even after long periods of abstinence. Patients who suffer from opioid use disorder often present with cognitive deficits that are potentially secondary to structural brain abnormalities that vary according to the chemical composition of the abused opioid. This review details the neurobiological effects of oxycodone, morphine, heroin, methadone, and fentanyl on brain neurocircuitries by presenting the acute and chronic effects of these drugs on the human brain. In addition, we review results of neuroimaging in opioid use disorder patients and/or histological studies from brains of patients who had expired after acute intoxication following long-term use of these drugs. Moreover, we include relevant discussions of the neurobiological mechanisms involved in promoting abnormalities in the brains of opioid-exposed patients. Finally, we discuss how novel strategies could be used to provide pharmacological treatment against opioid use disorder.

Efficacy of N-acetylcysteine in the prevention of alcohol relapse-like drinking: Study in long-term ethanol-experienced male rats.

Alcohol use disorders are chronic and highly relapsing disorders, thus alcoholic patients have a high rate of recidivism for drug use even after long periods of abstinence. The literature points to the potential usefulness of N-acetylcysteine (NAC) in the management of several substance use disorders probably due to its capacity to restore brain homeostasis of the glutamate system disrupted in addiction. However, there is little evidence in the case of alcohol. The aim of this study was to explore the potential anti-relapse efficacy of NAC using the alcohol deprivation effect (ADE) model in long-term experienced rats. Two experiments were performed in male Wistar rats to: (a) test the efficacy of NAC to prevent relapse and (b) discriminate the best administration schedule (intermittent vs. continuous) for NAC. In the first experiment, animals were implanted with mini-osmotic pumps delivering 0 or 1mg/hr NAC during 14days. In a second experiment, rats received 0, 60, or 100mg/kg once daily by subcutaneous injection. The efficacy to prevent ADE was evaluated in both experiments. NAC subcutaneously administered, either by continuous infusion or by intermittent injections regimen, is able to block the ADE. The best results were obtained after using 60mg/kg NAC dose. Our findings support the hypothesis that NAC may represent a valuable therapy in the management of alcohol relapse.