Agmatine alleviates ethanol withdrawal-associated cognitive impairment and neurochemical imbalance in rats.

The present study aimed to investigate the role of agmatine in the neurobiology underlying memory impairment during ethanol withdrawal in rats. Sprague-Dawley rats were subjected to a 21-day chronic ethanol exposure regimen (2.4 % w/v ethanol for 3 days, 4.8 % w/v for the next 4 days, and 7.2 % w/v for the following 14 days), followed by a withdrawal period. Memory impairment was assessed using the passive avoidance test (PAT) at 24, 48, and 72 h post-withdrawal. The ethanol-withdrawn rats displayed a significant decrease in step-through latency in the PAT, indicative of memory impairment at 72 h post-withdrawal. However, administration of agmatine (40 µg/rat) and its modulators (L-arginine, arcaine, and amino-guanidine) significantly increases the latency time in the ethanol-withdrawn rats, demonstrating the attenuation of memory impairment. Further, pretreatment with imidazoline receptor agonists enhances agmatine's effects, while antagonists block them, implicating imidazoline receptors in agmatine's actions. Neurochemical analysis in ethanol-withdrawn rats reveals dysregulated glutamate and GABA levels, which was attenuated by agmatine and its modulators. By examining the effects of agmatine administration and modulators of endogenous agmatine, the study aimed to shed light on the potential therapeutic implications of agmatinergic signaling in alcohol addiction and related cognitive deficits. Thus, the present findings suggest that agmatine administration and modulation of endogenous agmatine levels hold potential as therapeutic strategies for managing alcohol addiction and associated cognitive deficits. Understanding the neurobiology underlying these effects paves the way for the development of novel interventions targeting agmatinergic signaling in addiction treatment.

ANK3 rs10994336 and ZNF804A rs7597593 polymorphisms: genetic interaction for emotional and behavioral symptoms of alcohol withdrawal syndrome.

OBJECTIVE: Alcohol withdrawal syndrome (AWS) is a complex condition associated with alcohol use disorder (AUD), characterized by significant variations in symptom severity among patients. The psychological and emotional symptoms accompanying AWS significantly contribute to withdrawal distress and relapse risk. Despite the importance of neural adaptation processes in AWS, limited genetic investigations have been conducted. This study primarily focuses on exploring the single and interaction effects of single-nucleotide polymorphisms in the ANK3 and ZNF804A genes on anxiety and aggression severity manifested in AWS. By examining genetic associations with withdrawal-related psychopathology, we ultimately aim to advance understanding the genetic underpinnings that modulate AWS severity. METHODS: The study involved 449 male patients diagnosed with alcohol use disorder. The Self-Rating Anxiety Scale (SAS) and Buss-Perry Aggression Questionnaire (BPAQ) were used to assess emotional and behavioral symptoms related to AWS. Genomic DNA was extracted from peripheral blood, and genotyping was performed using PCR. RESULTS: Single-gene analysis revealed that naturally occurring allelic variants in ANK3 rs10994336 (CC homozygous vs. T allele carriers) were associated with mood and behavioral symptoms related to AWS. Furthermore, the interaction between ANK3 and ZNF804A was significantly associated with the severity of psychiatric symptoms related to AWS, as indicated by MANOVA. Two-way ANOVA further demonstrated a significant interaction effect between ANK3 rs10994336 and ZNF804A rs7597593 on anxiety, physical aggression, verbal aggression, anger, and hostility. Hierarchical regression analyses confirmed these findings. Additionally, simple effects analysis and multiple comparisons revealed that carriers of the ANK3 rs10994336 T allele experienced more severe AWS, while the ZNF804A rs7597593 T allele appeared to provide protection against the risk associated with the ANK3 rs10994336 mutation. CONCLUSION: This study highlights the gene-gene interaction between ANK3 and ZNF804A, which plays a crucial role in modulating emotional and behavioral symptoms related to AWS. The ANK3 rs10994336 T allele is identified as a risk allele, while the ZNF804A rs7597593 T allele offers protection against the risk associated with the ANK3 rs10994336 mutation. These findings provide initial support for gene-gene interactions as an explanation for psychiatric risk, offering valuable insights into the pathophysiological mechanisms involved in AWS.

Differential effects of acute and prolonged morphine withdrawal on motivational and goal-directed control over reward-seeking behaviour.

Opioid addiction is a relapsing disorder marked by uncontrolled drug use and reduced interest in normally rewarding activities. The current study investigated the impact of spontaneous withdrawal from chronic morphine exposure on emotional, motivational and cognitive processes involved in regulating the pursuit and consumption of food rewards in male rats. In Experiment 1, rats experiencing acute morphine withdrawal lost weight and displayed somatic signs of drug dependence. However, hedonically driven sucrose consumption was significantly elevated, suggesting intact and potentially heightened reward processing. In Experiment 2, rats undergoing acute morphine withdrawal displayed reduced motivation when performing an effortful response for palatable food reward. Subsequent reward devaluation testing revealed that acute withdrawal disrupted their ability to exert flexible goal-directed control over reward seeking. Specifically, morphine-withdrawn rats were impaired in using current reward value to select actions both when relying on prior action-outcome learning and when given direct feedback about the consequences of their actions. In Experiment 3, rats tested after prolonged morphine withdrawal displayed heightened rather than diminished motivation for food rewards and retained their ability to engage in flexible goal-directed action selection. However, brief re-exposure to morphine was sufficient to impair motivation and disrupt goal-directed action selection, though in this case, rats were only impaired in using reward value to select actions in the presence of morphine-paired context cues and in the absence of response-contingent feedback. We suggest that these opioid-withdrawal induced deficits in motivation and goal-directed control may contribute to addiction by interfering with the pursuit of adaptive alternatives to drug use.

Menthol versus tobacco e-liquid flavor: Impact on acute subjective effects, puff patterns, and intentions for use among Black and White menthol smokers.

BACKGROUND: The proposed FDA product standard to prohibit menthol as a characterizing flavor in combustible cigarettes has the potential to significantly reduce tobacco-related health disparities. Whether a menthol e-liquid product standard would improve or hinder public health is unknown. No known research has directly examined the impact of menthol vs. tobacco flavored e-liquid use on acute e-cigarette use patterns, subjective experience, behavioral intentions, and craving and withdrawal among menthol cigarette smokers. METHODS: Black (n = 47) and White (n = 4) nicotine-deprived menthol smokers with limited e-cigarette experience completed two counterbalanced in-laboratory 30-minute ad libitum vaping sessions with menthol and tobacco nicotine salt-based e-liquid in a randomized crossover pilot trial design. Questionnaires assessed reductions in craving and withdrawal and post-session subjective experience and behavioral intentions. Puff topography was measured continuously throughout each vaping session. RESULTS: Measures of puff topography did not differ significantly by e-liquid flavor (all p > .40). Similarly, menthol and tobacco flavored e-cigarettes were both rated positively in terms of subjective effects and behavioral intentions (all p > .10) and about 40 % of participants reported a preference for the tobacco-flavored e-liquid. Finally, participants showed comparable reductions in craving (p = .210) and withdrawal (p = .671) from pre- and post-session regardless of e-liquid flavor. CONCLUSIONS: Among menthol smokers in a lab-based setting, findings suggest that menthol vs tobacco e-liquid flavor has little impact on acute changes in puff patterns, subjective experience, behavioral intentions, or craving and withdrawal.

Hereditary and cortical morphological biomarker of sensitivity to reward in short-term withdrawal methamphetamine abusers.

Higher sensitivity to reward (SR) and weaker sensitivity to punishment (SP) construct the fundamental craving characteristics of methamphetamine abuse. However, few studies have appraised relationships between SR/SP (SR or SP) and cortical morphological alterations in methamphetamine abusers and whether hereditary factors take effects on SR/SP is unclear. Based on surface-based morphometric analysis, cortical discrepancy was investigated between 38 methamphetamine abusers and 37 healthy controls. Within methamphetamine abusers, correlation profiling was performed to discover associations among aberrant neuroimaging substrates, SR, SP, and craving. According to nine single nucleotide polymorphism sites of dopamine-related genes, we conducted univariate general linear model to find different effects of genotypes on cortical alterations and SR/SP/craving (SR, SP, or craving). Ultimately, mediation analyses were conducted among single nucleotide polymorphism sites, SR/SP/craving, and cortical morphological alterations to discover their association pathways. Compared to healthy controls, thinner cortices in inferior temporal gyrus, lateral orbitofrontal cortex, medial orbitofrontal cortex, inferior parietal lobule, and lateral occipital cortex in the left hemisphere were found in methamphetamine abusers (P < 0.05, family-wise error corrected). Cortical thickness in the inferior temporal gyrus was negatively correlated with SR scores. We found that rs1800497 A-containing genotypes had lower cortical thickness in the left inferior parietal lobule than the GG genotype. The rs5751876 had effects on SR scores. This study would provide convincing biomarkers for SR in methamphetamine abusers and offer potential genetic targets for personalizing relapse prevention.

Is impulsivity related to attentional bias in cigarette smokers? An exploration across levels of nicotine dependency and deprivation.

Research has largely focused on how attentional bias to smoking-related cues and impulsivity independently influence the development and maintenance of cigarette smoking, with limited exploration of the relationship between these mechanisms. The current experiments systematically assessed relationships between multiple dimensions of impulsivity and attentional bias, at different stages of attention, in smokers varying in nicotine dependency and deprivation. Nonsmokers (NS; n  = 26), light-satiated smokers (LS; n  = 25), heavy-satiated smokers (HS; n  = 23) and heavy 12-hour nicotine-deprived smokers (HD; n  = 30) completed the Barratt Impulsivity Scale, delayed discounting task, stop-signal task, information sampling task and a visual dot-probe assessing initial orientation (200 ms) and sustained attention (2000 ms) toward smoking-related cues. Sustained attention to smoking-related cues was present in both HS and LS, while initial orientation bias was only evident in HS. HS and LS also had greater levels of trait motor and nonplanning impulsivity and heightened impulsive choice on the delay discounting task compared with NS, while heightened trait attentional impulsivity was only found in HS. In contrast, in HD, nicotine withdrawal was associated with no attentional bias but heightened reflection impulsivity, poorer inhibitory control and significantly lower levels of impulsive choice relative to satiated smokers. Trait and behavioral impulsivity were not related to the extent of attentional bias to smoking-related cues at any stage of attention, level of nicotine dependency or state of deprivation. Findings have both clinical and theoretical implications, highlighting the unique and independent roles impulsivity and attentional bias may play at different stages of the nicotine addiction cycle.

LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependence.

Alcohol use disorder (AUD) remains a major public health concern. The dynorphin (DYN)/κ-opioid receptor (KOP) system is involved in actions of alcohol, particularly its withdrawal-associated negative affective states. This study tested the ability of LY2444296, a selective, short-acting, KOP antagonist, to decrease alcohol self-administration in dependent male and female Wistar rats at 8 h abstinence. Animals were trained to orally self-administer 10% alcohol (30 min/day for 21 sessions) and were made dependent via chronic intermittent alcohol vapor exposure for 6 weeks or exposed to air (nondependent). After 6 weeks, the effect of LY2444296 (0, 3, and 10 mg/kg, p.o.) was tested on alcohol self-administration at 8 h of abstinence. A separate cohort of rats was prepared in parallel, and their somatic withdrawal signs and alcohol self-administration were measured after LY2444296 administration at 8 h, 2 weeks, and 4 weeks abstinence. LY2444296 at 3 and 10 mg/kg significantly reduced physical signs of withdrawal in dependent rats at 8 h abstinence, only. Furthermore, 3 and 10 mg/kg selectively decreased alcohol self-administration in dependent rats at only 8 h abstinence. These results highlight the DYN/KOP system in actions of alcohol during acute abstinence, suggesting KOP antagonism could be beneficial for mitigating acute withdrawal signs and, in turn, significantly reduce excessive alcohol consumption associated with AUD.

Behavioral characterization of early nicotine withdrawal in the mouse: a potential model of acute dependence.

BACKGROUND: Clinical and preclinical research have demonstrated that short-term exposure to nicotine during the initial experimentation stage can lead to early manifestation of withdrawal-like signs, indicating the state of "acute dependence". As drug withdrawal is a major factor driving the progression toward regular drug intake, characterizing and understanding the features of early nicotine withdrawal may be important for the prevention and treatment of drug addiction. In this study, we corroborate the previous studies by showing that withdrawal-like signs can be precipitated after short-term nicotine exposure in mice, providing a potential animal model of acute dependence on nicotine. RESULTS: To model nicotine exposure from light tobacco use during the initial experimentation stage, mice were treated with 0.5 mg/kg (-)-nicotine ditartrate once daily for 3 days. On the following day, the behavioral tests were conducted after implementing spontaneous or mecamylamine-precipitated withdrawal. In the open field test, precipitated nicotine withdrawal reduced locomotor activity and time spent in the center zone. In the elevated plus maze test, the mecamylamine challenge increased the time spent in the closed arm and reduced the number of entries irrespective of nicotine experience. In the examination of the somatic aspect, precipitated nicotine withdrawal enhanced the number of somatic signs. Finally, nicotine withdrawal did not affect cognitive functioning or social behavior in the passive avoidance, spatial object recognition, or social interaction test. CONCLUSIONS: Collectively, our data demonstrate that early nicotine withdrawal-like signs could be precipitated by the nicotinic antagonist mecamylamine in mice, and that early withdrawal from nicotine primarily causes physical symptoms.

Alcohol withdrawal and pain: Peripheral mechanisms join central circuits.

Negative affective aspects of alcohol withdrawal and pain involve converging brain circuits. In this issue of Neuron, Son et al.1 identify a peripheral mechanism of an alcohol-withdrawal-induced headache-like condition, which is centered on mast-cell-specific receptor MrgprB2 activated by corticotropin-releasing factor (CRF) in dura mater to drive nociception.

Acute effects of outdoor and indoor walking on cigarette cravings, withdrawal symptoms and affective response during temporary smoking abstinence.

RATIONALE: Cigarette smoking is one of the leading preventable causes of premature death worldwide. There is evidence in the literature that brief exercise units indoors can improve well-being in temporarily abstinent smokers and reduce cigarette cravings and withdrawal symptoms. OBJECTIVE: Because exercise in natural environments showed enhanced psychological effects, the aim of our study was to examine the acute effects of outdoor exercise compared with indoor exercise on craving, withdrawal symptoms and affective response in temporarily abstinent smokers. METHODS: In a randomized controlled within-subject-design, temporarily abstinent smokers (N = 16) participated in three interventions lasting 10 min: outdoor walking (OUT-EX), indoor walking (IN-EX) and a sedentary control condition (CC). Self-reported cigarette craving, withdrawal symptoms and affective response were assessed pre-, mid-, post-interventions and at follow-up. RESULTS: In contrast to CC, OUT-EX and IN-EX significantly reduced cigarette cravings during and at the end of the intervention compared to pre-intervention, but not at 20 min follow-up. Cigarette withdrawal symptoms decreased significantly over time in all three groups, but no significant group differences were found. OUT-EX and IN-EX, but not CC, showed significantly improved affective valence at the end of the intervention and at follow-ups. Outdoor walking resulted in significantly lower cigarette cravings than indoor walking at the end of the intervention. CONCLUSION: The study adds to existing evidence that short bouts of indoor or outdoor exercise can help reduce cigarette cravings and increase well-being in abstinent smokers. Further studies are needed to address the potential additional effect of outdoor exercise on craving, affective states and smoking cessation.

Associations Between Childhood Trauma and Tobacco Use Outcomes in Adults after Overnight Abstinence.

INTRODUCTION: Childhood trauma is known to be associated with nicotine dependence, yet limited smoking outcomes have been examined and few studies have assessed associations between specific trauma subscales and smoking. Additionally, sex differences in trauma-smoking relations are understudied. This study examined associations between childhood trauma and several smoking-related outcomes in adults who smoke after overnight abstinence. AIMS AND METHODS: People who smoke (N = 205) completed self-report and biochemical assessments evaluating childhood trauma, affect, nicotine dependence, smoking urges, withdrawal, and plasma cortisol and cotinine levels. Smoking outcomes were compared between those with and without a history of moderate to severe childhood trauma among the total sample and by sex. RESULTS: Relative to those with no to minimal abuse, those with moderate to severe abuse had higher negative affect, withdrawal severity, and plasma cotinine levels. Exploratory analyses revealed that women were more likely than men to have urges to smoke for negative reinforcement and have higher withdrawal severity, but no interactions between abuse group and sex were observed. Examining specific trauma subscales, the moderate to severe emotional abuse group had more severe nicotine dependence, negative affect, and withdrawal compared to the no to minimal group. The moderate to severe sexual abuse group had more severe nicotine dependence and withdrawal compared to the no to minimal group. CONCLUSIONS: Exposure to childhood trauma is associated with more severe nicotine dependence, negative affect, withdrawal, and higher plasma cotinine levels. Findings also indicate that different types of trauma may differentially affect smoking behaviors. IMPLICATIONS: This study of adults who smoke finds that childhood trauma history may be a marker for smoking susceptibility and suggests that individuals with experiences of emotional and sexual abuse may require targeted forms of smoking cessation interventions. Moreover, findings suggest that smoking risks may differ for men and women. Findings inform public health interventions intended to reduce cigarette use in individuals with exposure to childhood trauma.

Biobehavioral and affective stress responses during nicotine withdrawal: Influence of regular cannabis co-use.

BACKGROUND: Co-use of cannabis is increasing in nicotine users and presents additional challenges in addressing nicotine dependence. This study examined the links between regular co-use of cannabis and nicotine with biobehavioral and affective changes in response to stress during nicotine withdrawal and ad libitum use. METHODS: Participants (N = 79) who regularly used nicotine-only, cannabis-only, both substances, or neither substance were invited to attend two laboratory stress assessment sessions. For nicotine users, one session occurred during ad libitum nicotine use and one occurred after abstinence from nicotine. During the stress sessions, participants provided saliva samples for cortisol assay and completed measures of subjective states. Cardiovascular measures were collected during resting baseline, exposure to acute stressors, and a recovery rest period. RESULTS: Nicotine-only users had higher average cortisol levels in the second lab session (nicotine withdrawal) relative to the first lab session (ad libitum nicotine use). Compared to nicotine non-users, nicotine users reported less positive affect and exhibited attenuated cortisol and systolic blood pressure (BP) stress responses. Cannabis users exhibited exaggerated diastolic BP responses to stress compared to cannabis non-users, and co-users of nicotine and cannabis had higher levels of cannabis craving than cannabis-only users (p < .01). CONCLUSIONS: This study partially replicated earlier findings on the effects of chronic nicotine use and provided novel results regarding the influence of cannabis co-use on physiological and affective responses to stress in nicotine users during nicotine withdrawal.

Management of Cholinergic Rebound After Abrupt Withdrawal of Clozapine: A Case Report and Systematic Literature Review.

BACKGROUND: Cholinergic discontinuation symptoms, also known as "cholinergic rebound," from abrupt clozapine discontinuation are characterized by a range of somatic and psychiatric symptoms. OBJECTIVE: The objective of this study was to describe the clinical features and management options for clozapine withdrawal-associated cholinergic rebound syndrome (henceforth referred to as CWCRS) and present an illustrative case report. METHODS: Based on a literature search of the databases PubMed, OVID Medline, and Embase as well as reviewing reference lists of relevant past reviews, we carried out a systematic review of case reports on the management of CWCRS from 1946 to 2023. RESULTS: We identified 10 previously published articles on the clinical management of CWCRS, with a total of 18 patients (6 female, 12 male) with an average age of 43 years (standard deviation 14). Half of the patients had a history of tardive dyskinesia. The mean dose of clozapine before discontinuation was 351 mg/day, with duration of clozapine treatment ranging from 3 weeks to 9 years. Clozapine was the most effective treatment, followed by benztropine. CONCLUSIONS: Given the small number of cases and the nonexperimental nature of the available studies, this review could not provide reliable data to guide management of CWCRS. The findings, however, suggest that clozapine may be more effective than other commonly used treatment options. With the high rates of discontinuation among patients on clozapine, there is a pressing need for further research into the epidemiology, natural history, and management of clozapine withdrawal syndromes.

Examining predictors of cocaine withdrawal syndrome at the end of detoxification treatment in women with cocaine use disorder.

BACKGROUND: Detoxification is frequently recommended as a treatment for moderate to severe Cocaine Use Disorder (CUD). However, the response to detoxification varies among patients, and previous studies have focused mostly on patterns of drug use behavior to test associations with treatment outcomes, overlooking the potential impact of psychosocial factors, other clinical variables, and individual life experiences. In this study we comprehensively examined several variables aiming to find the most relevant predictors to classify patients with severe versus non-severe cocaine withdrawal symptoms at the end of detoxification. METHODS: Data from 284 women with CUD who enrolled in a 3-week detoxification program was used in this longitudinal study. Psychosocial, clinical, and drug use behavior characteristics were evaluated, generating a dataset with 256 potential predictors. We tested six different machine learning classification algorithms. RESULTS: The best classification algorithm achieved an average accuracy and ROC-AUC of approximately 70%. The 16 features selected as best predictors were the severity of psychiatric, family, and social problems and the level of exposure to childhood maltreatment. Features associated with drug-use behavior included days consuming drugs and having craving symptoms in the last month before treatment, number of previous drug/alcohol-related treatments, and a composite score of addiction severity. The level of cocaine withdrawal syndrome at the beginning of detoxification was also a key feature for classification. A network analysis revealed the pattern of association between predictors. CONCLUSION: These variables can be assessed in real-world clinical settings, potentially helping clinicians to identify individuals with severe cocaine withdrawal that is likely to be sustained over the course of detoxification.

Prevalence and correlates of DSM-5 opioid withdrawal syndrome in U.S. adults with non-medical use of prescription opioids: results from a national sample.

Background: In the U.S. non-medical use of prescription opioids (NMOU) is prevalent and often accompanied by opioid withdrawal syndrome (OWS). OWS has not been studied using nationally representative data.Objectives: We examined the prevalence and clinical correlates of OWS among U.S. adults with NMOU.Methods: We used data from 36,309 U.S. adult participants in the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III, 1,527 of whom reported past 12-month NMOU. Adjusted linear and logistic regression models examined associations between OWS and its clinical correlates, including psychiatric disorders, opioid use disorder (OUD; excluding the withdrawal criterion), medical conditions, and healthcare utilization among people with regular (i.e. ≥3 days/week) NMOU (n = 534).Results: Over half (50.4%) of the sample was male. Approximately 9% of people with NMOU met criteria for DSM-5 OWS, with greater prevalence of OWS (∼20%) among people with regular NMOU. Individuals with bipolar disorder, dysthymia, panic disorder, and borderline personality disorder had greater odds of OWS (aOR range = 2.71-4.63). People with OWS had lower mental health-related quality of life (ß=-8.32, p < .001). Individuals with OUD also had greater odds of OWS (aOR range = 26.02-27.77), an association that increased with more severe OUD. People using substance use-related healthcare services also had greater odds of OWS (aOR range = 6.93-7.69).Conclusion: OWS was prevalent among people with OUD and some psychiatric disorders. These findings support screening for OWS in people with NMOU and suggest that providing medication- assisted treatments and behavioral interventions could help to reduce the burden of withdrawal in this patient population.

Fluoxetine rescues the depressive-like behaviour induced by reserpine and the altered emotional behaviour induced by nicotine withdrawal in zebrafish: Involvement of tyrosine hydroxylase.

BACKGROUND: Nicotine cessation leads to anxiety and depression. AIMS: The suitability of the zebrafish model of anhedonia using reserpine and fluoxetine was evaluated. Fluoxetine was also used to reduce nicotine withdrawal-induced anhedonic state. METHODS: Zebrafish were exposed to reserpine (40 mg/l) and then to fluoxetine (0.1 mg/l) for 1 week. Anhedonia was evaluated in the Novel Tank Diving and Compartment Preference tests. Another group was exposed to nicotine (1 mg/l/2 weeks) and then exposed to fluoxetine. Anxiety and anhedonia were evaluated 2-60 days after. Tyrosine hydroxylase (TH) immunoreactivity and microglial morphology (labelled by 4C4 monoclonal antibody) in the parvocellular pretectal nucleus (PPN), dorsal part, and of calcitonin gene-related peptide (CGRP) in the hypothalamus were also analysed. RESULTS: Less time in the top and increased latency to the top in reserpine compared to a drug-free group was found. Fluoxetine rescued reserpine-induced the reduced time in the top. Seven and 30 days after nicotine withdrawal more time in the bottom and similar time in the Compartment Preference test, rescued by fluoxetine, were shown. In the PPN, 30-day withdrawal induced an increase in TH immunoreactivity, but fluoxetine induced a further significant increase. No changes in PPN microglia morphology and hypothalamic CGRP were detected. CONCLUSIONS: Our findings validate the suitability of the zebrafish model of anhedonia using the reserpine-induced depression-like behaviour and the predictivity using fluoxetine. Fluoxetine rescued nicotine withdrawal-induced anhedonic state, opening the possibility to screen new drugs to alleviate anxiety and depression in smokers during abstinence.

Opioid withdrawal: role in addiction and neural mechanisms.

Withdrawal from opioids involves a negative affective state that promotes maintenance of drug-seeking behavior and relapse. As such, understanding the neurobiological mechanisms underlying withdrawal from opioid drugs is critical as scientists and clinicians seek to develop new treatments and therapies. In this review, we focus on the neural systems known to mediate the affective and somatic signs and symptoms of opioid withdrawal, including the mesolimbic dopaminergic system, basolateral amygdala, extended amygdala, and brain and hormonal stress systems. Evidence from preclinical studies suggests that these systems are altered following opioid exposure and that these changes mediate behavioral signs of negative affect such as aversion and anxiety during withdrawal. Adaptations in these systems also parallel the behavioral and psychological features of opioid use disorder (OUD), highlighting the important role of withdrawal in the development of addictive behavior. Implications for relapse and treatment are discussed as well as promising avenues for future research, with the hope of promoting continued progress toward characterizing neural contributors to opioid withdrawal and compulsive opioid use.

Acute effects of exercise among individuals with schizophrenia who smoke cigarettes.

People with schizophrenia (SCZ) have a shorter life expectancy than those without psychiatric conditions. Of note, people with SCZ have high rates of cigarette smoking, physical inactivity, and obesity. These factors all coalesce to contribute to compromised health in this population, with smoking as a primary contributor. Therefore, it is paramount to develop effective smoking cessation strategies for this population. The purpose of this study was to investigate whether walking at a brisk pace, relative to engaging in passive activity, would reduce acute cigarette craving, nicotine withdrawal, and negative affect (NA) among people with SCZ who smoke cigarettes. Using a within-subjects design, twenty participants completed four laboratory sessions with condition sequence counterbalanced: 1) exposure to smoking cues + treadmill walking, 2) exposure to neutral cues + treadmill walking, 3) exposure to smoking cues + passive/sedentary activity, 4) exposure to neutral cues + passive/sedentary activity. Relative to sedentary activity, walking resulted in greater decreases in nicotine withdrawal but did not significantly affect craving or NA. These results did not vary as a function of cue type. These findings suggest that walking may be a helpful strategy to reduce acute nicotine withdrawal symptoms among people with SCZ. However, it should be used in conjunction with other strategies for smoking cessation.

L-theanine attenuates nicotine reward and withdrawal signs in mice.

BACKGROUND: L-theanine, 2-amino-4-(ethylcarbamoyl) butyric acid, an amino acid detected in green tea leaves, is used as a dietary supplement to attenuate stress and enhance mood and cognition. Furthermore, L-theanine induces anxiolytic effects in humans. Recently, L-theanine was reported to reduce morphine physical dependence in primates, suggesting the potential usefulness of L-theanine for drug dependence intervention. OBJECTIVE: The aim of this study is to determine whether L-theanine attenuates nicotine-withdrawal (somatic and affective signs) and nicotine reward in mice. We also investigated the effects of L-theanine on nicotinic receptors binding and function. METHODS: ICR male mice rendered dependent to nicotine through implanted subcutaneous osmotic minipumps for 14 days undertook precipitated nicotine withdrawal by mecamylamine on day 15. Anxiety-like behaviors using LDB, somatic signs observation and hot plate latency were assessed consecutively after treatment with L-theanine. Furthermore, we examined the effect of L-theanine on acute nicotine responses and nicotine conditioned reward in mice and on expressed nicotinic receptors in oocytes. KEY FINDINGS: L-theanine reduced in a dose-dependent manner anxiety-like behavior, hyperalgesia and somatic signs during nicotine withdrawal. Also, L-theanine decreased the nicotine CPP, but it did not affect the acute responses of nicotine. Finally, L-theanine did not alter the binding or the function of expressed α4ß2 and α7 nAChRs. CONCLUSION: Our results support the potential of L-theanine as a promising candidate for treating nicotine dependence.

The antidepressant agomelatine attenuates morphine-induced reinstatement but not self-administration or precipitated withdrawal.

BACKGROUND: Exogenous melatonin appears to have anti-addictive properties and was recently shown to improve mental health and metabolic measures in patients receiving chronic opioid maintenance therapy. Agomelatine is a marketed antidepressant which acts as a melatonin agonist. We evaluated its effects using a rat model of morphine-reinforced behavior. METHODS: After pretreatment with noncontingent morphine, male Wistar rats were trained to self-administer intravenous morphine (1.0 mg/kg-injection) under a progressive-ratio schedule. Rats were pretreated with vehicle or agomelatine during extinction, reinstatement, and reacquisition of morphine-reinforced behavior. RESULTS: Daily treatment with 10 mg/kg-day of agomelatine decreased the number of ratios completed and prolonged latency during morphine-induced reinstatement. There were no significant effects on cue-induced reinstatement, morphine self-administration, or naloxone-precipitated withdrawal. Treatment with 32 mg/kg-day of agomelatine caused postural changes. That dose prolonged withdrawal-induced loss of body weight and caused delayed reductions in food reinforcement. SUMMARY: In addition to postural effects, high-dose agomelatine worsened the course of spontaneous withdrawal and produced nonspecific effects on food-reinforced behavior. When administered at a selective dose, agomelatine did not modify morphine self-administration or precipitated withdrawal, but decreased morphine-induced reinstatement. Our findings show potential detrimental effects of high-dose agomelatine, with reductions in opioid-seeking behavior after a lower, more selective dose.