Abstinence Phase Research Articles

Step-wise formation of germinal center B cells is completed by a requisite phase of Th cell disengagement and CD40 signaling abstinence

Abstract There are conflicting reports on the role of CD40 signaling in the initiation and maintenance of germinal centers (GC). CD40 signaling invokes the nuclear translocation of RelB, a transcription factor that promotes IRF4 expression. We examined the early stages of GC B cell differentiation without any phenotypic preconceptions by the adoptive transfer of tagged antigen-specific B cells. As expected, B cells were first observed to express intermediate levels of BCL6 within the interfollicular (IF) zone shortly after immunization. However, these GC B cell precursors had only a partial GC phenotype and co-expressed RelB and IRF4, transcription factors known to repress BCL6 transcription. This initial co-expression of mutually antagonistic transcription factors is short-lived: follicular BCL6hi GC B cells with diminished levels of RelB and IRF4 emerge shortly thereafter, coupled with the disappearance of the immediate precursors as a function of cell division. Interestingly, potentiating T cell help at the GC initiation stage blocks this transition and diverts the fate of GC immediate precursors towards plasma cells, suggesting that ongoing T cell engagement discourages GC B cell formation. Consistent with this idea, we found that reducing the amount of antigen at the time of immunization accelerates GC B cell formation. Similarly, discontinuing T-cell derived factors in an in-vitro culture system promotes the generation of BCL6hi RelB− IRF4− cells with GC B cell properties. Taken together these results suggest that CD40 signaling in B cells is necessary to generate the immediate precursors of GC B cells, but transition to the BCL6hi follicular state is completed by a period of abstinence from Th cell CD40L.

Weighing the Evidence: A Systematic Review on Long-Term Neurocognitive Effects of Cannabis Use in Abstinent Adolescents and Adults.

Findings on neurocognitive effects of sustained cannabis use are heterogeneous. Previous work has rarely taken time of abstinence into account. In this review, we focus on understanding sustained effects of cannabis, which begin when clinical symptoms of the drug have worn off after at least 14days. We conducted a search between 2004 and 2015 and found 38 studies with such a prolonged abstinence phase. Study-design quality in terms of evidence-based medicine is similar among studies. Studies found some attention or concentration deficits in cannabis users (CU). There is evidence that chronic CU might experience sustained deficits in memory function. Findings are mixed regarding impairments in inhibition, impulsivity and decision making for CU, but there is a trend towards worse performance. Three out of four studies found evidence that motor function remains impaired even after a time of abstinence, while no impairments in visual spatial functioning can be concluded. Functional imaging demonstrates clear differences in activation patterns between CU and controls especially in hippocampal, prefrontal and cerebellar areas. Structural differences are found in cortical areas, especially the orbitofrontal region and the hippocampus. Twenty studies (57%) reported data on outcome effects, leading to an overall effect size of r mean = .378 (CI 95% = [.342; .453]). Heavy use is found to be more consistently associated with effects in diverse domains than early age of onset. Questions of causality-in view of scarce longitudinal studies, especially those targeting co-occurring psychiatric disorders-are discussed.

Plasma Cannabinoid Pharmacokinetics After Controlled Smoking and Ad libitum Cannabis Smoking in Chronic Frequent Users.

More Americans are dependent on cannabis than any other illicit drug. The main analytes for cannabis testing include the primary psychoactive constituent, Δ(9)-tetrahydrocannabinol (THC), equipotent 11-hydroxy-THC (11-OH-THC) and inactive 11-nor-9-carboxy-THC (THCCOOH). Eleven adult chronic frequent cannabis smokers resided on a closed research unit with unlimited access to 5.9% THC cannabis cigarettes from 12:00 to 23:00 during two ad libitum smoking phases, followed by a 5-day abstinence period in seven participants. A single cigarette was smoked under controlled topography on the last day of the smoking and abstinence phases. Plasma cannabinoids were quantified by two-dimensional gas chromatography-mass spectrometry. Median plasma maximum concentrations (Cmax) were 28.3 (THC), 3.9 (11-OH-THC) and 47.0 μg/L (THCCOOH) 0.5 h after controlled single cannabis smoking. Median Cmax 0.2-0.5 h after ad libitum smoking was higher for all analytes: 83.5 (THC), 14.2 (11-OH-THC) and 155 μg/L (THCCOOH). All 11 participants' plasma samples were THC and THCCOOH-positive, 58.3% had THC ≥5 μg/L and 79.2% were 11-OH-THC-positive 8.1-14 h after last cannabis smoking. Cannabinoid detection rates in seven participants 106-112 h (4-5 days) after last smoking were 92.9 (THC), 35.7 (11-OH-THC) and 100% (THCCOOH), with limits of quantification of 0.5 μg/L for THC and THCCOOH, and 1.0 μg/L for 11-OH-THC. These data greatly expand prior research findings on cannabinoid excretion profiles in chronic frequent cannabis smokers during ad libitum smoking. Smoking multiple cannabis cigarettes led to higher Cmax and AUC compared with smoking a single cigarette. The chronic frequent cannabis smokers exhibited extended detection windows for plasma cannabinoids, reflecting a large cannabinoid body burden.

Activation of Melatonin Receptors Reduces Relapse-Like Alcohol Consumption.

Melatonin is an endogenous synchronizer of biological rhythms and a modulator of physiological functions and behaviors of all mammals. Reduced levels of melatonin and a delay of its nocturnal peak concentration have been found in alcohol-dependent patients and rats. Here we investigated whether the melatonergic system is a novel target to treat alcohol addiction. Male Wistar rats were subjected to long-term voluntary alcohol consumption with repeated abstinence phases. Circadian drinking rhythmicity and patterns were registered with high temporal resolution by a drinkometer system and analyzed by Fourier analysis. We examined potential antirelapse effect of the novel antidepressant drug agomelatine. Given that agomelatine is a potent MT1 and MT2 receptor agonist and a 5-HT2C antagonist we also tested the effects of melatonin itself and the 5-HT2C antagonist SB242084. All drugs reduced relapse-like drinking. Agomelatine and melatonin administered at the end of the light phase led to very similar changes on all measures of the post-abstinence drinking behavior, suggesting that effects of agomelatine on relapse-like behavior are mostly driven by its melatonergic activity. Both drugs caused a clear phase advance in the diurnal drinking pattern when compared with the control vehicle-treated group and a reduced frequency of approaches to alcohol bottles. Melatonin given at the onset of the light phase had no effect on the circadian phase and very small effects on alcohol consumption. We conclude that targeting the melatonergic system in alcohol-dependent individuals can induce a circadian phase advance, which may restore normal sleep architecture and reduce relapse behavior.

Glutamatergic neurometabolites during early abstinence from chronic methamphetamine abuse.

Background:The acute phase of abstinence from methamphetamine abuse is critical for rehabilitation success. Proton magnetic resonance spectroscopy has detected below-normal levels of glutamate+glutamine in anterior middle cingulate of chronic methamphetamine abusers during early abstinence, attributed to abstinence-induced downregulation of the glutamatergic systems in the brain. This study further explored this phenomenon.Methods:We measured glutamate+glutamine in additional cortical regions (midline posterior cingulate, midline precuneus, and bilateral inferior frontal cortex) putatively affected by methamphetamine. We examined the relationship between glutamate+glutamine in each region with duration of methamphetamine abuse as well as the depressive symptoms of early abstinence. Magnetic resonance spectroscopic imaging was acquired at 1.5 T from a methamphetamine group of 44 adults who had chronically abused methamphetamine and a control group of 23 age-, sex-, and tobacco smoking-matched healthy volunteers. Participants in the methamphetamine group were studied as inpatients during the first week of abstinence from the drug and were not receiving treatment.Results:In the methamphetamine group, small but significant (5–15%, P<.05) decrements (vs control) in glutamate+glutamine were observed in posterior cingulate, precuneus, and right inferior frontal cortex; glutamate+glutamine in posterior cingulate was negatively correlated (P<.05) with years of methamphetamine abuse. The Beck Depression Inventory score was negatively correlated (P<.005) with glutamate+glutamine in right inferior frontal cortex.Conclusions:Our findings support the idea that glutamatergic metabolism is downregulated in early abstinence in multiple cortical regions. The extent of downregulation may vary with length of abuse and may be associated with severity of depressive symptoms emergent in early recovery.

Focused transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex modulates specific domains of self-regulation

Recent neuroscience theories suggest that different kinds of self-regulation may share a common psychobiological mechanism. However, empirical evidence for a domain general self-regulation mechanism is scarce. The aim of this study was to investigate whether focused anodal transcranial direct current stimulation (tDCS), facilitating the activity of the dorsolateral prefrontal cortex (dlPFC), acts on a domain general self-regulation mechanism and thus modulates both affective and appetitive self-regulation. Twenty smokers participated in this within-subject sham controlled study. Effects of anodal left, anodal right and sham tDCS over the dlPFC on affective picture appraisal and nicotine craving-cue appraisal were assessed. Anodal right tDCS over the dlPFC reduced negative affect in emotion appraisal, but neither modulated regulation of positive emotion appraisal nor of craving appraisal. Anodal left stimulation did not induce any significant effects. The results of our study show that domain specific self-regulation networks are at work in the prefrontal cortex. Focused tDCS modulation of this specific self-regulation network could probably be used during the first phase of nicotine abstinence, during which negative affect might easily result in relapse. These findings have implications for neuroscience models of self-regulation and are of relevance for the development of brain stimulation based treatment methods for neuropsychiatric disorders associated with self-regulation deficits.

Borderline personality disorder and comorbid addiction: epidemiology and treatment.

Borderline personality disorder (BPD) affects 2.7% of adults. About 78% of adults with BPD also develop a substance-related disorder or addiction at some time in their lives. These persons are more impulsive and clinically less stable than BPD patients without substance dependency. They display suicidal behavior to a greater extent, drop out of treatment more often, and have shorter abstinence phases. The combination of borderline personality disorder with addiction requires a special therapeutic approach. This review is based on a selective literature search about the treatment of patients with BPD and addiction, with particular attention to Cochrane Reviews and randomized controlled trials (RCT). The available evidence is scant. In two RCTs, Dialectical Behavior Therapy for Substance Use Disorders (DBT-SUD) was found to improve patients' overall functional level (standardized mean difference, 1.07-1.78) and to increase the number of abstinence days (effect strength [ES], 1.03) and negative urine samples (ES, 0.75). Dual focus schema therapy (DFST) was evaluated in three RCTs. Because of methodological problems, however, no useful quantitative comparison across trials is possible. In one RCT, dynamic deconstructive psychotherapy (DDP) was found to have only a moderate, statistically insignificant effect. Only a single study provides data about potentially helpful drug therapy over the intermediate term. Patients with borderline personality disorder and comorbid addiction should be treated as early as possible for both conditions in a thematically hierarchical manner. There is no evidence for any restriction on drug therapy to prevent recurrent addiction in these patients. The psychotherapeutic techniques that can be used (despite the currently inadequate evidence base) include DBT-SUD, DFST, and DDP. These patients need qualified expert counseling in choosing a suitable type of psychotherapy. Specific treatment is available in only a few places, and the relevant treatment networks in Germany are just beginning to be constructed.

Amplified reacquisition of nicotine self-administration in rats by repeated stress during abstinence

Quitting smoking is often very challenging, leading to frequent relapse. Exposure to acute and chronic stress during abstinence increases the likelihood of relapse to smoking. In rodents, stress acutely reinstates nicotine seeking after extinction of nicotine self-administration (SA). However, whether reacquisition of nicotine taking is amplified by chronic stress during abstinence from nicotine SA has not been determined in animals. We sought to determine effects of repeated restraint stress during abstinence on reacquisition of nicotine SA. Rats acquired nicotine SA (23 h/day) under a fixed-ratio (FR) 5 schedule of reinforcement, which was followed by an abstinence phase. Restraint (0, 2, and 4 times) was administered during abstinence. Animals reacquired nicotine SA, first under a progressive ratio (PR) schedule, beginning immediately after the final stress, followed by an FR5 schedule. In another experiment, reacquisition (FR5) began 24 h after the final stress. No PR testing was conducted. Four restraint stress exposures during abstinence, but not only two, enhanced reacquisition of nicotine SA by increasing nicotine injections under a PR schedule beginning immediately after the final stress (p < 0.05) followed by increasing nicotine intake under an FR5 schedule (p < 0.05). This was observed even when the final stress and reacquisition trial were separated by 24 h. Moreover, repeated stress-induced nicotine taking during the behaviorally inactive phase (i.e., lights on) of the 24-h diurnal cycle. Chronic (i.e., repeated) stress during abstinence promotes reacquisition of nicotine SA and affects diurnal pattern of nicotine intake.

Chapter 18 - Molecular imaging in alcohol dependence

The cellular mechanisms of alcohol's effects in the brain are complex, targeting multiple transmitter systems. Molecular imaging has been used to study the effects of alcohol and alcohol use disorders on these various systems. Studies of dopaminergic indices have provided robust evidence for deficits in D2-mediated transmission in the striatum of chronic recently detoxified alcoholics. Their presence in the at-risk state prior to excessive drinking, and their recovery after long-term sobriety, are unclear and represent an active area of current research. Investigations of the GABAergic system have shown generalized deficits in various brain regions in the chronic abstinence phase. Studies of the opiate system have suggested alterations in some subtypes in discrete brain regions, including the ventral striatum, while studies of serotonin have been negative and those of the cannabinoid system have been inconclusive. Future investigations should target the glutamatergic system, which plays an important role both in the acute intoxicating effects of alcohol as well as in the long-term effects associated with dependence.

Ecological Momentary Assessment of Posttraumatic Stress Disorder Symptoms During a Smoking Quit Attempt

Smokers with posttraumatic stress disorder (PTSD) tend to lapse more quickly following a quit attempt, which might be explained by changes in PTSD symptoms during a quit attempt. The present study examines changes in PTSD symptoms, negative affect, and craving before and during a quit attempt. Participants in this study were 52 smokers with PTSD who completed random-alarm ecological momentary assessments of PTSD symptoms, negative affect, cigarette craving, and smoking behavior throughout a prequit phase of ad hoc smoking, a phase of abstinence from smoking, and a postlapse phase. Relative to the prequit phase, the abstinent phase was marked by decreases in PTSD reexperiencing, avoidance, and numbing clusters (ps ≤ .01). The odds of PTSD symptom or negative affect variability from one reading in the ecological momentary assessment (EMA)to the next reading was decreased in PTSD reexperiencing, avoidance, and numbing clusters (ps ≤ .02). Smoking cravings were also mildly decreased in the abstinent and postlapse phases (ps < .01), although some cravings in both phases were rated at the maximum intensity. Increased craving was predicted by the previous EMA reading of PTSD symptoms. Results suggested that smoking abstinence is not associated with exacerbation of PTSD symptoms, but PTSD symptoms during abstinence were related to craving levels during the quit attempt.

Region-specific effects on BDNF expression after contingent or non-contingent cocaine i.v. self-administration in rats

Brain-derived neurotrophic factor (BDNF) dynamic changes were investigated in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) during use and the early phases of cocaine abstinence after 14 sessions (2 h self-administration/d; 0.25mg/0.1ml.6s infusion) by employing a 'yoked control-operant paradigm'. The effect on BDNF was region-specific and dependent on the withdrawal time. In the NAc, BDNF protein levels increased immediately after the last self-administration session, with a larger increase in passively cocaine-exposed rats. In the mPFC, BDNF expression was elevated 24 h after the last self-administration session, independently of how the drug was encountered. No changes were found in NAc and mPFC 7 d after the last self-administration session. Analysis of transcript levels in the mPFC indicated that action on exon I might contribute to BDNF's cortical induction. These findings indicate a finely tuned modulation of BDNF expression during use and early phases of cocaine abstinence.

Neural substrates of acupuncture in the modulation of cravings induced by smoking-related visual cues: an FMRI study

Cue reactivity is a key factor in modulating motivational and goal-directed behaviors associated with compulsive drug intake and relapse. Smoking-associated cues produce smoking urges and cravings and are accompanied by the activation of brain regions involved in attention, motivation, and reward. We investigated whether acupuncture ameliorates cravings induced by smoking-related visual cues, and we explored the neural mechanisms underlying the effects of acupuncture on modulating smoking urges. After 36 h of smoking abstinence, 25 right-handed male smokers underwent fMRI, during which smoking-related and neutral visual cues were presented. Twelve subjects were treated with real acupuncture (RA) at HT7 and 13 subjects received sham acupuncture (SA). During the scanning sessions, craving scores to smoking-related visual cues were assessed before and after RA or SA treatment. The differences in brain responses to smoking vs. neutral cues after treatment between the RA and SA groups were detected using three-way ANOVAs (Cue × Session × Group). After treatment, the craving scores were significantly decreased in the RA group, as compared to the SA group. When we explored the neural substrates of acupuncture on the modulation of cravings induced by smoking cues, significant differences were found in the medial prefrontal cortex, the premotor cortex, the amygdala, the hippocampus, and the thalamus. These findings suggest that acupuncture alleviates cue-induced cravings through the regulation of activity in brain regions involved in attention, motivation, and reward relative to craving scores in the initial abstinence phase.

Modafinil, Inhibitory Control, and Alcoholism

A lcohol is implicated as a causal factor in numerous diseases and injuries; its harmful use accounts for approximately 2.5 million deaths worldwide each year, according to the World Health Organization’s Global Status Report on Alcohol and Health, 2011. Alcohol dependence is by definition a heterogenous disorder, characterized by the past 12-month occurrence of at least three of seven DSM criteria (Fourth Revision, American Psychiatric Association). Examples of these criteria include tolerance, withdrawal symptoms, and continued use despite knowledge of physical/psychologic alcohol-related harm. Despite some success from psychosocial and pharmacologic interventions, there is an ongoing search for more effective treatments. People with alcohol dependence manifest cognitive deficits that likely contribute to persistence of addiction and interfere with the ability to engage with and successfully deploy psychologic techniques. Response inhibition involves the suppression of a habitual or prepotent response that would ordinarily be made, when an unpredictable change occurs in the external environment. This ability is important in day-to-day life and is often impaired in attention-deficit/hyperactivity disorder and in substance addiction including alcohol (1). In heavy alcohol drinkers, relative baseline deficits in response inhibition were significantly predictive of the subsequent development of alcohol dependence (1). In addition, neural abnormalities during inhibitory control have been identified in alcohol-dependent patients, even during the early phases of abstinence (2). Response inhibition thus represents a candidate therapeutic target for people with alcohol dependence, and, theoretically, for people at risk of alcohol dependence. Modafinil is a wake-promoting agent with cognitive-enhancing potential (3). Schmaal et al. (4) in the current issue of Biological Psychiatry explored the effects of modafinil on response inhibition and its neurobiologic substrates in people with alcohol dependence and in healthy volunteers, using functional magnetic resonance imaging in a double-blind, placebo-controlled design (4). Response inhibition was measured using a stop-signal task, in which participants observed a series of stimuli appearing one per time and made speeded responses (a left button in response to a left-facing stimulus; and vice versa). On a subset of trials, a stop signal occurred (a visual cross), indicating to the participant that they had to attempt to suppress the response. By adjusting the time interval between the go and stop signal, stop-signal tasks such as these yield the stop-signal reaction time: an estimate of the time taken by the brain to stop a response that would normally be undertaken. Longer stop-signal reaction times equate to worse motor inhibition. Several tiers of research have indicated that response inhibition, thus operationalized, is dependent on a distributed neural network including the inferior

The effect of nimodipine on memory impairment during spontaneous morphine withdrawal in mice: Corticosterone interaction

Effects of the nimodipine, L-type calcium channel antagonist, has been studied on memory loss caused by spontaneous morphine withdrawal in mice. Mice were made dependent by increasing doses of morphine over three days. Memory was evaluated using object recognition task, which is based on tendency of rodents to exploration of new objects. The test was comprised of three sections: 15min habitation, 12min first trial and 5min test trial. Recognition index was evaluated 4h after the last dose of morphine. Nimodipine was administrated either in chronic form (1, 5 and 10mg/kg) with daily doses of morphine or it was given as a single injection (5 and 10mg/kg) on the last day. Nimodipine in both treatment forms prevented the memory impairment following spontaneous morphine withdrawal. Corticosterone concentration was increased in brain and blood of mice during abstinence phase and pretreatment with nimodipine prevented the increase in brain and blood corticosterone concentration. The results show that blockade of L-type calcium channels improves memory deficits caused by morphine withdrawal. This indicates that some kind of treatments, such as nimodipine, administrated over the acute withdrawal phase, can prevent memory deficit during withdrawal.

Nicotine-induced anxiety-like behavior in a rat model of the novelty-seeking phenotype is associated with long-lasting neuropeptidergic and neuroplastic adaptations in the amygdala: Effects of the cannabinoid receptor 1 antagonist AM251

A rat model of the novelty-seeking phenotype predicts vulnerability to the expression of behavioral sensitization to nicotine, where locomotor reactivity to novelty is used to screen experimentally-naïve rats for high (HR) versus low (LR) responders. The present study examines the long-term neuropeptidergic and neuroplastic adaptations associated with the expression of locomotor sensitization to a low dose nicotine challenge and social anxiety-like behavior following chronic intermittent nicotine exposure during adolescence in the LRHR phenotype. Our data show that the expression of behavioral sensitization to nicotine and abstinence-related anxiety are detected in nicotine pre-exposed HRs even across a long (3 wks) abstinence. Moreover, these behavioral effects of nicotine are accompanied by a persistent imbalance between neuropeptide Y and corticotrophin releasing factor systems, and a persistent increase in brain-derived neurotrophic factor (BDNF) and spinophilin mRNA levels in the amygdala. Furthermore, treatment with the cannabinoid receptor 1 antagonist, AM251 (5 mg/kg) during a short (1 wk) abstinence is ineffective in reversing nicotine-induced anxiety, fluctuations in BDNF and spinophilin mRNAs, and the neuropeptidergic dysregulations in the amygdala; although this treatment is effective in reversing the expression of locomotor sensitization to challenge nicotine even after a long abstinence. Interestingly, the identical AM251 treatment administered during the late phase of a long abstinence further augments anxiety and associated changes in BDNF and spinophilin mRNA in the basolateral nucleus of the amygdala in nicotine pre-exposed HRs. These findings implicate long-lasting neuropeptidergic and neuroplastic changes in the amygdala in vulnerability to the behavioral effects of nicotine in the novelty-seeking phenotype.

Chronic treatment with curcumin enhances methamphetamine locomotor sensitization and cue-induced reinstatement of methamphetamine self-administration

ObjectivesCurcumin, a major active component of Curcuma longa, possesses antidepressant effects that are mediated by the 5-HT system. However, little is known about the effect of curcumin on the behavioral consequences of methamphetamine (METH). MethodsThe subjects were male, adult Sprague–Dawley rats. In Experiment 1, the effects of 20 and 40mg/kg curcumin (i.p.) on response rates and breakpoints of 0.06mg/kg/infusion METH were evaluated. In Experiment 2, rats were self-administering METH for 10days followed by a 14-day abstinence period. During the abstinence period, the animals were treated with DMSO, 20 or 40mg/kg curcumin. All rats were then tested for extinction responding and cue-induced reinstatement. In Experiment 3, rats were treated with DMSO, 20, or 40mg/kg curcumin15min before a METH-induced locomotor activity test for 14 consecutive days. In Experiment 4, rats were pretreated with DMSO or curcumin (20mg/kg or 40mg/kg) for 13days and were subsequently tested for METH-induced locomotor activity on the 14th day. In Experiment 5, three groups were tested for locomotor activity after an injection of DMSO, 20, or 40mg/kg curcumin. The test was repeated for 14days. ResultsCurcumin produced little effect on response rates and breakpoints maintained by METH. Chronic treatment of only 40mg/kg curcumin during the abstinence phase enhanced cue-induced reinstatement of METH self-administration. Chronic administration of curcumin increased METH-induced sensitization of locomotor activity at the lower (20mg/kg) but not higher (40mg/kg) dose. However pretreatment of curcumin alone showed no significant effect on acute locomotor responses to METH and locomotor responses per se. ConclusionsCurcumin enhanced, rather than inhibited the behavioral effects of METH.

Oral tobacco products: Preference and effects among smokers

BackgroundRecently, oral tobacco products have been marketed specifically towards cigarette smokers. These products come in different nicotine doses and formulations (snus vs. lozenge). To date, little research has been conducted to determine how smokers respond to these products. The goal of this study was to examine if smokers prefer certain oral tobacco products based on their specific characteristics. MethodsSmokers interested in quitting underwent a sampling phase and a treatment phase. The sampling phase consisted of testing five different products varying in nicotine dose (high vs. moderate vs. low) and formulation (snus vs. lozenge): General Snus, Camel Snus, Marlboro Snus, Stonewall and Ariva. Each product was sampled in the natural environment on separate days. At the end of the sampling period, subjects chose which product they would use during the 2-week cigarette abstinence phase. ResultsGeneral Snus (high nicotine) was not preferred by any smoker. No significant differences in preferences were observed across the other tobacco products. During the smoking cessation phase, Camel Snus was generally associated with greater craving relief and satisfaction, reduced use of cigarettes, and greater abstinence during follow-up compared to other products. ConclusionThere were no differences in preferences for four of the five oral tobacco products but higher nicotine oral tobacco products were associated with better cessation outcomes among smokers who chose these products.

Effects of baclofen and mirtazapine on a laboratory model of marijuana withdrawal and relapse

Only a small percentage of individuals seeking treatment for their marijuana use achieves sustained abstinence, suggesting more treatment options are needed. We investigated the effects of baclofen (study 1) and mirtazapine (study 2) in a human laboratory model of marijuana intoxication, withdrawal, and relapse. In study 1, daily marijuana smokers (n = 10), averaging 9.4 (+/-3.9) marijuana cigarettes/day, were maintained on placebo and each baclofen dose (60, 90 mg/day) for 16 days. In study 2, daily marijuana smokers (n = 11), averaging 11.9 (+/-5.3) marijuana cigarettes/day, were maintained on placebo and mirtazapine (30 mg/day) for 14 days each. Medication administration began outpatient prior to each 8-day inpatient phase. On the first inpatient day of each medication condition, participants smoked active marijuana (study 1: 3.3% THC; study 2: 6.2% THC). For the next 3 days, they could self-administer placebo marijuana (abstinence phase), followed by 4 days in which they could self-administer active marijuana (relapse phase); participants paid for self-administered marijuana using study earnings. In study 1, during active marijuana smoking, baclofen dose-dependently decreased craving for tobacco and marijuana, but had little effect on mood during abstinence and did not decrease relapse. Baclofen also worsened cognitive performance regardless of marijuana condition. In study 2, mirtazapine improved sleep during abstinence, and robustly increased food intake, but had no effect on withdrawal symptoms and did not decrease marijuana relapse. Overall, this human laboratory study did not find evidence to suggest that either baclofen or mirtazapine showed promise for the potential treatment of marijuana dependence.

Increased Acid Sphingomyelinase Activity in Peripheral Blood Cells of Acutely Intoxicated Patients With Alcohol Dependence

Acid sphingomyelinase (ASM; EC 3.1.4.12) hydrolyses membrane sphingomyelin into the bioactive lipid ceramide and is thus involved in different cellular processes such as differentiation, immunity, or cell death. Activation of ASM has been reported in particular in conjunction with the cellular stress response to several external stimuli, and increased ASM activity was observed in a variety of human diseases. Ethanol-induced activation of ASM has been observed in different cell culture systems, thus raising the question about the effect of alcohol intoxication in human subjects on ASM activity in vivo. We determined ASM activity in peripheral blood mononucleated cells of 27 patients suffering from alcohol dependence. Patients were classified according to their blood alcohol concentration at admission, and ASM activity was determined repeatedly from all patients during alcohol withdrawal. Acutely intoxicated patients displayed significantly higher ASM activity than patients in early abstinence (Mann-Whitney U test: Z = - 2.6, p = 0.009). ASM activity declined in acutely intoxicated patients to normal values with the transition from the intoxicated state to early abstinence (Wilcoxon test: Z = -2.7, p = 0.007). At the end of withdrawal, ASM activity was significantly increased again compared to the early phase of abstinence in both patient groups (Wilcoxon test: Z = -2.691, p = 0.007 and Z = -2.275, p = 0.023, respectively). Alcohol-induced activation of ASM occurs in human subjects and might be responsible for deleterious effects of ethanol intoxication. Chronic alcohol abuse may induce deregulation of sphingomyelin metabolism in general, and this impairment may cause side effects during withdrawal from alcohol.

DRD2 -related TaqIA polymorphism modulates motivation to smoke

TaqIA polymorphism, a genetic variant associated with the expression level of dopamine D2 receptors in the brain, has been linked to various aspects of smoking behavior, including smoking prevalence, affective withdrawal symptoms, and smoking cessation outcome. However, its involvement in motivation to smoke cigarettes has not been elucidated. The present study examined the possible differences in self-reported reasons to smoke and craving for smoking in 160 smokers participating in a clinical trial. Individuals with at least one A1 allele of the TaqIA polymorphism were more likely to report smoking for stimulating effects and to reduce negative affect compared with those lacking an A1 allele. The association of the A1 genotype with a higher probability and stronger motive to smoker to enhance cognitive functioning was evident in female but not in male smokers. Female A1 carriers also expected a greater likelihood of smoking for pleasure than those without an A1 allele. A1 subjects reported stronger craving for cigarettes during early days and the last phase of a 6-week abstinence period. These results support the idea that dopaminergic transmission plays an important role in the neurobiological basis of reasons for smoking and that the TaqIA variant is one of the genetic factors underlying individual differences in these aspects. These findings also have implications for improving treatment strategies to help individuals quit smoking by controlling their motivation to continue cigarette consumption.