The delta opioid receptor antagonist, SoRI-9409, decreases yohimbine stress-induced reinstatement of ethanol-seeking

A major problem in treating alcohol use disorders (AUDs) is the high rate of relapse due to stress and re-exposure to cues or an environment previously associated with alcohol use. Stressors can induce relapse to alcohol-seeking in humans or reinstatement in rodents. Delta opioid peptide receptors (DOP-Rs) play a role in cue-induced reinstatement of ethanol-seeking; however, their role in stress-induced reinstatement of ethanol-seeking is not known. The objective of this study was to determine the role of DOP-Rs in yohimbine-stress-induced reinstatement of ethanol-seeking. Male, Long-Evans rats were trained to self-administer 10% ethanol in daily 30-minute operant self-administration sessions using a FR3 schedule of reinforcement, followed by extinction training. Once extinction criteria were met, we examined the effects of the DOP-R antagonist, SoRI-9409 (0–5 mg/kg, i.p.) on yohimbine (2 mg/kg, i.p.) stress-induced reinstatement. Additionally, DOP-R-stimulated [35S]GTPS binding was measured in brain membranes and plasma levels of corticosterone (CORT) were determined. Pre-treatment with SoRI-9409 decreased yohimbine stress-induced reinstatement of ethanol-seeking but did not affect yohimbine-induced increases in plasma CORT levels. Additionally, yohimbine increased DOP-R-stimulated 35[S]GTPS binding in brain membranes of ethanol-trained rats, an effect that was inhibited by SoRI-9409. This suggests that the DOP-R plays an important role in yohimbine-stress-induced reinstatement of ethanol-seeking behavior, and DOP-R antagonists may be promising candidates for further development as a treatment for AUDs.

Neuronal nicotinic acetylcholine receptors : neuroplastic changes underlying alcohol and nicotine addictions

Addictive drugs can activate systems involved in normal reward-related learning, creating long-lasting memories of the drug's reinforcing effects and the environmental cues surrounding the experience. These memories significantly contribute to the maintenance of compulsive drug use as well as cue-induced relapse which can occur even after long periods of abstinence. Synaptic plasticity is thought to be a prominent molecular mechanism underlying drug-induced learning and memories. Ethanol and nicotine are both widely abused drugs that share a common molecular target in the brain, the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are ligand-gated ion channels that are vastly distributed throughout the brain and play a key role in synaptic neurotransmission. In this review, we will delineate the role of nAChRs in the development of ethanol and nicotine addiction. We will characterize both ethanol and nicotine's effects on nAChR-mediated synaptic transmission and plasticity in several key brain areas that are important for addiction. Finally, we will discuss some of the behavioral outcomes of drug-induced synaptic plasticity in animal models. An understanding of the molecular and cellular changes that occur following administration of ethanol and nicotine will lead to better therapeutic strategies.

Varenicline decreases alcohol consumption in heavy-drinking smokers

Rationale Emerging evidence suggests that the α4β2 form of the nicotinic acetylcholine receptor (nAChR) modulates the rewarding effects of alcohol. The nAChR α4β2 subunit partial agonist varenicline (Chantix™), which is approved by the Food and Drug Administration for smoking cessation, also decreases ethanol consumption in rodents (Steensland et al., Proc Natl Acad Sci U S A 104:12518–12523, 2007) and in human laboratory and open-label studies (Fucito et al., Psychopharmacology (Berl) 215:655–663, 2011; McKee et al., Biol Psychiatry 66:185–190 2009). Objectives We present a randomized, double-blind, 16-week study in heavy-drinking smokers (n = 64 randomized to treatment) who were seeking treatment for their smoking. The study was designed to determine the effects of varenicline on alcohol craving and consumption. Outcome measures included number of alcoholic drinks per week, cigarettes per week, amount of alcohol craving per week, cumulative cigarettes and alcoholic drinks consumed during the treatment period, number of abstinent days, and weekly percentage of positive ethyl glucuronide and cotinine screens. Results Varenicline significantly decreases alcohol consumption (χ 2 = 35.32, p < 0.0001) in smokers. Although varenicline has previously been associated with suicidality and depression, side effects were low in this study and declined over time in the varenicline treatment group. Conclusions Varenicline can produce a sustained decrease in alcohol consumption in individuals who also smoke. Further studies are warranted to assess varenicline efficacy in treatment-seeking alcohol abusers who do not smoke and to ascertain the relationship between varenicline effects on smoking and drinking.

The α5 neuronal nicotinic acetylcholine receptor subunits plays an important role in the sedative effects of ethanol but does not modulate consumption in mice

Alcohol use disorders (AUDs) are a major public health problem, and the few treatment options available to those seeking treatment offer only modest success rates. There remains a need to identify novel targets for the treatment of AUDs. The neuronal nicotinic acetylcholine receptors (nAChRs) represent a potential therapeutic target in the brain, as recent human genetic studies have implicated gene variants in the α5 nAChR subunit as high risk factors for developing alcohol dependence. Here, we evaluate the role of 5* nAChR for ethanol-mediated behaviors using α5+/+ and α5-/- mice. We characterized the effect of hypnotic doses of ethanol and investigated drinking behavior using an adapted Drinking-in-the Dark (DID) paradigm that has been shown to induce high ethanol consumption in mice. We found the α5 subunit to be critical in mediating the sedative effects of ethanol. The α5-/- mice showed slower recovery from ethanol-induced sleep, as measured by loss of righting reflex. Additionally the α5-/- mice showed enhanced impairment to ethanol-induced ataxia. We found the initial sensitivity to ethanol and ethanol metabolism to be similar in both α5+/+ and α5-/- mice. Hence the enhanced sedation is likely due to a difference in the acute tolerance of ethanol in mice deficient of the α5 subunit. However the α5 subunit did not play a role in ethanol consumption for ethanol concentrations ranging from 5% to 30% in the DID paradigm. Additionally, varenicline (Chantix®) was effective in reducing ethanol intake in α5-/- mice. Together, our data suggest that the α5 nAChR subunit is important for the sedative hypnotic doses of ethanol but does not play a role in ethanol consumption. Varenicline can be a treatment option even when there is loss of function of the α5 nAChR subunit.

The dual orexin/hypocretin receptor antagonist, almorexant, in the ventral tegmental area attenuates ethanol self-administration

Recent studies have implicated the hypocretin/orexinergic system in reward-seeking behavior. Almorexant, a dual orexin/hypocretin R1 and R2 receptor antagonist, has proven effective in preclinical studies in promoting sleep in animal models and was in Phase III clinical trials for sleep disorders. The present study combines behavioral assays with in vitro biochemical and electrophysiological techniques to elucidate the role of almorexant in ethanol and sucrose intake. Using an operant self-administration paradigm, we demonstrate that systemic administration of almorexant decreased operant selfadministration of both 20% ethanol and 5% sucrose. We further demonstrate that intraventral tegmental area (VTA) infusions, but not intra substantia nigra infusions, of almorexant reduced ethanol self-administration. Extracellular recordings performed in VTA neurons revealed that orexin-A increased firing and this enhancement of firing was blocked by almorexant. The results demonstrate that orexin/hypocretin receptors in distinct brain regions regulate ethanol and sucrose mediated behaviors.

Smoking cessation

21. Smoking cessation 21.1 Epidemiology of cigarette smoking 21.2 Nicotine, addiction and pharmacokinetics 21.3 Nicotine replacement therapy 21.4 Varenicline 21.5 Bupropion

'It had to be my choice' Indigenous smoking cessation and negotiations of risk, resistance and resilience

While Australia is considered a world leader in tobacco control, smoking rates within the Aboriginal and Torres Strait Islander population have not declined at the same rate. This failure highlights an obvious shortcoming of mainstream anti-smoking efforts to effectively understand and engage with the socio-cultural context of Indigenous smoking and smoking cessation experiences. The purpose of this article is to explore the narrative accounts of 20 Indigenous ex-smokers within an urban community and determine the motivators and enablers for successful smoking cessation. Our findings indicated that health risk narratives and the associated social stigma produced through anti-smoking campaigns formed part of a broader apparatus of oppression among Indigenous people, often inspiring resistance and resentment rather than compliance. Instead, a significant life event and supportive relationships were the most useful predictors of successful smoking cessation acting as both a motivator and enabler to behavioural change. Indigenous smoking cessation narratives most commonly involved changing and reordering a person’s life and identity and autonomy over this process was the critical building block to reclaiming control over nicotine addiction. Most promisingly, at an individual level, we found the important role that individual health professionals played in encouraging and supporting Indigenous smoking cessation through positive rather than punitive interactions. More broadly, our findings highlighted the central importance of resilience, empowerment, and trust within health promotion practice.

Family-based programmes for preventing smoking by children and adolescents

BACKGROUND: There is evidence that children's decisions to smoke are influenced by family and friends. OBJECTIVES: To assess the effectiveness of interventions to help family members to strengthen non-smoking attitudes and promote non-smoking by children and other family members. SEARCH STRATEGY: We searched 14 electronic bibliographic databases, including the Cochrane Tobacco Addiction Group specialized register, MEDLINE, EMBASE, PsycINFO and CINAHL. We also searched unpublished material, and the reference lists of key articles. We performed both free-text Internet searches and targeted searches of appropriate websites, and we hand-searched key journals not available electronically. We also consulted authors and experts in the field. The most recent search was performed in July 2006. SELECTION CRITERIA: Randomized controlled trials (RCTs) of interventions with children (aged 5-12) or adolescents (aged 13-18) and family members to deter the use of tobacco. The primary outcome was the effect of the intervention on the smoking status of children who reported no use of tobacco at baseline. Included trials had to report outcomes measured at least six months from the start of the intervention. DATA COLLECTION AND ANALYSIS: We reviewed all potentially relevant citations and retrieved the full text to determine whether the study was an RCT and matched our inclusion criteria. Two authors independently extracted study data and assessed them for methodological quality. The studies were too limited in number and quality to undertake a formal meta-analysis, and we present a narrative synthesis. MAIN RESULTS: We identified 19 RCTs of family interventions to prevent smoking. We identified five RCTs in Category 1 (minimal risk of bias on all counts); nine in Category 2 (a risk of bias in one or more areas); and five in Category 3 (risks of bias in design and execution such that reliable conclusions cannot be drawn from the study).Considering the fourteen Category 1 and 2 studies together: (1) four of the nine that tested a family intervention against a control group had significant positive effects, but one showed significant negative effects; (2) one of the five RCTs that tested a family intervention against a school intervention had significant positive effects; (3) none of the six that compared the incremental effects of a family plus a school programme to a school programme alone had significant positive effects; (4) the one RCT that tested a family tobacco intervention against a family non-tobacco safety intervention showed no effects; and (5) the one trial that used general risk reduction interventions found the group which received the parent and teen interventions had less smoking than the one that received only the teen intervention (there was no tobacco intervention but tobacco outcomes were measured). For the included trials the amount of implementer training and the fidelity of implementation are related to positive outcomes, but the number of sessions is not. AUTHORS' CONCLUSIONS: Some well-executed RCTs show family interventions may prevent adolescent smoking, but RCTs which were less well executed had mostly neutral or negative results. There is thus a need for well-designed and executed RCTs in this area.

Diagnostic Dilemmas in Comorbidity

This high prevalence of comorbid mental health and substance use disorders makes the accurate diagnosis of comorbid disorders an important clinical priority. However, the presence of comorbid disorders creates a number of diagnostic dilemmas, which have hindered our understanding of the comorbid disorders. This chapter discusses these diagnostic dilemmas, including issues with the reliability, validity and clinical utility of current systems of psychiatric nomenclature’s approach to diagnosing comorbid disorders. A number of alternative models for understanding comorbid disorders are briefly discussed, followed by suggestions for how research can improve our understanding of comorbid disorders.

Drug abusers perceptions of their parents.

Many clinicians in the area of drug addiction believe that emotional problems arise from particular styles of parenting. To investigate this link, 63 young male and female addicts who had sought treatment completed the Parental Bonding Instrument which tapped their perceptions of their relationship with each parent. Addicts reported early parental experiences differing from those of a control group. Drug abusers judged their parents as cold, indifferent, controlling and intrusive. In addition, these perceptions were shared by male and female addicts. These results, together with previous research suggest that these perceptions might well point to a general risk factor for the development of a broad range of psychological and psychiatric disorders. In addition, the issue of family factors in the design and implementation of drug treatment programs needs to be addressed.

Tragedy and assimilation : reciprocity between surface and subject

Here we unveil a tragic triptych of three Australian women painfully painted onto the walls of interior surfaces. The woman at the centre of the triptych is Florence Broadhurst whose tragic death still remains a mystery. To the right is Australian skin illustrator Emma Hack who recreates Broadhurst’s wallpapers, mimicking their colourful patterns onto live models. Hack perfectly assimilates the models’ body into the wallpaper, camouflaging bodies except for small hints at something more in the foreground. In the process of Hack’s images, the models become statues, standing painfully still holding their breath for minutes at a time. The third woman, to the left of the triptych, is the fictional character Candy from the 2006 Australian film Candy. Candy’s traumatic struggle with addiction ends with her conveying her pain in a poem she writes on the walls of her home; culminating her tragic story into a disturbed domestic wall surface. This research tries to understand this relationship with the surface through tragedy as a reciprocal agreement between surface and subject and not a permanent transference between one state and another. What the surface provides in times of personal struggle and turmoil is a method for us to come to terms with out material existence.

Ethanol exposure alters monoamine oxidase gene-expression in neuronal SH-SY5Y cells

Abstract: Monoamine Oxidase (MAO) enzymes catabolise, and thus modulate abundance of, neurotransmitters in the brain. Variation in MAO enzyme activity has been linked to alcohol abuse behaviour, although the molecular mechanisms underlying this association are not understood. The present study evaluated relative gene-transcript abundance of MAO-A and MAO-B in the SH-SY5Y human neuroblastoma cell-line in response to ethanol exposure and following ethanol withdrawal. We found that each isoform of MAO was significantly transcriptionally up-regulated 55-80% in response to 100mM ethanol exposure. This trend was maintained following prolonged exposures (24 h-72 h) and with short exposures (24 h) followed by a period of ethanol withdrawal, suggesting that the transcriptional regulation is the result of a cellular change occurring within the first 24 hours of ethanol exposure. These results suggest a role for MAO transcriptional regulation in the complex neurobiochemical changes underlying alcohol addiction.

A qualitative investigation of drug use among Pakistani road users

Background Statistics on drug use by Pakistani drivers are not available, yet considerable numbers of drivers are believed to be drug addicted. The National Drug Abuse Assessment 2006/07, conducted by the United Nation Office on Drugs and Crime and the Ministry of Narcotics Control Pakistan reported that opiate users numbered 628,000, of which 77%were chronic heroin abusers. Injecting drug users have reportedly doubled in the decade to 2006 and drug use has been linked with many major crashes involving professional drivers. Aims This study explored a broad range of risk taking behaviours of road users, including drug use. It also investigated associations between risky road use and fatalism and other cultural beliefs. Methods This paper reports findings relating to drug driving in the cities of Lahore, Rawalpindi and Islamabad. Thirty semi-structured interviews were conducted with bus, truck, and taxi drivers, policy makers and field police officers. Results Interviews suggested widespread use of illicit drugs, particularly among bus, truck and taxi drivers. Reasons for drug use included recreational purposes, stimulants during long driving episodes, and substance addiction. Furthermore, the use of drugs and any association with road crashes was generally viewed as linked to fatalism rather than to any fault of an individual. In other words, people did not believe there was an association between drug use and road crashes, even if they had personally experienced such. Police knowledge of drug use among drivers was evident, although there is no formal drug driving testing regime in Pakistan. Discussion and conclusions The substantial increase in drug use among the population in recent years highlights a significant public health challenge in Pakistan. This qualitative research, although recognized as not representative of the broader population, suggests that there is significant cause for concern about drug driving, especially among professional drivers, and a need for further investigation and intervention.