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The brain oxytocin system is involved in a wide range of addictive behaviors, inhibiting prime- and cue-induced relapse in preclinical models of substance use disorders. Animal studies linked oxytocin’s effects on drug ingestion to modulation of neurotransmission in the nucleus accumbens (NAc). We set out to investigate whether oxytocin can modulate alcohol cue-induced functional connectivity between the brain reward system and cortical regions.
Fifteen male heavy social drinkers were enrolled in a randomized double-blind placebo-controlled cross-over functional magnetic resonance imaging study (fMRI) investigating the effect of 24 IU oxytocin on alcohol cue-modulated functional connectivity.
Results of the functional connectivity analyses show that oxytocin application significantly reduced connectivity between the NAc and cuneus and thalamo-occipital connectivity, while enhancing connectivity between the paracingulate gyrus and precentral gyrus (tow-sided seed-level false discovery rate pFDR < 0.05). These effects were specific to the alcohol presentation and were absent during processing of neutral pictures. In addition, the NAc-cuneus connectivity significantly correlated with subjective alcohol cue-induced craving during the scanning session (r = 0.538, p = 0.024). Conclusion: Results provide initial evidence for condition-specific and significant attenuation of NAc connectivity by oxytocin in a sample of heavy social drinkers that was related to lower subjective alcohol craving during the fMRI task. Oxytocin-induced attenuation of NAc connectivity was specific to processing alcohol stimuli and might reflect an attenuation of alcohol-cue saliency by oxytocin that could lead to a reduction of the sensitivity towards the appetitive aspects of alcohol cues.
Although the majority of studies associated the function of orexin neurons with arousal and sleep and leptin with balancing energy expenditure and food craving these neuropeptides were also shown to directly affect dopaminergic transmission in mesolimbic reward pathways. This indicates a possible role for orexin and leptin in reward function and motivation and thus in addictive diseases. Aim of our study was to test whether both peptides are involved in nicotine craving in a standardized setting. We studied orexin and leptin plasma concentrations (RIA) in tobacco smokers (n = 60) compared to healthy controls (n = 64). In smoking subjects we assessed craving for nicotine applying the Questionnaire of Smoking Urges (QSU) after three hours of withdrawal from nicotine. As main results we found a significant negative correlation between orexin plasma concentration and nicotine craving (r = -0.28; p < .05) and a positive association between nicotine craving and leptin (r = 0.29; p < .05). Our results show a bidirectional association between craving for nicotine and plasma concentrations of orexin and leptin suggesting that both neuropeptides may be regulators for the dopaminergic transmission in nicotine withdrawal and, thus, modulators for craving for nicotine.
Genetic and environmental influences are both known to be causal factors in the development and maintenance of obesity. Stress related chronic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis and resulting increased glucocorticoid exposure is known to be an important pathophysiological mechanism in the development of obesity. We show that the natriuretic peptide system, that mediates endocrine and behavioural responses to stress, plays a role in the control of long-term body weight in chronically ethanol drinking mice. In mice lacking functional NPR-A receptors, physical, and in particular psychological stress leads to enhanced and continuous increase in body weight in homozygote NPR-A mice. The effect of repeated stress on body weight appeared rapidly and persisted throughout life. Over a longer period of time without stress, body weights do not differ between the different genotypes. Moreover, we could demonstrate that NPR-A homozygote mice show significant higher corticosterone levels following stress. Heterozygote animals show an intermediate phenotype concerning body weights and corticosterone levels following stress. Alterations in the NPR-A receptor gene may constitute a genetic risk factor for stress-induced eating and obesity.
The selective alpha4-beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline has been shown to be effective in the treatment of tobacco dependence by counteracting withdrawal symptoms and reducing smoking reward. However, the need to test safety, especially in smokers with varying co-morbidities and risk patterns is highlighted. There are some publications reporting exacerbation of psychiatric symptoms in subjects with pre-existing psychiatric disorders associated with varenicline treatment.
This case-report describes a patient whose several smoking cessation attempts led to enduring nicotine-related symptoms such as depression and suicidal tendencies. All further cessation attempts under medical control with nicotine patches, bupropion and psychotherapy failed. At lest reducing her daily dose by one cigarette already led to suicidal thoughts. We took her into inpatient treatment and started an uptitration with varenicline. Unlike earlier attempts there were no complications during the detoxication and depressive symptoms improved clearly.
Affective symptoms like depression are known to develop during nicotine cessation. The improving of affective symptoms in this case might be a result of the partial agonistic effects of varenicline.
Alcohol intake is known to modulate plasma concentrations of neuroendocrine peptides. However, recent results suggest that the endocrine system may not only respond passively to alcohol intake, but that -vice versa- it also actively modulates alcohol intake behaviour. The most coherent body of data concerns the hypothalamo-pituitary-adrenocortical (HPA) axis, with low corticotropin releasing hormone (CRH) being associated with more intense craving and increased probability of relapse after acute detoxification. It is important to bear in mind that dysregulation of the HPA system, as observed in alcohol dependence, is also a feature of anxiety and depression, two conditions which are frequently linked with alcohol dependence and have been reported to be associated with a poor prognosis. In depression, increased secretion of CRH seems to be one crucial mechanism. It has been found as a marker of depressive symptoms, which normalises when depression is successfully treated. Hypersecretion of CRH is associated with a general hyperactivity of the HPA system, notably elevated plasma levels of ACTH and cortisol, a blunted cortisol stress response and a blunted dexamethasone suppression test. In any case, HPA dysregulation, alcohol dependence, and depression are closely interrelated. Exactly which component of this triad is the driving force behind the various neuroendocrine correlates of drinking behaviour is currently unclear, and will need to be elucidated by future research. This will allow for an enlightened choice of potentially therapeutic agents for the treatment of co-morbid anxiety, depression, and alcohol dependence, acting primarily on the HPA system.
Dysregulation in the neuroendocrine stress system has been attributed repeatedly to the stressful and anxiogenic state observed during alcohol withdrawal. Activity of the atrial natriuretic peptide (ANP) has been shown to inhibit the release of corticotrophin releasing hormone (CRH) and corticotrophin (ACTH) and opioid neurotransmission also plays a role in counteracting effects of sustained stress by facilitating the termination of the hypothalamo-pituitary-adrenocortical (HPA) axis stress response. Thus ANP and ß-endorphin may be involved in modulating the HPA axis activity in alcohol withdrawal. Aim of the study was to evaluate the anxiolytic activity of ANP and ß-endorphin during alcohol withdrawal in mice habitated to chronic alcohol intake.
24 male mice (C57/Bl6J) were studied following 21 days of free-choice and forced alcohol intake. Anxiety related behavior (elevated plus maze, open field) was tested during acute ethanol withdrawal (12 hours after last ethanol consumption). 30 minutes before testing, randomized groups of mice were given i.p. injections of ANP (60 μg/kg), ß-endorphin (2 μg/kg) or saline.
Acute alcohol withdrawal in alcohol habituated mice was associated with increased anxiety related behavior. Application of both, ß-endorphin and ANP, was significantly associated with reduced anxiety related behavior.
Taking into consideration data from studies in humans, where decreased levels of ß-endorphin and ANP were associated with anxiety during acute and protracted alcohol withdrawal, our results suggest a causal relationship between ANP, ß-endorphin and withdrawal-induced anxiety in alcohol related disorders.
Recent results suggest that the endocrine system can affect as well as modulate ethanol drinking behavior. In mice and humans a correlation has been found between ANP plasma concentration and craving, anxiety as well as the severity of the withdrawal symptoms. To further elucidate the involvement of the natriuretic peptide system in neurobehavioral effects of alcohol, we examined ethanol drinking behavior in mice lacking a functional natriuretic peptide-A (NPR-A) receptor.
NPR-A heterozygote, -knockout and wild-type mice were given a free choice between water and increasing concentrations of ethanol. Once a stable baseline of 16% ethanol consumption was established, access to ethanol was withdrawn for 2 weeks and then reinstated to measure the alcohol deprivation effect (ADE). A forced swim stress was performed thereafter on 3 consecutive days.
Data analysis revealed a higher ethanol preference and voluntary ethanol intake in NPR-A-transgenic mice. Throughout the experiments the ethanol intake was highest in heterozygote animals. Stress-induced drinking led to an immediate increase in ethanol consumption in the homozygote subgroup. Deprivation from alcohol resulted in a classical ADE in wild-type and heterozygote animals. The homozygote mice do not show an increase in alcohol intake during the ADE.
We demonstrated that the NPR-A receptor gene is involved in free choice ethanol consumption, preference and ethanol consumption following stress. Mice lacking a functional NPR-A receptor represent a useful animal model to adress the question of whether a dysfunctonal natriuretic peptide receptor system influences longterm alcohol self-administration and stress induced alcohol drinking.
Long-lasting memories that associate environmental stimuli with the effects of alcohol are known to be a main cause of relapse and are a major challenge in the treatment of alcohol addiction. It is reasonable to hypothesize that disrupting consolidated alcohol-related memories might help to prevent relapses. The reconsolidation theory states that a consolidated memory could again become labile and susceptible to disruption by protein synthesis inhibition or NMDA-antagonism after memory retrieval. This has been shown for cocaine- and morphine-associated memories in several recent studies. The aim of our investigations was to examine in an animal model for cue-induced relapse to alcohol-seeking behavior whether the behavioral impact of previously conditioned alcohol associated cues is significantly reduced by blocking the reconsolidation of learned alcohol associations. We show that reconsolidation of alcohol memories is disrupted by post-retrieval ICV-administration of the protein synthesis inhibitor anisomycin. Similarly, post-retrieval i.p.-administration of the NMDA antagonist MK-801 reduced alcohol seeking behavior during the following test day as compared to vehicle treated rats. Pharmacological disruption of reconsolidation of alcohol-associated memories may thus provide a potential therapeutic strategy for the prevention of relapse in alcohol addiction.
A synopsis of current treatment options shows only moderate effect sizes. They could be improved considerably if individual predictors were available.
Previous attempts to identify predictors for the treatment response in alcoholism have mainly concentrated on social and personality variables. Project MATCH was such an attempt which finally failed. The same holds true for similar attempts in pharmacotherapy. Therefore, we set out for a large oligocentre trial “Project PREDICT”. 432 patients are randomly assigned to treatment with acamprosate, naltrexone or placebo. At baseline patients are assessed with a battery of interviews, questionnaires and biological examinations (e.g. genetics). Specific emphasis is put on patients’ individual pathways into relapse. It is determined whether relapse drinking respresented a positive reinforcer (“reward craving”) or a negative reinforcer (“relief craving”). This is assessed with questionnaires, the startle reflex and fMRI. We hypothesize, that patients who are a priori identified as “positive reinforcers” better respond to naltrexone. Negative reinforcers should benefit most from acamprosate.
All patients have been included by now. Preliminary analyses suggest that it is possible to distinguish between the two craving types. The equivalent of positive reinforcement in the startle reflex correlates with fMRI responses to cues with a positive valence of about 0.7. These methods might offer a platform for a targeted pharmacotherapy in alcoholism.
Mechanisms contributing to the development and maintenance of obesity remain to be elucidated especially regarding the interaction between appetite regulating hormones and mesolimbic reward circuits. Leptin was recently suggested to attenuate dopamine release in mesolimbic reward pathways. We now test the functional relevance assessing whether leptin plasma concentration affects the BOLD-response following the presentation of food cues.
21 obese and 23 normal weight subjects were investigated. Visual food cues and neutral stimuli were presented in a block design during fMRI. Blood-samples were collected immediately prior to the scan to assess plasma leptin concentration. Using linear regression analyses, the association between BOLD response to food cues and the body mass index (BMI) as well as plasma leptin concentration was examined.
Food-cues elicited activation of large cortical and subcortical networks, whereas only in obese patients food cues activated the left ventral and right dorsal striatum. Mean plasma concentration of leptin was significantly increased in obese subjects compared to normal weight controls. We found a significant positive correlation between the food cue-induced BOLD signal change in the ventral striatum and leptin plasma concentration. Furthermore, ventral and dorsal striatum BOLD response to food cues was significantly positive associated with the body mass index (BMI).
These findings suggest a physiological role of the satiety factor leptin in modulating responsivity of reward pathways towards food cues. Altered homeostatic feedback regulation of the mesolimbic brain reward circuit might explain the inability of obese patients to adapt their food intake according to physiologically needs.
The orexins (hypocretins) are neuropeptides recently identified as neurotransmitters in lateral hypothalamus neurons. Although the majority of studies associated the function of orexin neurons with arousal and sleep, these neurons also project to reward-associated brain regions, including the nucleus accumbens and ventral tegmental area. This indicates a possible role for orexins in reward function and motivation and thus in addictive diseases. Additionally, there is growing evidence from preclinical studies for an involvement of orexins in the regulation of stress, affectivity and drug seeking behavior.
We investigated orexin plasma concentrations and psychological symptoms in a sample of 34 alcohol dependent subjects on day 1 and day 14 of detoxification. For this purpose we used the Brief Symptom Inventory (BSI) as well as the Obsessive-Compulsive Drinking Scale to identify self-reported clinically relevant psychological symptoms including alcohol craving.
As a main result a significant positive correlation between orexin plasma concentration and depression as well as global distress indicies of the BSI was detected during early withdrawal (day 1), which is not shown after detoxification on day 14. No association with subjective craving for alcohol was found.
Our data indicate that orexins may be directly involved in affective dysregulation in alcohol dependent patients; moreover the effects of orexins on reinstatement of drug seeking behaviors might be mediated by impaired brain stress systems.
Addictive behaviour associated with alcoholism is a brain disease characterized by craving for alcohol, loss of control over consumption, development of tolerance and dependence, while simultaneously the repertoire of social functioning not related to intake behaviour declines dramatically. To understand the factors that compel some individuals to drink excessively and to identify targets for pharmacological intervention, addiction research has focused on the identification of brain mechanisms that support reinforcing actions of alcohol and the progression of changes in neural function induced by chronic drug or ethanol intake. Cellular and molecular mechanisms of tolerance, sensitization, and dependence have been investigated intensively. The ability of most drugs to enhance dopamine neurotransmission particularly within the mesocorticolimbic dopamine (“reward”) system was demonstrated repeatedly. However, the past decade has placed the dopamine system within a broader context of neuronal circuitry involved in drug seeking, drug taking, and recovery. Specific effects on other receptors symptoms provide particular challenges given the almost ubiquitous expression of these receptors throughout the CNS. Additionally, new emphasis on various neuropeptide systems has reemerged, including opioid peptides and the stress-related peptides of the hypothalamus-pituitary-adrenal axis. Continued research is warranted on the various neurobiological based components that underlie the transition from drug intake to addiction to define drug targets for innovative pharmacological treatment options.
Multiple neurochemical pathways have been identified to be involved in mediating craving and relapse to alcohol and, further, animal models greatly assist in investigating pharmacological interventions of relapse behaviour. Opioidergic and glutamatergic systems play a key role in alcoholism as demonstrated by the clinically effective compounds naltrexone and acamprosate acting through these systems. Although the dopaminergic system has been in the focus of alcohol research for many years, clinical trials interfering with several components of this system displayed rather disappointing results. This situation, however, could change in light of the discovery that dopamine D3 receptor antagonism produces very consistent and robust results in preclinical studies. Corticotropin-releasing factor signalling and the endocannabinoid system integrate stress-related events and thereby mediate relapse behaviour. Thus, many new targets have been identified and several new compounds are currently undergoing clinical testing. However, given the heterogeneity in treatment response, genetic and protein markers as well as endophenotypes are currently characterised for individualised pharmacotherapy.
Multiple neurochemical pathways have been identified to be involved in mediating craving and relapse to alcohol. Additionally, animal models greatly assist in investigating pharmacological interventions of relapse behaviour. Opioidergic and glutamatergic systems play a key role in alcoholism as demonstrated by clinically effective compounds. Moreover, many new targets have been identified and several new compounds are currently undergoing clinical testing. Given the heterogeneity in treatment response, genetic and protein markers as well as endophenotypes are currently characterised for individualised pharmacotherapy.
In humans alcohol seeking behavior is frequently evoked by the retrieval of memories associated with an alcohol experience. Consolidated memories can become labile if reactivated by reexposure. The aim of our study was to examine whether the behavioral impact of previously conditioned alcohol associated cues is significantly reduced by blocking the reconsolidation of the previously learned alcohol associations that are retrieved by reexposition. For this purpose we applied an animal model for cue-induced relapse to alcohol-seeking behavior. We show that post-retrieval i.p.-administration of 0.1 mg/kg of the NMDA antagonist MK-801 (n=8-10 per group) significantly reduced alcohol seeking behavior during the following test day as compared to vehicle treated animals. Similarly, memory reconsolidation was disrupted by ICV administration of 400 μg of the protein synthesis inhibitor anisomycin (n=9-11 per group). Pharmacological disruption of reconsolidation of alcohol-associated memories may thus provide a potential therapeutic strategy for the prevention of relapse in alcohol addiction.
Ghrelin plays an orexigenic role in regulating appetite and energy balance. Preclinical studies also provided support for an important role of ghrelin in the neurobiology of addiction-related reward pathways. In contrast, clinical data have failed to support an association between ghrelin and alcohol craving, possibly due to analysing the pharmacologically inactive, preprohormone ghrelin instead of ghrelin in its active, acetylated form.
Materials and methods
In a sample of 61 alcohol-dependent male inpatients we assessed plasma concentrations of both active and total ghrelin, using blood samples taken at the onset of withdrawal and then again after 14 days of controlled abstinence. During this time, we also assessed the patients' alcohol cravings (applying the obsessive compulsive drinking scale, OCDS), symptoms of depression (Beck Depression Inventory; BDI) and anxiety (State Trait Anxiety Inventory; STAI). The severity of alcohol dependence was assessed using the alcohol dependence scale (ADS).
We found a significant positive correlation between the plasma concentration of active ghrelin and alcohol craving in both blood samples. In a linear regression model, the plasma concentration of active ghrelin on day one, the scores of the ADS, and the BDI explained 36% of the variance in OCDS sum score (p < 0.0001). By day 14, these same factors accounted for 54% (p < 0.0001). We did not detect any association between the plasma concentration of total ghrelin and patients' alcohol cravings.
Our results suggest that biologically active, acetylated ghrelin is involved in reward-associated craving during alcohol withdrawal and early abstinence in alcohol-dependent patients.
In the phase 3 programme on nalmefene for reduction of alcohol consumption in alcohol dependent patients, an as-needed dosing regimen was used. Patients were instructed to take one tablet on each day they perceived a risk of drinking alcohol, preferably 1 to 2 hours prior to the anticipated time of drinking. Tablets could be taken up to once daily. As-needed use is a patient-centered approach engaging patients in active and responsible management of their illness. It should be seen as an integral part of disease management, increasing awareness of drinking amount and patterns, facilitating identification of at-risk situations.
Explore the feasibility of as-needed use of nalmefene in alcohol dependence.
The Timeline Follow-back was used to obtain estimates of daily drinking and to record daily medication intake. Pooled data (treated patients: nalmefene=643; placebo=633) from the two randomised controlled 6 month studies (ESENSE 1 [NCT00811720] and ESENSE 2 [NCT00812461]) was used. Adherence was defined as medication intake and alcohol consumption, or no alcohol consumption (with or without medication intake).
Nalmefene was taken on approximately half of the study days; placebo was taken more often than nalmefene. In each treatment group, medication intake varied according to patients’ needs as intake correlated with baseline drinking pattern. 68% of the nalmefene treated patients (78% of the study completers) adhered to the as-needed treatment regimen on at least 80% of the study days.
These results demonstrate that patients understand, accept, and adhered to the as-needed treatment regimen.
Pathological gambling and comorbide alcohol dependence are common occuring diseases. Disulfiram is one of the proven drugs for alcohol dependence. It was shown recently, that Disulfiram is also effective in relapse prevention of cocaine addiction. In addition to its inhibiting effect of the acetaldehyde dehydrogenase (ADH), disulfiram inhibits the dopamine β-hydroxylase (DBH) and thereby augments dopamine and depletes norepinephrine concentrations in the CNS. Inhibition of the DBH is suggested to be the responsible mechanism of Disulfiram acting in cocaine addiction. Previous research indicates common neurochemical substrates for pathological gambling and cocaine addiction. This suggests that dopamine substrates may directly govern the reinforcement process in pathological gambling.
In this report we now present the clinical data of a patient who was treated with disulfiram in our outpatient unit for addiction treatment due to existing alcohol dependence. The patient suffered also from severe pathological gambling.
Initialy we started to treat the patient with supervised disulfiram because of his alcohol dependence. During the treatment with disulfiram the patient’ desire for gambling disappeared entirely and he has not gambled anymore since then.
However, the exact mechnism of action by which disulfiram reduces urge to gamble is not fully unterstood, yet. Because craving is a key contributor to relapse, strategies aimed at modulate dopamine increases are likely to be therapeutically beneficial in gambling. Although uncontrolled case observations can only be interpreted with caution disulfiram seems to deserve further investigation and may hold the potential for preventing relapse in gamblers suffering from additional alcohol dependence.
Among abstinent alcohol-dependent patients, sleep disorders are a wide-spread and persistent problem and have been associated with the risk of alcohol relapse. The melatonin-agonist agomelatine has been shown to improve overall sleep quality without daytime sedation.
To examine the effect of agomelatine on sleep quality in abstinent alcohol-dependet patients suffering from chronic sleep disorders.
9 alcohol-dependet patients suffering from chronic sleep disorders received nightly doses between 25 and 50 mg of agomelatine. Sleep quality was assesed using the Pittsburgh Sleep Quality Index prior and following 6 weeks of treatment with agomelatine. Prior and during treatment with agomelatine all patients were monitored for serum levels of liver enzymes.
After 6 weeks of agomelatine treatment, the Pittsburgh Sleep Quality Index global score for all patients had decreased significantly.
The present data suggest that agomelatine may improve the sleep quality of alcohol-dependent patients suffering from chronic sleep disorders.