Role of acetaldehyde in alcohol addiction : current evidence and future perspectives

The effects of alcohol have been widely studied during the past century, corroborating the idea that this tiny chemical compound acts throughout most of our neurotransmitter systems since it is capable of inducing addictive behaviour. Two of the most serious problems of alcohol addiction are craving and relapse; several studies have demonstrated that relapse is related to the anxious state which occurs during withdrawal, and it has been proved that this behavioural modifications results from an alteration of the dopaminergic and serotonergic systems. An important role in the neurobiology of alcohol addiction is played by acetaldehyde (ACD), ethanol first metabolite. Our recent studies indeed, have demonstrated that ACD itself is able to induce CRH release from hypothalamic explants, underlying the central role played by ACD in alcohol-induced modifications of the HPA axis. Moreover, for the first time, this group has shown that ACD is able to induce and maintain an operant drinking behaviour after repeated abstinence periods, and in the presence of a conflict situation in rats, mimicking the same characteristics as alcohol. ACD is produced either peripherally or within the brain by alcohol dehydrogenase and catalase, respectively. Studies assert that the highest concentrations of catalase in the brain are mainly located in aminergic neurons suggesting that ACD could take part in alcohol action in those circuitries. Further investigations are then necessary to fully understand the molecular mechanisms underlying the neurochemical and behavioural modifications induced by ACD, as a mediator of alcohol activity in the brain.peer-reviewe

Targeting the Stress System During Gestation: Is Early Handling a Protective Strategy for the Offspring?

The perinatal window is a critical developmental time when abnormal gestational stimuli may alter the development of the stress system that, in turn, influences behavioral and physiological responses in the newborns. Individual differences in stress reactivity are also determined by variations in maternal care, resulting from environmental manipulations. Despite glucocorticoids are the primary programming factor for the offspring’s stress response, therapeutic corticosteroids are commonly used during late gestation to prevent preterm negative outcomes, exposing the offspring to potentially aberrant stress reactivity later in life. Thus, in this study, we investigated the consequences of one daily s.c. injection of corticosterone (25 mg/kg), from gestational day (GD) 14–16, and its interaction with offspring early handling, consisting in a brief 15-min maternal separation until weaning, on: (i) maternal behavior; and (ii) behavioral reactivity, emotional state and depressive-like behavior in the adolescent offspring. Corticosterone plasma levels, under non-shock- and shock-induced conditions, were also assessed. Our results show that gestational exposure to corticosterone was associated with diminished maternal care, impaired behavioral reactivity, increased emotional state and depressive-like behavior in the offspring, associated with an aberrant corticosterone response. The early handling procedure, which resulted in increased maternal care, was able to counteract the detrimental effects induced by gestational corticosterone exposure both in the behavioral- and neurochemical parameters examined. These findings highlight the potentially detrimental consequences of targeting the stress system during pregnancy as a vulnerability factor for the occurrence of emotional and affective distress in the adolescent offspring. Maternal extra-care proves to be a protective strategy that confers resiliency and restores homeostasis

Work-Related Stress, Physio-Pathological Mechanisms, and the Influence of Environmental Genetic Factors

Work-related stress is a growing health problem in modern society. The stress response is characterized by numerous neurochemicals, neuroendocrine and immune modifications that involve various neurological systems and circuits, and regulation of the gene expression of the different receptors. In this regard, a lot of research has focused the attention on the role played by the environment in influencing gene expression, which in turn can control the stress response. In particular, genetic factors can moderate the sensitivities of specific types of neural cells or circuits mediating the imprinting of the environment on different biological systems. In this current review, we wish to analyze systematic reviews and recent experimental research on the physio-pathological mechanisms that underline stress-related responses. In particular, we analyze the relationship between genetic and epigenetic factors in the stress response

Acetaldehyde, motivation and stress: Behavioral evidence of an addictive ménage à trois

Acetaldehyde (ACD) contributes to alcohol’s psychoactive effects through its own rewarding properties. Recent studies shed light on the behavioral correlates of ACD administration and the possible interactions with key neurotransmitters for motivation, reward and stress-related response, such as dopamine and endocannabinoids. This mini review article critically examines ACD psychoactive properties, focusing on behavioral investigations able to unveil ACD motivational effects and their pharmacological modulation in vivo. Similarly to alcohol, rats spontaneously drink ACD, whose presence is detected in the brain following chronic self-administration paradigm. ACD motivational properties are demonstrated by operant paradigms tailored to model several drug-related behaviors, such as induction and maintenance of operant self-administration, extinction, relapse and punishment resistance. ACD-related addictive-like behaviors are sensitive to pharmacological manipulations of dopamine and endocannabinoid signaling. Interestingly, the ACD-dopamine-endocannabinoids relationship also contributes to neuroplastic alterations of the NPYergic system, a stress-related peptide critically involved in alcohol abuse. The understanding of the ménage-a-trois among ACD, reward- and stress-related circuits holds promising potential for the development of novel pharmacological approaches aimed at reducing alcohol abuse

Drinking pattern matters: effects on maternal care and offspring vulnerability to alcohol in rats

Alcohol drinking during pregnancy and post-partum period is a major concern because of the persistent neurobehavioral deficits in the offspring, which include increased vulnerability to substance abuse (1). The intermittent pattern of alcohol consumption induces higher drinking levels and deeper neurobiological changes in addiction-related brain regions, with respect to traditional free-access paradigms in male rats (2, 3). Nevertheless, no studies investigated on the effects of the drinking pattern on female subjects during pregnancy and perinatal time. To this aim, this study explored the consequences of continuous vs. intermittent drinking pattern on maternal behaviour and on offspring vulnerability to alcohol, during adulthood. Dams were given two-bottle choice to water and 20% alcohol with either continuous- or intermittent access (CA vs IA), along a 12-week period. They suspended alcohol drinking during breeding and resumed alcohol self-administration from late gestation throughout lactation, when they were assessed for home-cage undisturbed maternal behaviour. In the adulthood, alcohol-exposed offspring were assessed for alcohol drinking behaviour in a free-choice paradigm and tested for the deprivation effect. Our results show that alcohol consumption and preference significantly decreased in IA group during pregnancy, returning to baseline during lactation. Alcohol drinking was able to disrupt spontaneous maternal behaviour, especially in IA exposed dams. On the other hand, perinatal CA exposure did not increase alcohol-drinking behaviour in the offspring with respect to controls, while rats perinatally exposed to IA displayed a high vulnerability to alcohol, in terms of drinking behaviour and deprivation effect. In conclusion, this study indicates for the first time that the pattern of alcohol consumption can be responsible for different extents of maternal behaviour disruption and detrimental consequences in the offspring. Therefore gender- but also pattern-related differences should be taken into account for contrasting alcohol abuse and dependence, especially during perinatal time.   1. McMurray MS, Williams SK, Jarrett TM, Cox ET, Fay EE, Overstreet DH, Walker CH, Johns JM. Neurotoxicol Teratol. 2008;30(6):475-86. 2. Stuber GD, Hopf FW, Hahn J, Cho SL, Guillory A, Bonci A. Alcohol Clin Exp Res. 2008 Oct;32(10):1714-20 3. George O, Sanders C, Freiling J, Grigoryan E, Vu S, Allen CD, Crawford E, Mandyam CD, Koob GF. Proc Natl Acad Sci U S A. 2012;109(44):18156-6

Addictive-like behaviour for Acetaldehyde: involvement of D2 receptors

Acetaldehyde (ACD), ethanol's first metabolite, is centrally active and shows rewarding and motivational properties. It is able to activate mesolimbic dopamine system, since it enhances neuronal firing of dopamine cells in ventral tegmental area and exerts dopamine release in the nucleus accumbens (Foddai et al., 2004; Melis et al., 2007; Deehan et al., 2013). ACD motivational properties are demonstrated by self-administration studies in rodents (Rodd et al., 2005), particularly behavioural evidence suggests that ACD could produce positive reinforcing effects in operant-conflict paradigms (Cacace et al., 2012). In order to shed light on neurobiological substrate underpinning ACD-related behaviours, the present study aims at investigating D2-receptor role in the different phases of an operant self-administration paradigm, able to mirror core feature of addictive phenotype. Male Wistar rats underwent ACD (3.2%) oral self-administration, in an operant paradigm which includes Training, Extinction, and repeated cycle of forced abstinence and relapse, as a simple reinstatement model. The effect of two different D2-receptor agonists was evaluated. Quinpirole (0.03 mg/kg, i.p.) was administered during Extinction and Relapse phases. Ropinirole (0.03; 0.05 mg/kg, i.p.) was injected daily during abstinence. Our results show that ACD is able to induce and maintain a drug-taking behaviour, which involves D2-receptor neurotransmission. In particular, Quinpirole administration can decrease the number of lever presses for ACD during Extinction and Relapse phases; Ropinirole daily administration during abstinence, at both dosages, is able to reduce the number of lever presses and ACD intake in the relapse phase. ACD has its own motivational properties, which involve dopamine neurotransmission. Activation of D2-autoreceptors by Quinpirole negatively affects operant behaviour for ACD, likely decreasing ACD-induced dopamine release. The activation of post-synaptical D2-receptor, by Ropinirole treatment during abstinence, could restore dopaminergic tone during withdrawal, leading to a decrease in the motivation to subsequent relapse. These data further strengthen the evidence that ACD may play a crucial role in ethanol's central effects

Musculoskeletal disorders and incongruous postures in workers on ropes: A pilot study

Background:Occupational hazards believed to cause musculoskeletal disorders in rope workers are traditionally associated with maintaining incongruous postures for prolonged periods of time. Design and methods:A cross-sectional survey was conducted on 132 technical operators in the wind energy and acrobatic construction sectors, who work on ropes, analysing the ergonomic characteristics of the environments, the way in which tasks are carried out, the strain perceived by individual workers, and assessing the presence of any musculoskeletal disorders (MSDs) by means of an objective examination focused on the anatomical districts that were the object of our study. Results:Analysis of the data obtained showed that there were differences in the perception of the level of physical intensity and perceived exertion between the groups of workers. Statistical analysis also revealed a significant association between the frequency of MSDs analysed and perceived exertion. Discussion:The most significant finding to emerge from this study is the high prevalence of MSDs of the cervical spine (52.94%), the upper limbs (29.41%), and the dorso-lumbar spine (17.65%). These values differ from those classically found in those exposed to the risk of conventional manual handling of loads. Conclusions:The high prevalence of disorders of the cervical spine, the scapulo-humeral girdle and the upper limbs, indicates the need to consider the forced position to be assumed for a large part of the work activity, staticity, and the inability to move the lower limbs for long periods as the predominant risk in rope work

Psychological assessment in pathological gamblers treated with escitalopram

Pathological Gambling (PG) is classified as a "Disorder of Impulse Control", but due to similarities with drug addiction is frequently described as a drug-free addiction (Potenza et al., 2012). PG is conceptualized as a behavioural addiction because of its neurobiologic, neurophysiologic and psychological features. Current therapeutical approaches seem unsatisfactory as they do not achieve definitive positive outcomes. Considering the well known psycopathological comorbidities, PG represents both a social (impact on relatives money/life) and a sanitary cost, in terms of pharmacological and psychological support. The compulsive behaviour detectable in PG, is a disease with neurophysiopathological basis now fairly well-defined which affects particularly vulnerable people. PG is linked to important changes in brain systems such as the prefrontal cortex, the nucleus accumbens, the endogenous opioid system and the extended amygdale. Recent fMRI studies associate PG with blunted mesolimbic activation to non-specific rewards, whereas increased prefrontal cortex, anterior cingulate and ventral striatum activation is observed during gambling-related cue-exposure paradigms. Several neuropsychological studies show higher impulsivity in PG (Odlaug BL. et al., 2013) that, together with specific psychopathological symptoms, such as anxiety and depressed mood, characterize different PG subtypes (Blaszczynski A, Nower L. 2002). Impulsivity transcends multiple psychiatric disorders and is thought to be central to impulse control disorders such as PG. Furthermore, many PGs suffers from depression and decreased mood

Manipulation of the DA signal on the onset of relapse of ACD

It's widely known that all addictive drugs show analogous pathological behaviours consisting in compulsive drug seeking,loss of self –control and propensity to relapse. This evidence is suggestive of a common brain mechanism involving the Ventral Tegmental Area and Nucleus Accumbens whereby mesocorticolimbimc dopamine pathway. Dfferent and apparently anthitetic classes of drugs of abuse manage to increase DA release, in the aforementioned areas (Di Chiara, 1988; 1995). Reductions in activity of the mesolimbic dopamine system in the nucleus accumbes occur during drug withdrawal in animal studies (Weiss F et al. 1992; 1996). Experimental evidences have proven D2 receptor involvement in drug seeking and reinstatement behaviours. In that, according to the hypo-dopaminergic hypothesis of drug abuse, striatal D2-receptors significantly decrease during forced abstinence (Thanos, 2008). These premises suggest that D2 receptor manipulations might represent a valid strategy for alcohol dependence. Ropinirole, a D2-D3 receptors agonist, apparently acting on post-synaptical terminal and thus previously administered in methamphetamine withdrawal (Hoefer, 2006), could reduce drug intake in the reinstatement by means of its presumable properties in compensating DA reduction during abstinence. Acetaldehyde, alcohol first metabolite, is able to induce and maintain an operantdrinking behaviour, because of its addictive properties (Cacace, 2012). This research pointed at evaluating Ropinirole protective effect on ACD relapse as a possible therapeutic tool, together with a dose-response investigation. Rats were trained to self-administer ACD 3,2% solution along 30 days. Then, animals underwent three cycles, each one consisting of withdrawal (7days) followed by relapse phase (5 days). The first withdrawal-relapse cycle provided basal information of animal responses for ACD. During the second withdrawal phase, rats were treated i.p. daily with Ropinirole under the dosage of 0.03mg/kg. A third cycle of withdrawal and relapse was performed so as to correlate the drug potency to a higher dosage of 0.05mg/kg. Preliminary data convey that the aforementioned DA agonist is able to reduce animal responses for ACD also at the latter dosage, which is proved by a lower frequency of lever presses during the third relapse phase. An open field test was used to exclude a not specific Ropinirole effect on reducing locomotor activity and to assess dopaminergic activation by measuring the number of episodes of stereotypes, such as grooming and rearing. Our results indicated that this DA agonist, administered during withdrawal phase, is able to limit ACD reinstatement with responses dose-related. Such studies may be implemented in order to assess Ropinirole efficacy in other drug addictions, starting with alcoholism investigation

Musculoskeletal disorders and incongruous postures in workers on ropes: A pilot study

Background: Occupational hazards believed to cause musculoskeletal disorders in rope workers are traditionally associated with maintaining incongruous postures for prolonged periods of time. Design and methods: A cross-sectional survey was conducted on 132 technical operators in the wind energy and acrobatic construction sectors, who work on ropes, analysing the ergonomic characteristics of the environments, the way in which tasks are carried out, the strain perceived by individual workers, and assessing the presence of any musculoskeletal disorders (MSDs) by means of an objective examination focused on the anatomical districts that were the object of our study. Results: Analysis of the data obtained showed that there were differences in the perception of the level of physical intensity and perceived exertion between the groups of workers. Statistical analysis also revealed a significant association between the frequency of MSDs analysed and perceived exertion. Discussion: The most significant finding to emerge from this study is the high prevalence of MSDs of the cervical spine (52.94%), the upper limbs (29.41%), and the dorso-lumbar spine (17.65%). These values differ from those classically found in those exposed to the risk of conventional manual handling of loads. Conclusions: The high prevalence of disorders of the cervical spine, the scapulo-humeral girdle and the upper limbs, indicates the need to consider the forced position to be assumed for a large part of the work activity, staticity, and the inability to move the lower limbs for long periods as the predominant risk in rope work