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

Acetaldehyde as a drug of abuse: Involvement of endocannabinoid- and dopamine neurotransmission

Acetaldehyde (ACD), the first metabolite of ethanol, directly enhances dopamine neurotransmission (1) and has rewarding and motivational properties in paradigms tailored for studying addictive-like behaviours (2, 3). The endocannabinoid system affects distinct drug-related behaviours, since it may in turn fine-tune dopamine cell activity (4, 5). In light of this, the present study aimed at investigating the effects of a direct manipulation of the DAergic synapse, and the contribution of the endocannabinoid system on oral ACD self-administration in rats. ACD drinking-behaviour was evaluated in an operant paradigm consisting of acquisition and maintenance; extinction; deprivation and relapse; conflict. D2-receptor agonists, quinpirole (0.03 mg/Kg, i.p.) and ropinirole (0.03 mg/Kg, i.p.), and CB1-receptor antagonist, AM281 (1 mg/Kg, i.p.), were administered during different phases of the experiment. Our results show that oral ACD readily induced the acquisition and maintenance of an operant drinking-behaviour, even during reinstatement and conflict. Quinpirole decreased lever presses for ACD during extinction (p<0.05) and relapse (p<0.01; p<0.001) Ropinirole, administered during abstinence, reduced ACD intake during reinstatement (p<0.001). AM281 significantly decreased lever presses for ACD during extinction (p<0.001), relapse (p<0.001) and conflict (p<0.001). These data suggest that whereas the direct modulation of the dopaminergic synapse influences drug-seeking and relapse behaviour, the endocannabinoid system may also play a role in shock-paired compulsive ACD intake. These findings highlight the mandatory need for further investigation on the therapeutical potential played by the endocannabinoid system taking into account its crucial role in alcohol, and ACD neuropharmacology

EFFECTS OF SHIFT WORK ON CARDIOVASCULAR ACTIVITY, SERUM CORTISOL AND WHITE BLOOD CELLS COUNT IN A GROUP OF ITALIAN FISHERMEN

We analyzed the effects of working activity and working shifts on the circadian rhythmicity and circadian phase relations of serum cortisol level, white blood cells count, resting heart rate and systolic/diastolic blood pressure in a group of italian fishermen. We observed a shift-induced displacement of cortisol secretion and a modification in leukocyte count. Moreover, systolic/diastolic blood pressure and resting heart rate were markedly influenced by the night shift, whereas no appreciable changes were observed after the morning and afternoon shifts, compared to pre-working values. These data suggest that the human circadian system is greatly influenced by shift work, and serum cortisol level, leukocyte count, systolic and diastolic blood pressure, and resting heart rate are sensitive indicators of the biological responses to a stress workload in shift workers, especially after a night shif

Conciliación. Problemas e incongruencias del nuevo Código Procesal Penal de la Nación

Adquirir una mirada crítica de la implementación del sistema acusatorio en el nuevo Código Procesal Penal de la Nación, a la luz de las reglas de disponibilidad de la acción –en particular de la introducción de la conciliación penal-, es la propuesta para el presente trabajo. El abordaje integral de la temática bajo estudio requiere repasar los términos en los que un sistema judicial puede denominarse acusatorio y la posición que debería ocupar la víctima en él. Además, es necesario analizar en qué medida las restricciones impuestas a la aplicación procesal de los institutos incorporados, tienden a la mera regulación de los mismos, o bien si acaban por desvirtuar su función en el procedimiento adversarial. Resulta indispensable, a tal fin, estudiar cómo afectaría dichas limitaciones a las víctimas de violencia doméstica o motivada en discriminación, y analizar así la conveniencia (o inconveniencia) de su aplicación

Pregnenolone sulphate improves memory processing in early-handled female rats

Early life experiences lead to sex-specific behavioural and neurochemical changes in adulthood. Indeed, early handling enhances learning and memory in male rats (Cannizzaro et al., 2005), whereas it impairs learning performance in female adult rats, a finding that has been correlated to decreased nitric oxide (NO) production in the hippocampus (Noschang et al., 2010). Pregnenolone sulfate (PREGS) is considered as one of the most potent memory-enhancing neurosteroids, since its activity as a potent positive modulator of N-methyl-d-aspartate receptors (NMDARs) and a negative modulator of gamma-aminobutyric acid(A) receptors (GABA(A)Rs) (Vallée et al., 2001). Given these premises, this study aims at characterizing the effect of PREGS on cognitive processes in adult female rats, subject to early handling protocol, by using an object-place association learning task, the ''Can test'', a motivated, non-aversive, spatial/object discrimination test (Popovic´ et al., 2001). Female Wistar rats underwent daily, brief, maternal separation from postnatal day 2 until 21. Once in adulthood, the effect of PREGS administration (10 mg/kg, s.c.) on correct responses, reference memory and working memory was assessed. Results show that PREGS was able to significantly increase the number of correct responses, and consistently, to decrease reference and working memory errors, compared with vehicle. No statistically significant effect of PREGS administration was observed in non-handled, control group. These findings sustain the impact of neurosteroids in learning and memory processing, and suggest a particular role for PREGS in reversing conditions of altered functionality, likely due to the modulation of the glutamate-NO-cGMP pathway (Cauli et al., 2011), and thus neurobiological mechanisms underlying learning and memory. As a consequence, PREGS may represent an important therapeutic tool as memory-enhancer, in order to tackle cognitive deficit caused by stress in early lif

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