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Treball Final de Grau. Grau en Psicologia. Codi: PS1048. Curs acadèmic 2016/2017 El alcohol es la droga más aceptada y consumida en el mundo, la cual puede causarte un alto nivel de dependencia, a causa, principalmente, del efecto reforzante que produce en tu cerebro. En el presente trabajo nos vamos a centrar en la importancia que tiene el salsolinol en nuestro organismo tras el consumo de alcohol, así pues, el objetivo es aceptar o refutar la siguiente hipótesis: Un producto de la condensación de acetaldehído y dopamina es el responsable del efecto reforzante del etanol. Es decir, el salsolinol, como producto derivado de la condensación no enzimática de acetaldehído y dopamina, es el responsable del reforzamiento positivo. Aparece tras el consumo de etanol, y gracias a la metabolización de este. Todavía no se sabe el mecanismo de acción del salsolinol, pero sabemos que juega un papel importante a la hora de crear dependencia, llegando a pensar que el alcohol actúa como una prodroga. El salsolinol es una molécula reforzante, más potente que el acetaldehído y el etanol. The alcohol is the drug most accepted and consumed in the world, which can cause a high level of dependence, to reason, principally, of the reinforcing effect that produces in your brain. In the present work, we us go to focus in the importance that salsolinol has in our organism after consume alcohol, this way so, the objective is to agree or to refuse the following hypothesis: A product of the condensation of acetaldehyde and dopamine is the responsible of the effect positive reinforcement of the ethanol. The salsolinol, as product derived from the non-enzymatically condenses of acetaldehyde and dopamine, is the responsible of the positive reinforcement. It appears after consume ethanol, and thanks to metabolizing of this one. The mechanism of action of the salsolinol is not yet known, but we know that it plays an important role in creating dependency, coming to think that alcohol acts as a prodrug. The salsolinol more reforcing molecule that acetaldehyde and ethanol.

BackgroundEthanol (EtOH), one of the most widely consumed substances of abuse, can induce brain damage and neurodegeneration. EtOH is centrally metabolized into acetaldehyde, which has been shown to be responsible for some of the neurophysiological and cellular effects of EtOH. Although some of the consequences of chronic EtOH administration on cell oxidative status have been described, the mechanisms by which acute EtOH administration affects the brain's cellular oxidative status and the role of acetaldehyde remain to be elucidated in detail.MethodsSwiss CD‐I mice were pretreated with the acetaldehyde‐sequestering agent d‐penicillamine (DP; 75 mg/kg, i.p.) or the antioxidant lipoic acid (LA; 50 mg/kg, i.p.) 30 minutes before EtOH (2.5 g/kg, i.p.) administration. Animals were sacrificed 30 minutes after EtOH injection. Glutathione peroxidase (GPx) mRNA levels; GPx and glutathione reductase (GR) enzymatic activities; reduced glutathione (GSH), glutathione disulfide (GSSG), glutamate, g‐L‐glutamyl‐L‐cysteine (Glut‐Cys), and malondialdehyde (MDA) concentrations; and protein carbonyl group (CG) content were determined in whole‐brain samples.ResultsAcute EtOH administration enhanced GPx activity and the GSH/GSSG ratio, while it decreased GR activity and GSSG concentration. Pretreatment with DP or LA only prevented GPx activity changes induced by EtOH.ConclusionsAltogether, these results show the capacity of a single dose of EtOH to unbalance cellular oxidative homeostasis.

Previous studies have shown that both 3-amino-1,2,4-triazole (AT), which inhibits metabolism of ethanol (EtOH) to acetaldehyde by inhibiting catalase, and D-penicillamine (D-P), an acetaldehyde-sequestering agent, modulate EtOH-conditioned place preference (CPP) in male albino Swiss (IOPS Orl) mice. These studies followed a reference-dose-like procedure, which involves comparing cues that have both been paired with EtOH. However, the role of EtOH-derived acetaldehyde has not been examined using a standard CPP method, and efficacy of these treatments could be different under the two circumstances. In the present investigation, we manipulated the strength of CPP across five separate studies and evaluated the effect of D-P and AT on EtOH-induced CPP following a standard unbiased CPP procedure. Mice received pairings with vehicle-saline injections with one cue and, alternatively, with AT- and D-P-EtOH with another cue. Our studies indicate that AT and D-P only disrupt CPP induced by EtOH in mice when the number of conditioning sessions and the dose of EtOH are low. These findings suggest that acquisition of EtOH-induced CPP may depend on the levels of acetaldehyde available during memory acquisition and the strength of the memory. Therefore, we propose that, at least when the memory processes are labile, brain acetaldehyde could participate in the formation of Pavlovian learning elicited by EtOH.

BackgroundThe cAMP‐dependent protein kinase (PKA) signaling transduction pathway has been shown to play an important role in the modulation of several ethanol (EtOH)‐induced behavioral actions. In vivo, short‐term exposure to EtOH up‐regulates the cAMP‐signaling cascade. Interestingly, different Ca2+‐dependent cAMP–PKA cascade mediators play a critical role in the neurobehavioral response to EtOH, being of special relevance to the Ca2+‐dependent adenylyl cyclases 1 and 8. We hypothesize an intracellular PKA activation elicited by EtOH administration, which may be regulated by a Ca2+‐dependent mechanism as an early cellular response. Thus, the present work aims to explore the role of Ca2+ (internal and external) on the EtOH‐activated PKA cascade.MethodsSwiss male mice received an intraperitoneal injection of EtOH (0 or 4 g/kg), and brains were dissected following a temporal pattern (7, 15, 30, 45, 90, or 120 minutes). Either the enzymatic PKA activity or its fingerprint was analyzed on different brain areas (cortex, hypothalamus, hippocampus, and striatum). To explore the role of Ca2+ on the EtOH‐activated PKA cascade, mice were pretreated with diltiazem (0 or 20 mg/kg), dantrolene (0 or 5 mg/kg), or 3,7‐Dimethyl‐1‐(2‐propynyl)xanthine (0 or 1 mg/kg) 30 minutes before EtOH (4 g/kg) administration. After 45 minutes of EtOH administration, brains were removed and dissected to measure the PKA activity or its fingerprint.ResultsResults from these experiments showed an EtOH‐dependent activation of PKA in different brain areas. Manipulations involving a disruption of intracellular Ca2+ release from the endoplasmic reticulum resulted in a decreased EtOH‐induced activation of PKA. On the contrary, extracellular‐to‐cytoplasm Ca2+ manipulations did not prevent the PKA activation by EtOH.ConclusionsAltogether, these results show the critical role of stored Ca2+ as an intracellular mediator of different neurobiological actions of EtOH and provide further evidence of a possible new target for EtOH within the central nervous system.

Hydrogen peroxide is the co-substrate used by the enzyme catalase to form Compound I (the catalase-H2O2 system), which is the major pathway for the conversion of ethanol (EtOH) into acetaldehyde in the brain. This acetaldehyde has been involved in many of the effects of EtOH. Previous research demonstrated that treatments that change the levels of cerebral H2O2 available to catalase modulate the locomotor-stimulating effects of EtOH and its volitional intake in rodents. However, the source of H2O2 which is used by catalase to form Compound I and mediates the psychoactive actions of EtOH is unknown. One cause of the generation of H2O2 in the brain comes from the deamination of biogenic amines by the activity of MAO-A. Here we explore the consequences of the administration of the MAO-A inhibitor clorgyline on EtOH-induced locomotion and voluntary EtOH drinking. For the locomotor activity tests, we injected Swiss (RjOrl) mice intraperitoneally (IP) with clorgyline (0-10mg/kg) and later (0.5-8h) with EtOH (0-3.75 g/kg; IP). Following these treatments, mice were placed in locomotor activity chambers to measure their locomotion. For the drinking experiments, mice of the C57BL/6J strain were injected IP with clorgyline prior to offering them an EtOH (20%) solution following a drinking-in-the-dark procedure. Additional experiments were performed to assess the selectivity of this compound in altering EtOH-stimulated locomotion and EtOH intake. Moreover, we indirectly tested the ability of clorgyline to reduce brain H2O2 levels. We showed that this treatment selectively reduced EtOH-induced locomotion and its self-administration. Moreover, this compound decreased central H2O2 levels available to catalase. We suggest that H2O2 derived from the deamination of biogenic amines by the activity of MAO-A could determine the formation of brain EtOH-derived acetaldehyde. This centrally-formed acetaldehyde within the neurons of the aminergic system could play a role in the neurobehavioral properties of EtOH.

Treball Final de Grau en Psicologia. Codi: PS1048. Curs 2013-2014 Ethanol is one of the most widely used recreational drugs, but also one of the most widely abused, causing vast economic, social and personal damage. The neurobiological processes by which ethanol seeking and consumption are established and maintained are thought to involve areas of the brain that mediate motivated behavior, such as the mesolimbic dopamine system. For many years, it has been suggested that drugs that interfere with dopamine (DA) transmission alter the “rewarding” impact of primary reinforcers such as food. Research and theory related to the functions of mesolimbic DA are undergoing a substantial conceptual restructuring, with the traditional emphasis on hedonia and primary reward yielding to other concepts and line of inquiry. The mesolimbic dopamine system is comprised of cells that originate in the ventral tegmental area (VTA) and project to several forebrain regions, including a prominent terminal area, the nucleus accumbens (NAcc). This area receives converging excitatory input from the cortex and amygdala and dopamine input from the VTA. Although forced ethanol administration enhances dopamine activity in the NAcc, conclusions regarding the role of mesolimbic dopamine in ethanol reinforcement cannot be made from these experiments. Behavioral experiments consistently show that pharmacological manipulations of the dopamine transmission in the NAcc alter responding for ethanol, although ethanol reinforcement is maintained after lesions of the accumbal dopamine system. Additionally, extracellular dopamine increases in the NAcc during operant self-administration of ethanol, which is consistent with a role of dopamine in ethanol reinforcement.

The cAMP signaling pathway has emerged as an important modulator of the pharmacological effects of ethanol. In this respect, the cAMP-dependent protein kinase has been shown to play an important role in the modulation of several ethanol-induced behavioral actions. Cellular levels of cAMP are maintained by the activity of adenylyl cyclases and phosphodiesterases. In the present work we have focused on ascertaining the role of PDE4 in mediating the neurobehavioral effects of ethanol. For this purpose, we have used the selective PDE4 inhibitor Ro 20-1724. This compound has been proven to enhance cellular cAMP response by PDE4 blockade and can be administered systemically. Swiss mice were injected intraperitoneally (i.p.) with Ro 20-1724 (0-5 mg/kg; i.p.) at different time intervals before ethanol (0-4 g/kg; i.p.) administration. Immediately after the ethanol injection, locomotor activity, loss of righting reflex, PKA footprint and enzymatic activity were assessed. Pretreatment with Ro 20-1724 increased ethanol-induced locomotor stimulation in a dose-dependent manner. Doses that increased locomotor stimulation did not modify basal locomotion or the suppression of motor activity produced by high doses of this alcohol. Ro 20-1724 did not alter the locomotor activation produced by amphetamine or cocaine. The time of loss of righting reflex evoked by ethanol was increased after pretreatment with Ro 20-1724. This effect was selective for the narcotic effects of ethanol since Ro 20-1724 did not affect pentobarbital-induced narcotic effects. Moreover, Ro 20-1724 administration increased the PKA footprint and enzymatic activity response elicited by ethanol. These data provide further evidence of the key role of the cAMP signaling pathway in the central effects of ethanol.

In the brain, the enzyme catalase by reacting with H(2)O(2) forms Compound I (catalase-H(2)O(2) system), which is the main system of central ethanol metabolism to acetaldehyde. Previous research has demonstrated that acetaldehyde derived from central-ethanol metabolism mediates some of the psychopharmacological effects produced by ethanol. Manipulations that modulate central catalase activity or sequester acetaldehyde after ethanol administration modify the stimulant effects induced by ethanol in mice. However, the role of H(2)O(2) in the behavioral effects caused by ethanol has not been clearly addressed. The present study investigated the effects of ebselen, an H(2)O(2) scavenger, on ethanol-induced locomotion.Swiss RjOrl mice were pre-treated with ebselen (0-50mg/kg) intraperitoneally (IP) prior to administration of ethanol (0-3.75g/kg; IP). In another experiment, animals were pre-treated with ebselen (0 or 25mg/kg; IP) before caffeine (15mg/kg; IP), amphetamine (2mg/kg; IP) or cocaine (10mg/kg; IP) administration. Following these treatments, animals were placed in an open field to measure their locomotor activity. Additionally, we evaluated the effect of ebselen on the H(2)O(2)-mediated inactivation of brain catalase activity by 3-amino-1,2,4-triazole (AT).Ebselen selectively prevented ethanol-induced locomotor stimulation without altering the baseline activity or the locomotor stimulating effects caused by caffeine, amphetamine and cocaine. Ebselen reduced the ability of AT to inhibit brain catalase activity.Taken together, these data suggest that a decline in H(2)O(2) levels might result in a reduction of the ethanol locomotor-stimulating effects, indicating a possible role for H(2)O(2) in some of the psychopharmacological effects produced by ethanol.