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The most disastrous heatwaves are very extreme events with return periods of hundreds of years, but traditionally, climate research has focussed on moderate extreme events occurring every couple of years or even several times within a year. Here, we use three Earth System Model large ensembles to assess whether very extreme heat events respond differently to global warming than moderate extreme events. We find that the warming signal of very extreme heat can be amplified or dampened substantially compared to moderate extremes. This modulation is detectable already in mid-century projections. In the mid-latitudes, it can be explained by changes in event soil moisture-temperature coupling during the hottest day of the year. The changes depend on the interplay of present soil moisture and coupling during heat events as well as projected precipitation changes. This mechanism is robust across models, albeit with large spatial uncertainties. Our findings are highly relevant for climate risk assessments and adaptation planning. Climatic changes in extreme events are well studied, but research has so far focused on moderate extremes. The authors show that changes in very extreme heat events can be, depending on the region, much stronger or weaker than changes in moderate extremes. [ABSTRACT FROM AUTHOR]

The adverse use of alcohol is a serious global public health problem. Maternal alcohol consumption during pregnancy usually causes prenatal alcohol exposure (PAE) in the developing fetus, leading to a spectrum of disorders known as fetal alcohol spectrum disorders (FASD) and even fetal alcohol syndrome (FAS) throughout the lifelong sufferers. The prevalence of FASD is approximately 7.7 per 1,000 worldwide, and is even higher in developed regions. Generally, Ethanol in alcoholic beverages can impair embryonic neurological development through multiple pathways leading to FASD. Among them, the leading mechanism of FASDs is attributed to ethanol-induced neuroinflammatory damage to the central nervous system (CNS). Although the underlying molecular mechanisms remain unclear, the remaining multiple pathological mechanisms is likely due to the neurotoxic damage of ethanol and the resultant neuronal loss. Regardless of the molecular pathway, the ultimate outcome of the developing CNS exposed to ethanol is almost always the destruction and apoptosis of neurons, which leads to the reduction of neurons and further the development of FASD. In this review, we systematically summarize the current research progress on the pathogenesis of FASD, which hopefully provides new insights into differential early diagnosis, treatment and prevention for patents with FASD. [ABSTRACT FROM AUTHOR]

Rationale: Previous studies have shown that gonadal hormones influence opioid self-administration in female rodents, but very few studies have examined these effects in male rodents. Objectives: The purpose of this study was to examine the effects of chronic hormone treatment on intravenous heroin self-administration in gonadectomized male rats using both physiological and supraphysiological doses of testosterone, estradiol, or progesterone. Methods: Gonadectomized male rats were surgically implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement. Using a between-subjects design, rats were treated daily with testosterone (0.175 or 1.75 mg, sc), estradiol (0.0005 or 0.005 mg, sc), progesterone, (0.0125 or 0.125 mg, sc), or their vehicles. After 14 days of chronic treatment, a dose–effect curve was determined for heroin (0.0003—0.03 mg/kg/infusion) over the course of one week. Results: Neither testosterone nor estradiol altered responding maintained by heroin. In contrast, the high dose of progesterone (0.125 mg) reduced responding maintained by all doses of heroin to saline-control levels. This dose of progesterone did not reduce responding maintained by food on a progressive ratio schedule in either food-restricted or food-sated rats. Conclusions: These data indicate that exogenous progesterone or a pharmacologically active metabolite selectively decreases heroin intake in male rodents, which may have therapeutic implications for men with opioid use disorder. [ABSTRACT FROM AUTHOR]

The ability of a suite of models contributing to the sixth phase of the Coupled Model Intercomparison Project (CMIP6) to simulate observed large-scale atmospheric circulation patterns over the Pacific Northwest of North America is evaluated. Twelve representative patterns of 500-hPa geopotential height (Z500) anomalies are identified using the self-organizing map method applied to reanalysis. CMIP6 Z500 anomalies from simulations of the historical period are mapped to each reanalysis-derived pattern, and the resulting differences between patterns, as well as differences in frequency of pattern occurrence, are quantified. In general, models are able to simulate the range of Z500 patterns with reasonable fidelity, although model skill varies across the 25-member ensemble. Surface temperature and precipitation anomalies associated with each Z500 pattern are found to also be reasonably simulated by the models, with some biases noted. This boosts confidence that the models are simulating temperature and precipitation patterns for the correct physical reasons. The models exhibit a range of skill at simulating pattern occurrence frequency and pattern persistence, with more agreement in winter than summer. Results indicate that the CMIP6 models are appropriate for assessing future projections of key atmospheric circulation patterns and their impacts on temperature and precipitation over the region. [ABSTRACT FROM AUTHOR]

Schizophrenia is a neurological disorder that alters the behavior and affects the quality of life of a patient. It is characterized by hallucinations, disorganized behavior, cognitive dysfunction, hyperlocomotion, and loss of the reward system. Schizophrenia constitutes three symptoms' domains, viz. positive, negative and cognitive. Typical and atypical antipsychotics do not fully resolve all the symptoms' domains thus paving the way to the genesis of the glutamatergic hypothesis, i.e. N-methyl-d-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Positive modulation of NMDA receptors by enhancing co-agonist, glycine effect is proposed to produce a therapeutic effect in schizophrenia. Hence, sarcosine (N-methyl glycine), natural amino acid, and a glycine transporter inhibitor (GlyT-1) which also acts on NMDA receptors were used in the present study. The present study unravels the role of sarcosine in the attenuation of ketamine-induced three symptom domains in a rat model through modulation of oxidative stress, mitochondrial dysfunction, and neuroinflammatory pathways. The animal model of schizophrenia was established by injecting ketamine intraperitoneal (ip) at a 30 mg/kg dose for 10 consecutive days, after which sarcosine (300, 600 mg/kg, ip) as a treatment was given for 7 days followed by behavioral, biochemical, molecular, and histopathological analysis. It was revealed that sarcosine reversed ketamine-induced behavioral impairments. Moreover, sarcosine ameliorated oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation and showed protective effects in histopathological examination by hematoxylin and eosin staining. Hence, conclusively, sarcosine was regarded to attenuate the behavioural symptoms of schizophrenia by alleviating oxidative stress, neuroinflammation, and mitochondrial dysfunction established by the ketamine. [ABSTRACT FROM AUTHOR]

Rationale: The role of ethanol-derived acetaldehyde has not been examined yet on performance in a model of operant oral self-administration. However, previous studies reported that an acetaldehyde-sequestering agent, d-penicillamine (DP) and an inhibitor of catalase-mediated acetaldehyde production, 3-amino-1,2,4-triazole (3-AT) reduce voluntary ethanol consumption. Objectives: The aim of our investigation was to evaluate the effects of DP and 3-AT on acquisition and maintenance of oral operant ethanol self-administration. Methods: Using operant chambers, rats learned to nose poke in order to receive ethanol solution (5-10 % v/ v) under an FR1 schedule of reinforcement in which discrete light and tone cues were presented during ethanol delivery. Results: DP and 3-AT impair the acquisition of ethanol self-administration, whereas its maintenance is not affected neither by drug given alone for both 10 or 5 % ethanol nor by drugs association for 5 % ethanol. Moreover, when the concentration of ethanol was diminished from 10 to 5 %, rats increased the rate of self-administration behaviour. Conclusions: These findings suggest that brain acetaldehyde plays a critical role during acquisition of operant self-administration in ethanol-naïve rats. In contrast, during the maintenance phase, acetaldehyde could contribute to ethanol self-administration by a combined mechanism: On one hand, its lack (by DP or 3-AT) might result in further ethanol-seeking and taking and, on the other, inhibition of ethanol metabolism (by 3-AT) might release an action of the un-metabolised fraction of ethanol that does not overall result in compromising maintenance of ethanol self-administration. [ABSTRACT FROM AUTHOR]

Alcohol exposure during pregnancy is harmful to the fetus and causes a wide range of long-lasting physiological and neurocognitive impairments, collectively referred to as fetal alcohol spectrum disorders (FASD). The neurobehavioral deficits observed in FASD result from structural and functional damages in the brain, with neurodegeneration being the most destructive consequence. Currently, there are no therapies for FASD. It is exigent to delineate the underlying mechanisms of alcohol neurotoxicity and develop an effective strategy of treatment. ER stress, caused by the accumulation of unfolded/misfolded proteins in the ER, is the hallmark of many neurodegenerative diseases, including alcohol-induced neurodegeneration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly discovered endoplasmic reticulum (ER) stress responsive neurotrophic factor that regulates diverse neuronal functions. This review summarizes the recent findings revealing the effects of MANF on the CNS and its protective role against neurodegeneration. Particularly, we focus the role of MANF on alcohol-induced ER stress and neurodegeneration and discuss the therapeutic potential of MANF in treating alcohol neurotoxicity such as FASD. [ABSTRACT FROM AUTHOR]

Rationale: Animal studies indicate that central acetaldehyde, dependent on catalase metabolism of ethanol (EtOH), modulates ethanol reinforcement. Brain catalase activity and acetaldehyde (ACD) production are significantly higher in rat pups compare d with adults. Interestingly, infant rats show high EtOH affinity for alcohol consumption and are particularly sensitive to the drug's reinforcing effects. Objectives: We tested whether central ACD is necessary and sufficient to induce appetitive conditioning in newborn rats through the artificial nipple technique. Methods: Vehicle, EtOH (100 mg%), and acetaldehyde (0.35 μmol) were administered into the cisterna magna (1 μl). Half of the animals also received a central administration of 75 μg (experiment 1) or 40 μg of d-penicillamine (experiment 2). Afterwards, pups were exposed to an olfactory cue (conditioned stimulus). One hour later, neonates were tested with an artificial nipple in the presence of the conditioned cue. Nipple attachment duration, mean grasp duration, and number of nipple disengagements served as dependent variables. Results: Positive responses to the scented nipple occurred in neonates conditioned with EtOH or ACD (experiments 1 and 2). In experiment 1, there were indications that d-penicillamine weakened the reinforcing effects of EtOH and ACD. In experiment 2, d-penicillamine (40 μg) significantly inhibited appetitive conditioned responses dependent upon EtOH or ACD. Conclusions: Appetitive conditioning was observed when employing either central EtOH or ACD as unconditioned stimuli. Central abduction of ACD inhibited conditioned appetitive responsiveness to the surrogate nipple. Central ACD is involved in the determination or modulation of EtOH's motivational properties during early stages in development. [ABSTRACT FROM AUTHOR]

Rationale: Opioid receptor antagonists reliably alter the expression or extinction of ethanol's conditioned motivational effects as indexed by the place conditioning procedure, suggesting endogenous opioids are normally involved. These studies examined how exogenous stimulation of opioid receptors alters ethanol's conditioned rewarding and aversive effects. Objectives: Drugs that either directly (morphine) or indirectly (ethanol) stimulate opioid receptors were tested for their effects on the expression and extinction of ethanol-induced conditioned place preference (CPP) and conditioned place aversion (CPA). Methods: Male DBA/2J mice were exposed to unbiased ethanol (2 g/kg) conditioning procedures that produced either CPP (experiments 1–2) or CPA (experiments 3–4). Morphine (0, 2.5, 5, or 10 mg/kg) was injected before three post-conditioning tests in experiments 1 and 3, whereas ethanol (0, 1, 2, or 3 g/kg) was injected before tests in experiments 2 and 4. All groups received vehicle on test 4 to determine whether the drug pretreatments altered the course of extinction. Results: Morphine dose-dependently enhanced CPP expression (experiment 1), but ethanol dose-dependently reduced CPP expression (experiment 2). Test 4 showed no differences between drug-treated mice and mice given vehicle on all tests. Morphine had no effect on expression or extinction of ethanol-induced CPA (experiment 3). The highest ethanol dose (3 g/kg) interfered with CPA expression, but not extinction (experiment 4). Conclusions: Pretreatment drug effects on ethanol CPP and CPA expression were most likely a byproduct of their activity altering effects rather than opioid-receptor mediated modulation of ethanol's conditioned motivational effects. Neither drug affected the course of extinction. [ABSTRACT FROM AUTHOR]

Background and Purpose: Toll-like receptors (TLRs) are a family of innate immune system receptors that respond to pathogen-derived and tissue damage-related ligands and are increasingly recognized for their impact on homeostasis and its dysregulation in the nervous system. TLR signaling participates in brain injury and addiction, but its role in the alcohol-seeking behavior, which initiates alcohol drinking, is still poorly understood. In this review, we discuss our findings designed to elucidate the potential contribution of the activated TLR4 signal located in neurons, on impulsivity and the predisposition to initiate alcohol drinking (binge drinking). Results: Our findings indicate that the TLR4 signal is innately activated in neurons from alcohol-preferring subjects, identifying a genetic contribution to the regulation of impulsivity and the alcohol-seeking propensity. Signal activation is through the non-canonical, previously unknown, binding of TLR4 to the α2 subunit of the γ-aminobutyric 2 acid A receptor (GABAAR α2). Activation is sustained by the stress hormone corticotrophin-releasing factor (CRF) and additional still poorly recognized ligand/scaffold proteins. Focus is on the effect of TLR4 signal activation on the balance between pro- and anti-inflammatory chemokines [chemokine (C-C motif) ligand 2 (CCL2)/chemokine (C-X3-C motif) ligand 1 (CX3CL1)] and its effect on binge drinking. Conclusion: The results are discussed within the context of current findings on the distinct activation and functions of TLR signals located in neurons, as opposed to immune cells. They indicate that the balance between pro- and anti-inflammatory TLR4 signaling plays a major role in binge drinking. These findings have major impact on future basic and translational research, including the development of potential therapeutic and preventative strategies. [ABSTRACT FROM AUTHOR]

Rationale: Alcohol use disorder (AUD) involves dysregulation of innate immune signaling in brain. Toll-like receptor 3 (TLR3), an innate immune receptor that is upregulated in post-mortem human alcoholics, leads to induction of interferon (IFN) signaling. IFNs have been linked to depressive-like symptoms and therefore may play a role in addiction pathology. Astrocyte-neuronal signaling may contribute to maladaptation of neuronal circuits. Objectives: In this manuscript, we examine ethanol (EtOH) induction of IFN signaling in neuronal, astrocyte, and microglial cell lines and assess astrocyte-neuronal interactions. Methods: U373 astrocytes, SH-SY5Y neurons, and BV2 microglia were treated with EtOH and analyzed for autocrine/paracrine IFN signaling. Results: EtOH induced TLR3, IFNβ, and IFNγ in SH-SY5Y neurons and U373 astrocytes, but not in BV2 microglia. The IFN response gene TRAIL was also strongly upregulated by TLR3 agonist Poly(I:C) and EtOH in U373 astrocytes. TRAIL blockage via neutralizing antibody prevented induction of IFNs in SH-SY5Y neurons but not in U373 astrocytes. Blocking TRAIL in conditioned media from EtOH-treated astrocytes prevented induction of IFNs in SH-SY5Y neurons. Finally, an in vivo model of chronic 10-day binge EtOH exposure in C57BL6/J mice, as well as single acute treatment with Poly(I:C), showed increased TRAIL +IR cells in both orbitofrontal and entorhinal cortex. Conclusions: This study establishes a role of astrocyte to neuron TRAIL release in EtOH-induced IFN responses. This may contribute to alcohol associated negative affect and suggest potential therapeutic benefit of TRAIL inhibition in AUD. [ABSTRACT FROM AUTHOR]

An unsafe level of manganese (Mn) was detected in the drinking water in some arsenic (As)-contaminated areas in Bangladesh. Mn is an essential trace element; however, the intake of a higher level of Mn through the drinking water is associated with the development of toxicity in humans. This study was designed to evaluate the effects of As and Mn co-exposure on neurobehavioral and biochemical alterations in a mouse model. Sodium arsenite (10 mg/kg body weight) and manganese chloride tetrahydrate (10 mg/kg body weight) were given to mice individually and in combination with drinking water for 90 days. Results showed that individual As and Mn exposure as well as co-exposure of As and Mn significantly (p < 0.05) reduced the percent of time spent in the open arms when compared with that of control mice. In addition, percent of time spent in open arms significantly (p < 0.05) increased in co-exposed mice compared with As exposure in elevated plus maze (42.05 ± 1.10 versus 38.94 ± 0.66). In the Morris water maze test, the mean time latency to find the platform was longer in metal-treated mice in comparison to that of control mice (p < 0.05). Importantly, the co-exposed group had shorter time when compared with the As-exposed group during the training periods (p < 0.05). Moreover, co-exposed mice stayed significantly (p < 0.05) more time in the target quadrant in the probe trial in comparison with that of As-exposed mice (27.25 ± 1.21 versus 23.83 ± 0.87 s) but less time than control mice (27.25 ± 1.21 versus 43.17 ± 1.49 s). In addition, a significant (p < 0.05) alteration of biochemical parameters such as ALT, AST, ALP, BChE, and SOD as well as urea and creatinine levels were noted in the As-exposed group compared with the control group and Mn significantly (p < 0.05) attenuated the effects of As in co-exposed mice. Therefore, the results of this study suggest that As and Mn may have some antagonistic effect and Mn could attenuate the As-induced neurobehavioral and biochemical alterations in co-exposed mice. [ABSTRACT FROM AUTHOR]

Chronic low-grade neuroinflammation is increasingly implicated in organ damage caused by alcohol abuse. Purinergic P2X7 receptors (P2X7Rs) play an important role in the generation of inflammatory responses during a number of CNS pathologies as evidenced from studies using pharmacological inhibition approach. P2X7Rs antagonism has not been tested during chronic alcohol abuse. In the present study, we tested the potential of P2X7R antagonist A804598 to reduce/abolish alcohol-induced neuroinflammation using chronic intragastric ethanol infusion and high-fat diet (Hybrid) in C57BL/6J mice. We have previously demonstrated an increase in neuroinflammatory response in 8 weeks of Hybrid paradigm. In the present study, we found neuroinflammatory response to 4 weeks of Hybrid exposure. A804598 treatment reversed the changes in microglia and astrocytes, reduced/abolished increases in mRNA levels of number of inflammatory markers, including IL-1β, iNOS, CXCR2, and components of inflammatory signaling pathways, such as TLR2, CASP1, NF-kB1 and CREB1, as well in the protein levels of pro-IL-1β and Nf-kB1. The P2X7R antagonist did not affect the increase in mRNA levels of fraktalkine (CX3CL1) and its receptor CX3CR1, an interaction that plays a neuroprotective role in neuron-glia communication. P2X7R antagonism also resulted in reduction of the inflammatory markers but did not alter steatosis in the liver. Taken together, these findings demonstrate how P2X7R antagonism suppresses inflammatory response in brain and liver but does not alter the neuroprotective response caused by Hybrid exposure. Overall, these findings support an important role of P2X7Rs in inflammation in brain and liver caused by combined chronic alcohol and high-fat diet. [ABSTRACT FROM AUTHOR]

Evidence suggests a predictive link between elevated basal activity within reward-related networks (e.g., cortico-basal ganglia-thalamic networks) and vulnerability for alcoholism. Both calcium channel function and cyclic adenosine monophosphate (cAMP)/protein kinase A-mediated signaling are critical modulators of reward neurocircuitry and reward-related behaviors. Calcium/calmodulin-stimulated adenylyl cyclases (AC) 1 and 8 are sensitive to activity-dependent increases in intracellular calcium and catalyze cAMP production. Therefore, we hypothesized AC1 and 8 regulate brain activity in reward regions of the cortico-basal ganglia-thalamic circuit and that this regulatory influence predicts voluntary ethanol drinking responses. This hypothesis was evaluated by manganese-enhanced magnetic resonance imaging and chronic, intermittent ethanol access procedures. Ethanol-naïve mice with genetic deletion of both AC1 and 8 (DKO mice) exhibited bilateral reductions in baseline activity within cortico-basal ganglia-thalamic regions associated with reward processing compared to wild-type controls (WT, C57BL/6 mice). Significant activity changes were not evident in regions either outside of the cortico-basal ganglia-thalamic network or within the network that are not associated with reward processing. Parallel studies demonstrated that reward network hypoactivity in DKO mice predicted a significant attenuation in consumption and preference levels to escalating ethanol concentrations (12, 20 and 30%) compared to WT mice, an effect that was maintained over extended access (14 sessions) to 20% ethanol. Summarizing, these data support a contribution of AC1 and 8 in cortico-basal ganglia-thalamic activity and the predictive value of this regulatory influence on ethanol drinking behavior, which merits the future evaluation of calcium-stimulated ACs in the neural processes that engender vulnerability to maladaptive alcohol drinking. [ABSTRACT FROM AUTHOR]

Groundwater particularly drinking water contamination with metals has created an environmental disaster in Bangladesh. Manganese (Mn), an essential trace element, plays a key role in the development and function of the brain. Excess Mn exposure is reported to be associated with complex neurological disorders. Here, we have found a notably large extent of Mn above the permissive limit in the tube-well water of Rajshahi and Naogaon districts in Bangladesh. Higher levels of Mn in hair and nail samples, and a decreasing level of butyrylcholinesterase (BChE) activity were detected in plasma samples of the human subjects recruited from Naogaon district. Mn concentrations in water, hair, and nails were negatively correlated with the plasma BChE levels in Mn-exposed populations. To compare and validate these human studies, an animal model was used to determine the in vivo effects of Mn on neurobehavioral changes and blood BChE levels. In elevated plus maze, the time spent was significantly reduced in open arms and increased in closed arms of Mn-exposed mice compared to control group. The mean latency time to find the platform was declined significantly in control mice compared to Mn-treated group during 7 days in Morris water maze test, and Mn-exposed group also spent significantly less time in the desired quadrant as compared to the control group in probe trial. BChE activity was significantly reduced in Mn-exposed mice compared to control mice. Taken together, these results suggest that plasma BChE levels may serve as reliable biomarker of Mn-induced neurotoxicity related to behavioral changes. [ABSTRACT FROM AUTHOR]

Chronic alcohol consumption induces damage to the brain that can cause various forms of dementia. An abundance of acetaldehyde is produced by excessive alcohol consumption and accumulates in the body to induce oxidative stress, apoptosis, and inflammation in neuronal cells, which results in learning and cognitive decline. In the present study, C57BL/N mice were orally administered alcohol (16%) and Carthamus tinctorius L. seed (CTS) (100 and 200 mg/kg/day). Behavioral experiments showed that memory and cognitive abilities were significantly higher in the CTS groups than the alcohol-treated control group in the T-maze test, novel object recognition test, and Morris water maze test. In addition, CTS inhibited alcohol-induced lipid peroxidation and nitric oxide production in the brain, kidney, and liver. Moreover, alcohol increased acetylcholinesterase activity in the brain, but this was significantly decreased by the administration of CTS. Therefore, CTS may play role in the prevention of alcohol-related dementia. [ABSTRACT FROM AUTHOR]

The role of norepinephrine (NE) in the development of alcohol use disorder (AUD) has been studied over the past several decades. However, the NE system has been largely ignored for many years as a potential target for medication development for AUD. More recently, preclinical and clinical studies have demonstrated the potential value of targeting NE signaling for developing new pharmacological treatments for AUD. This review contributes to a special issue of Psychopharmacology focused on promising targets for alcohol addiction. Specifically, this review coalesces preclinical and clinical neuroscience that re-evaluate the noradrenergic system, and in particular the alpha-1 receptor, as a potential target for AUD. [ABSTRACT FROM AUTHOR]

Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) is a tetrahydroisoquinoline derivative whose presence in humans was first detected in the urine of Parkinsonian patients on l-DOPA ( l-dihydroxyphenylalanine) medication. Thus far, multiple hypotheses regarding its physiological/pathophysiological roles have been proposed, especially related to Parkinson's disease or alcohol addiction. The aim of this review was to outline studies related to salsolinol, with special focus on in vivo and in vitro experimental models. To begin with, the chemical structure of salsolinol together with its biochemical implications and the role in neurotransmission are discussed. Numerous experimental studies are summarized in tables and the most relevant ones are stressed. Finally, the ability of salsolinol to cross the blood-brain barrier and its possible double-faced neurobiological potential are reviewed. [ABSTRACT FROM AUTHOR]

Glutamate carboxypeptidase II (GCPII) inactivates the peptide neurotransmitter N-acetylaspartylglutamate (NAAG) following synaptic release. Inhibitors of GCPII increase extracellular NAAG levels and are efficacious in animal models of clinical disorders via NAAG activation of a group II metabotropic glutamate receptor. mGluR2 and mGluR3 knock-out (ko) mice were used to test the hypothesis that mGluR3 mediates the activity of GCPII inhibitors ZJ43 and 2-PMPA in animal models of memory and memory loss. Short- (1.5 h) and long- (24 h) term novel object recognition tests were used to assess memory. Treatment with ZJ43 or 2-PMPA prior to acquisition trials increased long-term memory in mGluR2, but not mGluR3, ko mice. Nine month-old triple transgenic Alzheimer's disease model mice exhibited impaired short-term novel object recognition memory that was rescued by treatment with a NAAG peptidase inhibitor. NAAG peptidase inhibitors and the group II mGluR agonist, LY354740, reversed the short-term memory deficit induced by acute ethanol administration in wild type mice. 2-PMPA also moderated the effect of ethanol on short-term memory in mGluR2 ko mice but failed to do so in mGluR3 ko mice. LY354740 and ZJ43 blocked ethanol-induced motor activation. Both GCPII inhibitors and LY354740 also significantly moderated the loss of motor coordination induced by 2.1 g/kg ethanol treatment. These data support the conclusion that inhibitors of glutamate carboxypeptidase II are efficacious in object recognition models of normal memory and memory deficits via an mGluR3 mediated process, actions that could have widespread clinical applications. [ABSTRACT FROM AUTHOR]

Arsenic (As) toxicity has caused an environmental tragedy affecting millions of people in the world. Little is known about the toxic effects of As on neurobehavioral and biochemical changes in vivo. Along this line of metal toxicity, co-exposure of lead (Pb) could aggravate the situation in the host. The present study was designed to explore the combined effects of As and Pb on behavioral changes like anxiety, spatial memory and learning impairment, and blood indices related to organ dysfunction. Exposure of mice to As (10 mg/kg body weight), Pb (10 mg/kg body weight), and As + Pb via drinking water significantly decreased the time spent exploring the open arms while it increased the time spent in the closed arms compared to control mice in the elevated plus maze. The mean latency time of the control group to find the platform decreased significantly during the learning for 7 days compared to all three treated groups in the Morris water maze test, and the As-exposed group spent significantly less time in the desired quadrant as compared to the control group in the probe trial. Both metals posed an anxiety-like behavior and deficits in spatial memory and learning, and also altered blood indices related to liver and kidney dysfunction, and a combined exposure of these metals inhibited the individual accumulation of As and Pb. Taken together, these data suggest that As has more toxic effects on neurobehavioral and biochemical changes than Pb, and there may be antagonism in the effects and accumulation between these two toxicants. [ABSTRACT FROM AUTHOR]

Ethanol is an important risk factor for the occurrence of several brain disorders that depend on the amount, period and frequency of its consumption. Chronic use of ethanol often leads to the development of neurodegenerative syndromes, which cause morphological and functional impairments such as foetal alcohol syndrome in newborns exposed to ethanol during pregnancy, Wernicke-Korsakoff Syndrome and, more rarely, Marchiafava-Bignami disease (MBD). MBD is characterized by primary degeneration of the corpus callosum, without inflammation and is associated with oxidative stress and hypovitaminosis, as well as altered mental status, to mention dementia, seizures, depression and so on. This review discusses MBD and poor nutrition as a risk factor for the development of such alcoholic syndrome, with focus on diagnosis, pathogenic aspects, signs and symptoms, as well as therapeutic perspectives. On the basis of the inclusion/exclusion criteria adopted, the performed search in scientific databases (Pubmed, Scielo and Google Scholar) resulted in 100 studies that are being presented and discussed in the present work. Review, case-control and cohort studies on alcoholism-associated hypovitaminosis, oxidative stress, MBD and ethanol metabolism pathways were admitted as relevant. We highlight that MBD is a poorly described, diagnosed, insidious and progressive condition, for which evidence suggests a synergism between ethanol-induced neurotoxic effects and hypovitaminosis B. Present treatment consists of vitamin B1(thiamine) supplementation. Nonetheless, other strategies such as the inclusion of antidepressants or steroidal anti-inflammatories as add-on therapies have been employed as an attempt to improve the damage. Indeed, both the diagnosis and treatment are difficult, and death occurs within few years. [ABSTRACT FROM AUTHOR]

This paper reports, for the first time, on the analysis of ethanol (EtOH) and acetaldehyde (AcH) concentrations in the blood and brains of Aldh2-knockout (Aldh2-KO) and C57B6/6J (WT) mice. Animals were administrated EtOH (1.0, 2.0 or 4.0 g/kg) or 4-methylpyrazole (4-MP, 82 mg/kg) plus AcH (50, 100 or 200 mg/kg) intraperitoneally. During the blood tests, samples from the orbital sinus of the eye were collected. During the brain tests, dialysates were collected every 5 min (equal to a 15 µl sample) from the striatum using in vivo brain microdialysis. Samples were collected at 5, 10, 15, 20, 25, 30 and 60 min intervals post-EtOH and -AcH injection, and then analyzed by head-space GC. In the EtOH groups, high AcH levels were found in the blood and brains of Aldh2-KO mice, while only small traces of AcH were seen in the blood and brains of WT mice. No significant differences in EtOH levels were observed between the WT and the Aldh2-KO mice for either the EtOH dose. EtOH concentrations in the brain were comparable to the EtOH concentrations in the blood, but the AcH concentrations in the brain were four to five times lower compared to the AcH concentrations in the blood. In the AcH groups, high AcH levels were found in both WT and Aldh2-KO mice. Levels reached a sharp peak at 5 min and then quickly declined for 60 min. Brain AcH concentrations were almost equal to the concentrations found in the blood, where the AcH concentrations were approximately two times higher in the Aldh2-KO mice than in the WT mice, both in the blood and the brain. Our results suggest that systemic EtOH and AcH administration can cause a greater increase in AcH accumulation in the blood and brains of Aldh2-KO mice, where EtOH concentrations in the Aldh2-KO mice were comparable to the EtOH concentrations in the WT mice. Furthermore, detection of EtOH and AcH in the blood and brain was found to be dose-dependent in both genotypes. [ABSTRACT FROM AUTHOR]

Rationale: Previous experiments in our laboratory have shown that d-penicillamine (DP) (acetaldehyde sequestering agent) is able to block the increase in ethanol consumption observed after a period of imposed deprivation (the so-called alcohol deprivation effect (ADE)), using a non-operant paradigm in Wistar rats. Objectives: This study is aimed at investigating the robustness and reproducibility of our previous data using an operant paradigm, which is considered to be a valid and reliable model of human drug consumption, and the ADE, probably the most often used measure of ethanol relapse-drinking behaviour in rats. Methods: Male Wistar rats with a limited (30-min sessions), intermittent and extended background of ethanol operant self-administration were used. In order to evaluate the efficacy of several DP doses (6.25, 12.5 and 25 mg/kg i.p.) in preventing alcohol relapse, we set up a protocol based on the ADE. In a separate experiment, the effect of DP on spontaneous motor activity of rats was also tested. Results: A significant ADE was observed in animals treated with saline. DP treatment blocked the increase in ethanol responses following the imposed abstinence period. The higher dose suppressed the ADE and provoked a significant reduction in ethanol consumption with respect to the baseline conditions. Basal motor activity was not altered after DP treatment. Conclusion: Our positive results with DP, using two different paradigms that evaluate relapse of ethanol drinking, will help to increase the positive predictive value of pre-clinical experiments and offer a solid base to inspire human studies with DP. [ABSTRACT FROM AUTHOR]

Substance use disorder is an emerging problem concerning to human health, causing severe side effects, including neurotoxicity. The use of illegal drugs and the misuse of prescription or over-the-counter drugs are growing in this century, being one of the major public health problems. Ethanol and cocaine are one of the most frequently used drugs and, according to the National Institute on Drug Abuse, their concurrent consumption is one of the major causes for emergency hospital room visits. These molecules act in the brain through different mechanisms, altering the nervous system function. Researchers have focused the attention not just in the mechanism of action of these drugs, but also in the mechanism by which they damage the nervous tissue (neurotoxicity). Therefore, the goal of the present review is to provide a global perspective about the mechanisms of the neurotoxicity of cocaine and ethanol. [ABSTRACT FROM AUTHOR]

In the present study, we evaluated the in vitro effects of homoarginine (hArg) at 1, 10 and 20 µM on thiobarbituric acid-reactive substances (TBA-RS), total sulfhydryl content and on the activity of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in plasma, erythrocytes, kidney and liver of rats (60 days old). We also investigated the influence of the antioxidants (each at 1 mM) α-tocopherol and ascorbic acid, as well as of the nitric oxide synthase inhibitor N-nitro- l-arginine methyl ester (L-NAME) at 1 mM, on the effects elicited by hArg on the parameters tested. In plasma, hArg at concentrations of 10 and 20 μM decreased moderately the total sulfhydryl content. At 20 µM, hArg enhanced moderately TBA-RS in the plasma. In plasma, the effects of hArg (20 µM) on TBA-RS and total thiol content were abolished by α-tocopherol, ascorbic acid and L-NAME. At all concentrations tested, hArg did not exert any effect on CAT, SOD or GSH-Px activity in the erythrocytes. In the kidney, hArg exerted effects only at 20 µM and in a different manner: TBA-RS levels increased and total thiol content and CAT activity decreased, while SOD and GSH-Px activity increased. In the renal medulla, α-tocopherol and ascorbic acid but not L-NAME abolished the effects of hArg (20 µM) on TBA-RS, while all agents inhibited the hArg-induced increase in SOD activity. In the renal cortex, α-tocopherol, ascorbic acid and L-NAME abolished the effects of hArg (20 µM) on the total sulfhydryl content and GSH-Px activity, but L-NAME did not reverse the inhibitory effects of hArg on CAT activity. In the liver, no effects of hArg were observed of all biomarkers measured. At the pathologically high concentration of 20 µM, as it may occur in plasma in hyperargininemia, hArg may enhance lipid peroxidation and thiol oxidation and inhibit CAT activity, but may increase SOD and GSH-Px activity predominantly in the kidney. [ABSTRACT FROM AUTHOR]

Rationale: The practice of binge drinking is very common among adolescents of both sexes. It can have long-term consequences with respect to drug consumption during adulthood, but knowledge on these effects in females is limited. Objectives: The long-lasting effects of intermittent exposure to ethanol (EtOH) during adolescence on different cocaine-elicited behaviours, including locomotor reactivity, conditioned place preference (CPP) and intravenous self-administration, were evaluated in male and female adult mice. It was hypothesized that an EtOH binge during adolescence would increase sensitivity to the effects of a sub-threshold dose of cocaine and has a differential impact on the drug's effects in males and females. Methods: Adolescent OF1 mice (postnatal day (PND) 26) underwent a 2-week pre-treatment schedule consisting of 16 doses of EtOH (2.5 g/kg) or saline (twice daily administrations separated by a 4-h interval i.p.) administered on two consecutive days separated by an interval of 2 days. Three weeks later (PND > 60), we assessed locomotor activity responses induced by an acute injection of different doses of cocaine in experiment 1 and the rewarding effects of cocaine on the CPP (1 mg/kg) and intravenous self-administration (1 mg/kg/infusion) paradigms in experiment 2. Results: Pre-exposure to EtOH during adolescence altered motor reactivity to cocaine in a dose- and sex-dependent manner, increased sensitivity to cocaine in CPP and enhanced self-administration in adult mice. Conclusions: The effects of intermittent exposure to ethanol during adolescence are evident in adulthood, during which greater sensitivity and intake of cocaine is observed and differ in each sex. [ABSTRACT FROM AUTHOR]

Rationale: The cAMP-dependent protein kinase A (PKA) signaling transduction pathway has been shown to play an important role in the modulation of several ethanol-induced behaviors. Different studies have demonstrated intracellular calcium (Ca)-dependent activation of the PKA cascade after ethanol administration. Thus, the cAMP cascade mediator Ca-dependent calmodulin (CaM) has been strongly implicated in the central effects of ethanol. Objectives: In this study, we assessed the role of the CaM inhibitor W7 on ethanol-induced stimulation, ethanol intake, and ethanol-induced activation of PKA. Methods: Swiss mice were pretreated with W7 (0-10 mg/kg) 30 min before ethanol (0-3.75 g/kg) administration. Immediately, animals were placed during 20 min in an open-field chamber. Ethanol (10 %, v/ v) intake in 2 h was assessed using a limited access paradigm. Experiments with caffeine (0-15 mg/kg), cocaine (0-4 mg/kg), and saccharine (0.1 %, w/ v) were designed to compare their results to those obtained with ethanol. Western blot was assayed 45 min after ethanol administration. Results: Results showed that pretreatment with W7, reduced selectively in a dose-dependent fashion ethanol-induced locomotor stimulation and ethanol intake. The ethanol-induced activation of PKA was also prevented by W7 administration. Conclusions: These results demonstrate that CaM inhibition resulted in a selective reduction of ethanol-stimulating effects and ethanol intake. The PKA activation induced by ethanol was blocked after the CaM blockade with W7. These results provide further evidence of the key role of cellular Ca-dependent pathways on the central effects of ethanol. [ABSTRACT FROM AUTHOR]

Rationale: We have shown previously, using an animal model of voluntary ethanol intake and ethanol-conditioned place preference (EtOH-CPP), that exposure to chronic psychosocial stress induces increased ethanol intake and EtOH-CPP acquisition in mice. Objective: Here, we examined the impact of chronic subordinate colony (CSC) exposure on EtOH-CPP extinction, as well as ethanol-induced reinstatement of CPP. Methods: Mice were conditioned with saline or 1.5 g/kg ethanol and were tested in the EtOH-CPP model. In the first experiment, the mice were subjected to 19 days of chronic stress, and EtOH-CPP extinction was assessed during seven daily trials without ethanol injection. In the second experiment and after the EtOH-CPP test, the mice were subjected to 7 days of extinction trials before the 19 days of chronic stress. Drug-induced EtOH-CPP reinstatement was induced by a priming injection of 0.5 g/kg ethanol. Results: Compared to the single-housed colony mice, CSC mice exhibited increased anxiety-like behavior in the elevated plus maze (EPM) and the open field tests. Interestingly, the CSC mice showed delayed EtOH-CPP extinction. More importantly, CSC mice showed increased alcohol-induced reinstatement of the EtOH-CPP behavior. Conclusion: Taken together, this study indicates that chronic psychosocial stress can have long-term effects on EtOH-CPP extinction as well as drug-induced reinstatement behavior and may provide a suitable model to study the latent effects of chronic psychosocial stress on extinction and relapse to drug abuse. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the neuroprotective effects of nerolidol in mice hippocampus against oxidative stress in neuronal cells compared to ascorbic acid (positive control) as well as evaluated the nerolidol sedative effects by open field test compared to diazepam (positive control). Thirty minutes prior to behavioral observation on open field test, mice were intraperitoneally treated with vehicle, nerolidol (25, 50 and 75 mg/kg), diazepam (1 mg/kg) or ascorbic acid (250 mg/kg). To clarify the action mechanism of of nerolidol on oxidative stress in animals subjected to the open field test, Western blot analysis of Mn-superoxide dismutase and catalase in mice hippocampus were performed. In nerolidol group, there was a significant decrease in lipid peroxidation and nitrite levels when compared to negative control (vehicle). However, a significant increase was observed in superoxide dismutase and catalase activities in this group when compared to the other groups. Vehicle, diazepam, ascorbic acid and nerolidol groups did not affected Mn-superoxide dismutase, catalase mRNA or protein levels. Our findings strongly support the hypothesis that oxidative stress occurs in hippocampus. Nerolidol showed sedative effects in animals subjected to the open field test. Oxidative process plays a crucial role on neuronal pathological consequence, and implies that antioxidant effects could be achieved using this sesquiterpene. [ABSTRACT FROM AUTHOR]

Rationale: Nowadays, very few approved anti-relapse treatments for alcoholism exist, and their overall efficacy can be considered moderate. An exciting rationale drug development opportunity for the treatment of chronic alcoholism is the use of acetaldehyde sequestering agents. Although these compounds are able to attenuate or prevent most of the behavioral and neurochemical effects of ethanol, the efficacy of acetaldehyde sequestration, by using agents such as d-penicillamine (DP), in relapse prevention has not been studied yet. Objectives: The aim of this study was to analyze the effects of DP treatment on the alcohol deprivation effect (ADE) in long-term ethanol-experienced rats as a model of relapse behavior and measure drug plasma and brain levels during treatment. Methods: Rats were subcutaneously implanted with mini-osmotic pumps delivering 0, 0.25, or 1 mg/h of DP during 1 week. The efficacy to prevent ADE was determined. DP plasma and brain levels achieved during its subcutaneous administration were measured. In a second experiment, animals received bilateral infusions of 0 or 1.5 μg/h of DP directly into pVTA, and the appearance of ADE was evaluated. Results: One milligram per hour, but not 0.25 mg/h, DP infusion prevented ADE and reduced the total ethanol preference in animals. DP plasma concentrations associated with ADE suppression were around 3-4 μg/ml, and brain DP levels in these conditions were about 2-3 % of those found in plasma. Intra-pVTA DP administration also suppressed ADE. Conclusion: DP is able to prevent alcohol-relapse-like drinking in rats suggesting that this drug may be a useful new tool in the management of relapse in alcohol-dependent patients. [ABSTRACT FROM AUTHOR]

The brain being highly sensitive to the action of alcohol is potentially susceptible to its carcinogenic effects. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the main enzymes involved in ethanol metabolism, which leads to the generation of carcinogenic acetaldehyde. Human brain tissue contains various ADH isoenzymes and possess also ALDH activity. The purpose of this study was to compare the capacity for ethanol metabolism measured by ADH isoenzymes and ALDH activity in cancer tissues and healthy brain cells. The samples were taken from 62 brain cancer patients (36 glioblastoma, 26 meningioma). For the measurement of the activity of class I and II ADH isoenzymes and ALDH activity, the fluorometric methods were used. The total ADH activity and activity of class III and IV isoenzymes were measured by the photometric method. The total activity of ADH, and activity of class I ADH were significantly higher in cancer cells than in healthy tissues. The other tested classes of ADH and ALDH did not show statistically significant differences of activity in cancer and in normal cells. Analysis of the enzymes activity did not show significant differences depending on the location of the tumor. The differences in the activity of total alcohol dehydrogenase, and class I isoenzyme between cancer tissues and healthy brain cells might be a factor for metabolic changes and disturbances in low mature cancer cells and additionally might be a reason for higher level of acetaldehyde which can intensify the carcinogenesis. [ABSTRACT FROM AUTHOR]

Rationale: Hydrogen peroxide (HO) is the co-substrate used by catalase to metabolize ethanol to acetaldehyde in the brain. This centrally formed acetaldehyde has been involved in several ethanol-related behaviors. Objectives: The present research evaluated the effect of the HO scavenger, alpha lipoic acid (LA), on the acquisition and reconditioning of ethanol-induced conditioned place preference (CPP). Methods: Mice received pairings of a distinctive floor stimulus (CS+) associated with intraperitoneal injections of ethanol (2.5 g/kg). On alternate days, animals received pairings of a different floor stimulus (CS−) associated with saline injections. A different group of animals received pairings with the (CS−) associated with saline injections, and on alternate days they received LA (100 mg/kg) injected 30 min prior to ethanol (2.5 g/kg) administration paired with the (CS+). A preference test assessed the effect of LA on the acquisition of ethanol-induced CPP. A similar procedure was followed to study the effect of LA on the acquisition of cocaine- and morphine-induced CPP. A separate experiment evaluated the effect of LA on the reconditioning of ethanol-induced CPP. In addition, we investigated the consequence of LA administration on central HO levels. Results: LA selectively blocked the acquisition of ethanol-induced CPP. Moreover, this compound impaired the reconditioning of ethanol-induced CPP. Additionally, we found that LA diminished HO levels in the brain. Conclusions: These data suggest that a decline in HO availability by LA might impede the formation of brain ethanol-derived acetaldehyde by catalase, which results in an impairment of the rewarding properties of ethanol. [ABSTRACT FROM AUTHOR]

Repetitive binge intoxication with ethanol (alcohol) in adult rats, mimicking chronic ethanol abuse in alcoholics, causes trauma-like brain edema and relatively selective neurodegeneration of hippocampal dentate granule cells and pyramidal neurons in the temporal cortex (especially entorhinal cortex). We have now modeled the aspects of this type of acquired brain damage in vitro with rat entorhino-hippocampal slice cultures of adult brain age (62 ± 3 days). When sequentially treated (four 16-h overnight exposures) with 100 mM ethanol, the slices display elevated levels of aquaporin-4 (AQP4) water channels accompanied by significant neurodegeneration. Increased AQP4 has been associated with neuroinflammatory responses including edema, pro-inflammatory cytokine elevations, arachidonic acid release, and oxidative stress. Co-treatment of ethanol-binged slice cultures with docosahexaenoic acid (DHA), an omega-3 fatty acid known to suppress brain damage from other insults, prevents both the AQP4 elevations and the neurodamage. Surmising that AQP4 augmentation is a causative neuroinflammatory component in this model, we are investigating several possibilities to explain the protective actions of the omega-3 fatty acid. Since the worldwide incidence of cognitive dysfunction and dementia from ethanol abuse and alcoholism is not inconsequential, DHA supplementation with chronic alcoholics could emerge to be a rational approach to potentially lessening brain disabilities. [ABSTRACT FROM AUTHOR]

Chronic binge alcohol exposure in adult rat models causes neuronal degeneration in the cortex and hippocampus that is not reduced by excitotoxic receptor antagonists, but is prevented by antioxidants. Neuroinflammatory (glial-neuronal) signaling pathways are believed to underlie the oxidative stress and brain damage. Based on our experimental results as well as increased knowledge about the pro-neuroinflammatory potential of glial water channels, we propose that induction of aquaporin-4 can be a critical initiating factor in alcohol's neurotoxic effects, through the instigation of cellular edema-based neuroinflammatory cascades involving increased phospholipase A2 activities, polyunsaturated fatty acid release/membrane depletion, decreased prosurvival signaling, and oxidative stress. A testable scheme for this pathway is presented that incorporates recent findings in the alcohol-brain literature indicating a role for neuroimmune activation (upregulation of NF-kappaB, proinflammatory cytokines, and toll-like receptors). We present the argument that such neuroimmune activation could be associated with or even dependent on increased aquaporin-4 and glial swelling as well. [ABSTRACT FROM AUTHOR]

The neuroactive steroid hormone progesterone attenuates cocaine's abuse-related effects in women and in rodents under some conditions, but the effects of testosterone are unknown. We compared the acute effects of progesterone (0.1, 0.2, and 0.3 mg/kg, intramuscularly (i.m.)), testosterone (0.001, 0.003, and 0.01 mg/kg, i.m.), and placebo on cocaine self-administration and cocaine discrimination dose-effect curves in female rhesus monkeys. Cocaine self-administration (0.03 mg/kg per inj.) was maintained on a fixed ratio 30 schedule of reinforcement, and monkeys had unlimited access to cocaine for 2 h each day. Cocaine doses were administered in an irregular order during each dose-effect curve determination, and the same dose order was used in each subject in all treatment conditions. Blood samples for hormone analysis were collected at the end of each test session. Banana-flavored food pellets (1 g) were also available in three 1-h daily sessions. In drug discrimination studies, the effects of pretreatment with progesterone (0.032-0.32 mg/kg, i.m.) and testosterone (0.001-0.01 mg/kg, i.m.) on the discriminative stimulus effects of cocaine (0.18 mg/kg, i.m.) were examined. Progesterone and testosterone did not alter cocaine discrimination, and did not substitute for cocaine. In contrast, progesterone and testosterone each significantly decreased cocaine self-administration, and produced a downward and rightward shift in the cocaine self-administration dose-effect curve. These findings are concordant with clinical reports that progesterone administration may decrease ratings of positive subjective effects of cocaine in women, and suggest the possible value of neuroactive steroid hormones for the treatment of cocaine abuse and reduction of risk for relapse. [ABSTRACT FROM AUTHOR]

A few clinical studies have shown that dual antidepressants (serotonergic (5-HT) and noradrenergic (NE) transporter inhibitors, SNRIs) may be effective in alcoholism treatment. We studied the effect of the dual antidepressant milnacipran on ethanol operant self-administration in acutely withdrawn ethanol-dependent and in -non-dependent Wistar rats, and used fluoxetine and desipramine to dissect both 5-HT and NE components, respectively, in the effect of milnacipran. Milnacipran was also tested for relapse after protracted abstinence and on ethanol-induced (1.0 g/kg) conditioned place preference in control rats and ethanol-induced locomotor sensitization in DBA/2J female mice. Milnacipran dose dependently (5-40 mg/kg) attenuated the increased ethanol self-administration observed during early withdrawal and was more potent in preventing reinstatement in dependent rats after protracted abstinence as compared with non-dependent rats. Desipramine and fluoxetine (10 mg/kg) blocked ethanol self-administration during early withdrawal, and recovery was delayed in dependent animals, indicating a potent effect. Ethanol self-administration was also reduced 1 day after treatment with desipramine and fluoxetine but not with milnacipran. Finally, milnacipran prevented ethanol-induced place preference in ethanol-naive rats and reduced the magnitude of ethanol-induced sensitization associated with a delayed induction in mice. Desipramine (20 mg/kg) countered sensitization development and reduced its expression at 1 week after treatment; fluoxetine (10 mg/kg) reduced sensitization expression. Thus, 5-HT and NE transmissions during sensitization expression may mediate the effect of milnacipran on sensitization induction. These results support that SNRIs may have a potential use in alcoholism treatment. [ABSTRACT FROM AUTHOR]

Microinjections of ethanol and acetaldehyde into ventral tegmental area (VTA) produce locomotor activation in rats through mechanisms dependent on the μ-opioid receptors. However, it is not clear how these drugs can interact with these receptors. It has been hypothesized that salsolinol could be the responsible for this interaction. The aim of the study was to investigate the ability of salsolinol to induce both motor activation and motor sensitization in rats after repeated intra-VTA administration. Rats received one microinjection into the posterior VTA of artificial cerebrospinal fluid (aCSF; 200 nL), salsolinol (0.3–3,000.0 pmol/200 nL), or salsolinol (30.0 pmol/200 nL) with either naltrexone (13.2 nmol/200 nL) or with the antagonist of the μ-opioid receptors, β-funaltrexamine (β-FNA; 2.5 nmol/300 nL). In the sensitization experiments, four microinjections of salsolinol (30.0 pmol/200 nL) or aCSF (200 nL) were performed over a 2-week period. This period was followed by a single challenge session, in which 0.3 pmol of salsolinol was microinjected to rats. Spontaneous activity was always monitored postinjection. Intra-VTA salsolinol administration induces an increase of the spontaneous motor activity of the rats with the maximal effect at the dose of 30.0 pmol/200 nL. Salsolinol effects were blocked by the treatment with naltrexone or β-FNA. Moreover, repeated injections of salsolinol produced locomotor sensitization. Salsolinol induces locomotor activity and motor sensitization after intra-VTA administration. Moreover, the implication of the μ-opioid receptors was shown since the treatment with naltrexone or β-FNA was able to suppress the salsolinol effects. [ABSTRACT FROM AUTHOR]

It is well-known that amphetamine induces increased locomotor activity in rodents. We previously found that intracerebroventricular (i.c.v.) administration of p-hydroxyamphetamine ( p-OHA), an amphetamine metabolite, increases synaptic dopamine (DA) levels in the striatum. In the present study, we investigated the effect of p-OHA on locomotor activity in rodents. In mice, i.c.v. administration of p-OHA significantly increased locomotor activity in a dose-dependent manner. p-Hydroxynorephedrine, another amphetamine metabolite, did not increase locomotor activity. This effect of p-OHA was inhibited by pretreatment with nomifensine, a dopamine-uptake inhibitor, but not by fluoxetine, a serotonin-uptake inhibitor, or diethyldithiocarbamate, a dopamine-β-hydroxylase inhibitor. Furthermore, we tested the effects of microinjections of p-OHA into the rat nucleus accumbens (NAc) on locomotor activity. Local infusion of p-OHA into the NAc significantly increased locomotor activity. As in mice, the increased locomotor activity induced by p-OHA microinjection into the NAc in rats was inhibited by nomifensine. These data suggest that dopaminergic systems in the NAc may play important roles in p-OHA-induced locomotor activity in rodents. [ABSTRACT FROM AUTHOR]

Previous findings have shown that intra-accumbens injection of naltrexone, a non-selective opioid antagonist, blocks the acquisition of rapid tolerance to ethanol in rats. This study investigates the effects of intra-accumbens injection of the selective mu-, delta-, and kappa-opioid antagonists, respectively, naloxonazine, naltrindole, and nor-binaltorphimine, on rapid tolerance to ethanol. Male Wistar rats with guide cannulae directed to the shell or the core portions of the nucleus accumbens received a microinjection of naloxonazine (2–4 μg), naltrindole (2–4 μg), nor-binaltorphimine (2.5–5 μg), or vehicle. After 5 min, each group was divided in two groups that received ethanol (2.7 g/kg i.p.) or saline. Rats were then tested for motor coordination on the tilting plane apparatus. Twenty four hours later, all rats received a challenge dose of ethanol (2.7 g/kg i.p.) and were tested on the tilt plane again. Repeated injections of ethanol caused a reduction in motor impairment suggesting the development of tolerance. However, rats injected with 4 μg naloxonazine into either core or shell portions of the nucleus accumbens did not exhibit tolerance when challenged with ethanol on day 2. Rats treated with 5 μg nor-binaltorphimine into accumbens core plus intraperitoneal saline on day 1 showed reduced motor impairment when challenged with ethanol on day 2, suggesting cross-tolerance to ethanol. Taken together, our results suggests that mu-opioid receptors in both shell and core portions of the nucleus accumbens, and possibly kappa-opioid in the core, participate in the modulation of rapid tolerance to ethanol. [ABSTRACT FROM AUTHOR]

Brain serotonin (5-HT) modulates the neural effects of ethanol. In the present study, we investigated the changes in 5-HT level, 5-HT2A receptor binding and aldehyde dehydrogenase (ALDH) activity in brain stem and liver of ethanol treated rats and 5-HT2A regulation on ALDH in hepatocyte cultures in vitro. The 5-HT content in the brain stem and liver significantly decreased with an increased 5-HIAA/5-HT ratio in the ethanol treated rats compared to control. Scatchard analysis of [3H] (±)2,3-dimethoxyphenyl-1-[2-(-4-piperidine)-methanol] [3H] MDL 100907 against ketanserin in brain stem of ethanol treated rats showed a significant increase in Bmax without any change in Kd compared to control. The competition curve for [3H] MDL 100907 against ketanserin fitted one-site model in both control and ethanol treated rats with unity as Hill slope value. A significant increase in Vmax of ALDH activity in liver and a significant decrease in Km in liver and brain stem of ethanol treated rats compared to control was observed. In 24 h culture studies, an increase in enzyme activity was observed in cells in medium with 10% ethanol. The elevated ALDH activity in ethanol treated cells was reversed to control level in presence of 10−5 and 10−7 M 5-HT. Ketanserin, an antagonist of 5-HT2A, reversed the effect of 5HT on 10% ethanol induced ALDH activity in hepatocytes. Our results showed that there was a decreased 5-HT content with an enhanced 5-HT2A receptor and aldehyde dehydrogenase activity in the brain stem of alcohol treated rats and in vitro hepatocyte cultures. The enhanced ALDH activity in ethanol supplemented hepatocytes was reversed to control level in presence of 10−5 and 10−7 M 5-HT. [ABSTRACT FROM AUTHOR]

A recently published study has shown that microinjections of ethanol, or its metabolite, acetaldehyde into the substantia nigra pars reticulata, are able to produce behavioral activation in rats. Another brain site that could participate in such effects is the ventral tegmental area (VTA). We have investigated the locomotor-activating effects of local microinjections of ethanol and acetaldehyde into the posterior VTA of rats and the role of opioid receptors in such effects. Cannulae were placed into the posterior VTA to perform microinjections of ethanol (75 or 150 nmol) or acetaldehyde (25 or 250 nmol) in animals not previously microinjected or microinjected with either the nonselective opioid antagonist naltrexone (13.2 nmol) or the irreversible antagonist of the µ-opioid receptors β-funaltrexamine (β-FNA; 2.5 nmol). After injections, spontaneous activity was monitored for 60 min. Injections of ethanol or acetaldehyde into the VTA increased the locomotor activity of rats with maximal effects at doses of 150 nmol for ethanol and 250 nmol for acetaldehyde. These locomotor-activating effects were reduced by previously administering naltrexone (13.2 nmol) or β-FNA (2.5 nmol) into the VTA. The posterior VTA is another brain region involved in the locomotor activation after the intracerebroventricular administration of ethanol or acetaldehyde. Our data indicate that opioid receptors, particularly the µ-opioid receptors, could be the target of the actions of these compounds in the VTA. These results are consistent with the hypothesis that acetaldehyde could be a mediator of some ethanol effects. [ABSTRACT FROM AUTHOR]

A frequently expressed criticism of the conditioned place preference (CPP) procedure is that it sometimes lacks a graded dose–response curve for many drugs. We used a combination of standard and reference-dose CPP procedures to examine the dose–response curve for ethanol-induced CPP in DBA/2J mice. In the standard procedure, ethanol (0.5, 1.5, 2, and 4 g/kg) was paired with a distinctive floor cue, whereas saline was paired with a different floor cue. In the reference-dose procedure, each cue was paired with a different dose of ethanol. All mice received four 5-min trials of each type in both procedures. Standard procedures yielded similar levels of CPP at doses of 1.5, 2, and 4 g/kg, whereas 0.5 g/kg did not produce significant CPP. However, in the reference-dose procedure, exposure to the 0.5-g/kg dose interfered with CPP normally produced by 1.5 or 2 g/kg. Moreover, mice showed significant preference for the 4-g/kg-paired cue over the 1.5-g/kg-paired cue. These studies show that a reference-dose procedure can reveal effects of low doses that are sometimes difficult to detect in a standard procedure. The reference-dose procedure may also uncover differences between higher doses that normally produce similar preference. Efficacy of the reference-dose procedure may be explained by a theoretical analysis that assumes the procedure places behavior between the extremes of the performance range, offering a more sensitive method for detecting effects of manipulations that produce small changes and/or differences in the rewarding effects of ethanol. [ABSTRACT FROM AUTHOR]

The mammalian adolescent period is characterized by enhanced vulnerability to drug-induced neuroadaptations. Epidemiological evidence indicates that individuals who start drinking alcohol during adolescence are four times more likely to develop alcohol dependence in adulthood, but little is known about the adaptive mechanism(s) that may underlie this observation. Behavioral sensitization in rodents is a model of neurobehavioral plasticity that occurs following repeated drug exposure and may underlie components of addiction. The goal of this study was to determine if adolescent mice are differentially sensitive to ethanol-induced locomotor sensitization as compared to adults. Adolescent and adult DBA/2J mice were treated with saline or ethanol (1.0, 1.5, 2.0, 2.5 g/kg) for 7, 11, or 15 days and tested for acute and sensitized locomotor activity. Blood ethanol clearance (BEC) was also assessed 10, 60, and 180 min following treatment with ethanol 2 g/kg. Adolescent mice were more sensitive than adult mice to the acute locomotor activating effects of ethanol. However, adolescent mice were less sensitive than adult mice to locomotor sensitization, as only the highest dose of ethanol (2.5 g/kg) induced sensitization in the adolescent mice, while lower doses of ethanol elicited sensitization in the adult mice. The differential response to ethanol sensitization was not related to duration of treatment or differential BEC . These results indicate that adolescent mice are less sensitive to ethanol sensitization, and this blunted behavioral response in adolescents might reflect differential ethanol-induced neurobehavioral adaptations. [ABSTRACT FROM AUTHOR]

Abstract  Ethanol exerts numerous pharmacological effects through its interaction with various neurotransmitters. The dopaminergic pathway is associated with cognitive, endocrine, and motor functions, and reinforcement of addictive substances or behaviours. Aldehyde dehydrogenase (ALDH) is a vital enzyme involved with alcohol metabolism and detoxification. In the present study, we investigated the role of cerebral cortex and brain stem dopamine D2 receptors in the functional regulation on ALDH enzyme activity, in ethanol administrated rats. Two groups of rats were selected viz. control and alcoholic. Cerebral cortex, brain stem and the liver dopamine content was decreased significantly (P P 0.05, 0.001 and 0.001), respectively in ethanol treated rats when compared to control. Scatchard analysis of [3H]YM-09151-2 binding to synaptic membrane preparations of cerebral cortex and brain stem showed a significant decrease (P 0.001, 0.05, respectively) in B max in ethanol treated rats compared to control and the K d also decreased significantly (P 0.05). The ALDH analysis showed a significant increase (P 0.05) in V max in cerebral cortex, plasma and liver of experimental rats when compared with control without having significant change in brain stem but with decreased K m (P 0.001). Our results suggest that decreased function of dopamine mediated through DA D2 receptor in the cerebral cortex and brain stem enhanced the brain, plasma and liver ALDH activity in ethanol treated rats. This ALDH regulation has significance to correct alcoholics from addiction due to allergic reaction observed in aldehyde accumulation. [ABSTRACT FROM AUTHOR]

We investigated the association of the OPRM1 genotype with long-term smoking cessation and change in body mass index (BMI) following a smoking cessation attempt among smokers who attempted to quit using the nicotine replacement therapy (NRT) patch or placebo in a randomized controlled trial, and were followed-up over an 8-year period following their initial cessation attempt. We also investigated possible sex differences in these relationships, given evidence for sex differences in smoking cessation and central opioid mechanisms, as well as some evidence for sex differences in response to NRT. Our results indicate that OPRM1 genotype may moderate the effect of transdermal nicotine patch compared to placebo during active treatment, with a benefit of active NRT treatment evident in the OPRM1 AA genotype group only and those carrying one or more copies of the G allele demonstrating no benefit of active NRT versus placebo patch. Our results also indicate a sex difference in change in BMI at 8-year follow-up following a smoking cessation attempt, with ex-smokers demonstrating an increase in BMI, and this increase being greater in female subjects than in male subjects. We did not observe any association of OPRM1 genotype with change in BMI, although there was a trend for genotype to influence the observed sex difference in change in BMI over time. Future studies should attempt to replicate these findings, and investigate the relationship between both short- and long-term weight gain and smoking cessation and investigate possible mechanisms that may underlie these processes. Future studies should also investigate the role of OPRM1 genotype and smoking cessation on other appetitive and reward behaviours such as alcohol consumption.The Pharmacogenomics Journal (2007) 7, 353–361; doi:10.1038/sj.tpj.6500432; published online 16 January 2007 [ABSTRACT FROM AUTHOR]

Catalepsy is a preclinical test that predicts extrapyramidal symptoms in humans. It models symptoms of acute extrapyramidal side effects induced at the beginning of antipsychotic treatment. Nitric oxide (NO) plays a role in a series of neurobiological functions underlying behavior. For example, inhibition of NO synthesis disrupts rodent exploratory behavior and induces catalepsy. Although several effects mediated by NO involve the activation of soluble guanylyl cyclase (sGC), the transduction mechanism of the catalepsy-inducing effect of NO has not yet been investigated. The study was designed to test if intracerebroventricular (i.c.v.) microinjection of NO-sensitive inhibitors of sGC (NO-sGC) induces catalepsy in mice similar to that induced by NO synthase (NOS) inhibitors. Exploratory behavior was tested in the open field. In addition, the effects of a NOS inhibitor on oxidative metabolites of NO were measured in the striatum. Drug effects were examined in the hanging-bar test after the following i.c.v. treatments: oxadiazolo-quinoxalin (ODQ, 30–300 nmol) or methylene blue (MB, 3–100 nmol), selective and nonselective sGC inhibitors, respectively, or 7-nitroindazole (7-NI, 3–90 nmol) and G-nitro- l-arginine methyl ester ( l-NAME, 3–90 nmol), selective and nonselective neuronal NOS inhibitors. To test if the effects were related to interference with the NO system, additional groups received 7-NI (30 nmol), ODQ (100 nmol), or L-NAME (90 nmol) preceded by l-arginine ( l-arg, 30–100 nmol, i.c.v. 30 min before). A possible interference of ODQ and 7-NI on exploratory behavior was tested in an open field. The concentration of nitrites and nitrates (NO x ) in striatum homogenates was measured by the Griess reaction. Both NO-sGC and NOS inhibitors induced catalepsy in mice that lasted for at least 2 h. The range of effective doses of these drugs, however, was limited, and the dose–effect curves had an inverted U shape. The cataleptic effect induced by l-NAME was inversely correlated with NO x products in the striatum. The cataleptic effect of 7-NI and ODQ was prevented by pretreatment with l-arginine. No drug changed exploratory behavior in the open field. This study showed that pharmacological disruption of the endogenous NO-sGC signaling in the central nervous system induces long-lasting catalepsy in mice. Moreover, the cataleptic effect of NOS inhibition correlates with the decrease in NO x products formation in the striatum. The results give further support to the hypothesis that NO plays a role in motor behavior control mediated, at least in part, by cyclic guanosine monophosphate production in the striatum. [ABSTRACT FROM AUTHOR]

Individual variation in drug metabolism is a major cause of unpredictable side effects during therapy. Drug metabolism is controlled by a class of orphan nuclear receptors (NRs), which regulate expression of genes such as CYP (cytochrome)3A4 and MDR-1 (multi-drug resistance-1), that are involved in this process. We have found that xenobiotic-mediated induction of CYP3A4 and MDR-1 gene transcription was inhibited by ketoconazole, a commonly used antifungal drug. Ketoconazole mediated its effect by inhibiting the activation of NRs, human pregnenolone X receptor and constitutive androstene receptor, involved in regulation of CYP3A4 and MDR-1. The effect of ketoconazole was specific to the group of NRs that control xenobiotic metabolism. Ketoconazole disrupted the interaction of the xenobiotic receptor PXR with the co-activator steroid receptor co-activator-1. Ketoconazole treatment resulted in delayed metabolism of tribromoethanol anesthetic in mice, which was correlated to the inhibition of PXR activation and downmodulation of cyp3a11 and mdr-1 genes and proteins. These studies demonstrate for the first time that ketoconazole represses the coordinated activation of genes involved in drug metabolism, by blocking activation of a specific subset of NRs. Our results suggest that ketoconazole can be used as a pan-antagonist of NRs involved in xenobiotic metabolism in vivo, which may lead to novel strategies that improve drug effect and tolerance.Oncogene (2007) 26, 258–268. doi:10.1038/sj.onc.1209788; published online 3 July 2006 [ABSTRACT FROM AUTHOR]

Ecstasy abuse commonly occurs in hot, overcrowded environments in combination with alcohol. Around 90% of ecstasy users take ethanol; over 70% of these users also often drink alcohol at hazardous levels. We wished to examine whether binge ethanol administration enhanced the long-lasting 5-HT neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats maintained at high ambient temperature and the role of acetaldehyde. Rats were treated with a 4-day ethanol regimen leading to plasma ethanol levels of around 450 mg/dl. On day 5, rats were placed at 30°C and administered MDMA (5 mg/kg). Rectal temperature and hydroxyl radical formation were measured immediately before and up to 6 h after MDMA. 5-HT concentration and 5-HT transporter density were determined 7 days later. A group of rats received cyanamide (50 mg/kg) on days 1 and 3 of the 4-day-ethanol inhalation. In ethanol treated rats, MDMA produced a hyperthermic response similar to that observed in controls but enhanced the loss of 5-HT concentration and 5-HT transporter density in the hippocampus. Cyanamide elevated the plasma acetaldehyde concentration fivefold to sevenfold, reduced the MDMA-induced hyperthermia and increased the neuronal damage with neurotoxicity also appearing in the cortex. MDMA increased hydroxyl radical production in the hippocampus, the effect being more marked in rats pre-exposed to ethanol. Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity by a mechanism not related to changes in acute hyperthermia but probably involving hydroxyl radical formation. The magnitude of this effect is more pronounced after increasing plasma acetaldehyde levels by aldehyde dehydrogenase inhibition. [ABSTRACT FROM AUTHOR]