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We aim to study the effect of neurodegeneration on the brain of rat pups caused by prenatal and postnatal ethanol exposure with modified liquid diet to elucidate protective effects of betaine and omega-3 supplementation. When ethanol is consumed during prenatal and postnatal periods, it may result in fetal alcohol syndrome (FAS) in the offspring.Rats were divided into control, ethanol, ethanol + betaine, ethanol + omega-3, ethanol + omega-3 + betaine groups. The effect of betaine and omega-3 in response to ethanol-induced changes on the brain, by biochemical analyses cytochrome c, caspase-3, calpain, cathepsin B and L, DNA fragmentation, histological and morfometric methods were evaluated.Caspase-3, calpain, cathepsin B, and cytochrome c levels in ethanol group were significantly higher than control. Caspase-3, calpain levels were decreased in ethanol + betaine, ethanol + omega-3, and ethanol + omega-3 + betaine groups compared to ethanol group. Cathepsin B in ethanol + omega-3 + betaine group was decreased compared to ethanol, ethanol + betaine groups. Cathepsin L and DNA fragmentation were found not statistically significant. We found similar results in histological and morfometric parameters.We found that pre- and postnatal ethanol exposure is capable of triggering necrotic cell death in rat brains, omega-3, and betaine reduce neurodegeneration. Omega-3 and betaine may prove beneficial for neurodegeneration, particularly in preventing FAS.

Alcoholism is associated with a higher incidence of smoking. In addition to the stimulatory effects of both ethanol and nicotine on the mesolimbic reward pathway, nicotine's ability to counteract some of the adverse effects of ethanol (e.g. ataxia) may be a powerful incentive for alcohol consumers to increase their tobacco (nicotine) intake. The cerebellum is believed to play an important role in ethanol-induced ataxia. In this study, we sought to test the hypothesis that nicotine would protect against toxic effects of ethanol in primary cultures of cerebellar granule cells. Moreover, it was postulated that the effects of nicotine would be mediated through nicotinic receptors. Primary cultures of cerebellar granule cells were prepared from 20-day embryos obtained from timed-pregnant Sprague Dawley rats. Cells were cultured for 10 days and were then exposed for 3 days to various concentrations of ethanol with and without pretreatment with nicotine and nicotinic antagonists. Cellular toxicity was evaluated by measuring the lactate dehydrogenase level. Administration of ethanol (10-100 mM) resulted in a dose-dependent toxicity. Pretreatment with nicotine 1-20 micro M resulted in a dose-dependent protection against ethanol-induced toxicity. The effects of nicotine were blocked by pretreatment with nicotinic antagonists such as mecamylamine 1-20 micro M, dihydro-beta-erythroidine 1.0 nM-1.0 micro M and methyllycaconitine 5 nM-5 micro M in a dose-dependent manner. Thus, ethanol-induced cytotoxicity in primary cultures of cerebellar granule cells is blocked by pretreatment with nicotine. The effects of nicotine, in turn, may be blocked by nicotinic antagonists, implicating both high and low affinity nicotinic receptors in mediating the actions of nicotine. The exact mechanism of ethanol-induced toxicity and/or neuroprotection through activation of nicotinic receptors in this paradigm remains to be elucidated. The neuroprotective effect of nicotine against ethanol-induced toxicity in cerebellar neurons may be a contributing factor to the high incidence of smoking among alcoholics.

Melanoma is defined as a disease that has been incurable in advanced stages, which shows the vital importance of timely diagnosis and treatment. To diagnose this type of cancer early, various methods and equipment have been used, almost all of which required a visit to the doctor and were not available to the public. In this study, an automated and accurate process to differentiate between benign skin pigmented lesions and malignant melanoma is presented, so that it can be used by the general public, and it does not require special equipment and special conditions in imaging. In this study, after preprocessing of the input images, the region of interest is segmented based on the Otsu method. Then, a new feature extraction is implemented on the segmented image to mine the beneficial characteristics. The process is then finalized by using an optimized Deep Believe Network (DBN) for categorization into 2 classes of normal and melanoma cases. The optimization process in DBN has been performed by a developed version of the newly introduced Thermal Exchange Optimization (dTEO) algorithm to obtain higher efficacy in different terms. To show the method’s superiority, its performance is compared with 7 different techniques from the literature.

AbstractAlthough the kappa-opioid receptor (KOR) and its endogenous ligand, dynorphin, are believed to be involved in ethanol drinking, evidence on the direction of their effects has been mixed. The nucleus accumbens (NAc) shell densely expresses KORs, but previous studies have not found KOR activation to influence ethanol drinking. Using microinjections into the NAc shell of male and female Long-Evans rats that drank under the intermittent-access procedure, we found that the KOR agonist, U50,488, had no effect on ethanol drinking when injected into the middle NAc shell, but that it promoted intake in males and high-drinking females in the caudal NAc shell and high-drinking females in the rostral shell, and decreased intake in males and low-drinking females in the rostral shell. Conversely, injection of the KOR antagonist, nor-binaltorphimine, stimulated ethanol drinking in low-drinking females when injected into the rostral NAc shell and decreased drinking in high-drinking females when injected into the caudal NAc shell. These effects of KOR activity were substance-specific, as U50,488 did not affect sucrose intake. Using quantitative real-time PCR, we found that baseline gene expression of the KOR was higher in the rostral compared to caudal NAc shell, but that this was upregulated in the rostral shell with a history of ethanol drinking. Our findings have important clinical implications, demonstrating that KOR stimulation in the NAc shell can affect ethanol drinking, but that this depends on NAc subregion, subject sex, and ethanol intake level, and suggesting that this may be due to differences in KOR expression.

Two hundred and fifty‐six consecutive alcoholics admitted for detoxification, but not having delirium tremens, were evaluated for hypertension. Thirty‐three per cent (84) of the alcoholics had a blood pressure ≥ 160/95 mm Hg on or within 72 hr of admission. In 71% (60 of 84) of alcoholics with hypertension, pressure elevation was transitory, whereas 29% (24 of 84) required therapy. After 4 to 5 days of abstinence, alcoholics with transitory hypertension, whose blood pressure was no longer elevated, had a larger increment of pressure (p amp;lt; 0.001) with a cold pressor test than did normotensive alcoholics. Hypertensive alcoholics were older and tended to use greater amounts of alcohol, but their liver enzymes, alcohol levels on admission, and serum magnesium concentrations did not distinguish them from normotensive alcoholics. Basal plasma renin activity and epinephrine were elevated in both hypertensive and normotensive alcoholics, whereas plasma norepinephrine was normal. Although plasma renin activity (4.08 ± 0.9 vs. 2.88 ± 0.4 ng/ml/hr) and epinephrine (138 ± 17 vs. 108 ± 28 pg/ml) were higher in alcoholics with hypertension than in normotensive alcoholics, differences were not significant. However, elevated plasma epinephrine was found in 86% of alcoholics with hypertension, whereas only 44% of normotensive subjects had elevations (x2= 5.49; p = 0.01). Although alcoholics with hypertension demonstrated an exaggerated catecholamine response with the cold pressor test, these changes per se did not explain the elevations in blood pressure. Thus, a transitory, reactive form of hypertension associated with increased catecholamines and vascular hyperresponsiveness is present in alcoholics.

C57BL/6J (C57) and DBA/2J (DBA) mice respond differently to drugs that affect dopamine systems, including alcohol. The current study compared effects of D1 and D2 receptor agonists and antagonists, and the interaction between D1/D2 antagonists and alcohol, on intracranial self-stimulation in male C57 and DBA mice to determine the role of dopamine receptors in the effects of alcohol on brain stimulation reward (BSR). In the initial strain comparison, dose effects on BSR thresholds and maximum operant response rates were determined for the D1 receptor agonist SKF-82958 (±-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.1–0.56 mg/kg) and antagonist SCH 23390 (+-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride; 0.003–0.056 mg/kg), and the D2 receptor agonist quinpirole (0.1–3.0 mg/kg) and antagonist raclopride (0.01–0.56 mg/kg). For the alcohol interaction, SCH 23390 (0.003 mg/kg) or raclopride (0.03 mg/kg) was given before alcohol (0.6–2.4 g/kg p.o.). D1 antagonism dose-dependently elevated and SKF-82958 dose-dependently lowered BSR threshold in both strains; DBA mice were more sensitive to SKF-82958 effects. D2 antagonism dose-dependently elevated BSR threshold only in C57 mice. Low doses of quinpirole elevated BSR threshold equally in both strains, whereas higher doses of quinpirole lowered BSR threshold only in C57 mice. SCH 23390, but not raclopride, prevented lowering of BSR threshold by alcohol in DBA mice. Conversely, raclopride, but not SCH 23390, prevented alcohol potentiation of BSR in C57 mice. These results extend C57 and DBA strain differences to D1/D2 sensitivity of BSR, and suggest differential involvement of D1 and D2 receptors in the acute rewarding effects of alcohol in these two mouse strains.

Rostromedial tegmental nucleus (RMTg) GABA neurons exert a primary inhibitory drive onto midbrain dopamine neurons and are excited by a variety of aversive stimuli. There is, however, little evidence that the RMTg-ventral tegmental area (VTA)-nucleus accumbens shell (Acb) circuit plays a role in the aversive consequences of alcohol withdrawal. This study was performed in adult male Long-Evans rats at 48-h withdrawal from chronic alcohol drinking in the intermittent schedule. These rats displayed clear anhedonia and depression-like behaviors, as measured with the sucrose preference, and forced swimming tests. These aberrant behaviors were accompanied by a substantial increase in cFos expression in the VTA-projecting RMTg neurons, identified by a combination of immunohistochemistry and retrograde-tracing techniques. Pharmacological or chemogenetic inhibition of RMTg neurons mitigated the anhedonia and depression-like behaviors. Ex vivo electrophysiological data showed that chemogenetic inactivation of RMTg neurons reduced GABA release and accelerated spontaneous firings of VTA dopamine neurons. Finally, using a functional hemispheric disconnection procedure, we demonstrated that inhibition of unilateral RMTg, when combined with activation of D1 and D2 dopamine receptors in the contralateral (but not ipsilateral) Acb, mitigated the anhedonia and depression-like behaviors in alcohol-withdrawal rats. These data show that the integrity in the RMTg-VTA-Acb pathway in a single hemisphere is sufficient to elicit depression-like behavior during ethanol-withdrawal. Overall, the present results reveal that the RMTg-VTA-Acb pathway plays a crucial role in the depression-like behavior in animals undergoing alcohol withdrawal, further advocating the RMTg as a potential therapeutic target for alcoholism.

The nucleus accumbens (NAc) is a ventral striatal structure underlying reward, reinforcement, and motivation, with extensive anatomic and functional connections to a wide range of affective processing structures (medial prefrontal cortex (mPFC), amygdala, and insula). Characterizing how acute alcohol intake affects resting state functional connectivity (rsFC) between the nucleus accumbens (NAc) and these regions will improve mechanistic understanding of alcohol's neurobehavioral effects, including the neural overlap between acute alcohol effects and pain processing.Fifteen healthy social drinkers (10 women; age: 25-45 years) were included in the study. Participants completed one session in which they consumed an alcohol dose targeting a breath alcohol concentration of 0.08 g/dL, and in a second a placebo beverage. Nine-minute resting state fMRI scans were acquired 30-35 min after beverage administration during each session. rsFC between NAc and a priori corticolimbic regions of interest (mPFC, amgydala, and insula), were compared between beverage conditions. We also conducted an exploratory whole-brain seed-to-voxel analysis of NAc FC.Alcohol intake reduced rsFC between NAc and mPFC, as well as NAc and amygdala. Alcohol also reduced rsFC between NAc and a 97-voxel cluster including bilateral paracingulate cortex and anterior cingulate cortex.Findings suggest that acute alcohol intake reduces rsFC between NAc and several structures, including mPFC, amygdala, and rostral ACC in healthy social drinkers. These structures underlie reward, motivated behavior, and emotion regulation, and may provide mechanistic insight to how alcohol affects related processes, including pain.