bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ethanol Directly Excites Dopaminergic Ventral Tegmental Area Reward Neurons
Authors: Brodie Mark S. , Pesold Christine , Appel Sarah B. 
Published: May 2006

Background: The mesolimbic/mesoeortical dopamine pathway mediates the rewarding effects of ethanol and other drugs of abuse like cocaine and opiates. Dopaminergic neurons of the ventral tegmental area (VTA) arc the cells of origin of the mesolimbic/mesocortical dopamine pathway. Ethanol's rewarding properties result from its ability to excite dopaminergic cell bodies in the VTA which results in increased dopamine release in the nucleus accumbens. Many recent papers have speculated that ethanol excitation of dopaminergic VTA neurons is indirect, either that ethanol acts on GABAergic or other interneurons, which in turn modulate the activity of dopaminergic VTA neurons, or that ethanol modulates the action of neurotransmitter‐gated ion channels in the VTA.Methods: VTA neurons were acutely dissociated and plated onto a cover slip in an electrophysiological recording chamber. These neurons generated spontaneous action potentials which could be measured with cell attached loose patch recording. The dissociation procedure truncated the dendritic trees, severed synaptic contacts and widely dispersed these neurons. Dopamine (10–50 nM) and ethanol (20–120 mM) were bath applied and their effects on firing rate were measured. After some experiments, plated cells were fixed and processed for immunostaining of tyrosine hydroxylase, the rate‐limiting enzyme in dopamine synthesis.Results: All neurons met electrophysiological criteria previously established for dopaminergic VTA neurons. Dopamine inhibited all VTA neurons tested, indicating the presence of dopamine autoreceptors. All neurons identified as dopaminergic by these electrophysiological and pharmacological criteria, and that were processed for immunohistochemistry, stained positive for tyrosine hydroxylase immunoreactivity. All acutely dissociated VTA neurons, identified as dopaminergic by electrophysiological, pharmacological and immunohistochemical criteria, were robustly excited by behaviorally relevant concentrations of ethanol. The ethanol‐induced excitation was concentration‐dependent.Conclusions: These data provide strong evidence that ethanol directly excites dopaminergic VTA neurons, 21s this excitation still occurs in the absence of input from surrounding neurons.
In Vivo Modulation of 73 kDa Heat Shock Cognate and 78 kDa Glucose‐Regulating Protein Gene Expression in Rat Liver and Brain by Ethanol
Authors: Tunici Patrizia , Schiaffonati Luisa , Rabellotti Elisa , Tiberio Laura , Perin Antonio , Sessa Angela 
Published: May 2006

Background: In cultured cells of various origin, ethanol induces the synthesis of 70 kDa family heat shock proteins (hsp70 family), which play a role in the protection of protein traffic and secretion, as well as in cytoskeleton organization. To assess whether ethanol also can induce such genes in vivo, we studied the behavior of hsp70, hsc73, and grp78 messenger ribonucleic acids (mRNAs) and related proteins in the liver and brain of rats acutely treated with ethanol. Methods: Overnight fasted Sprague‐Dawley rats (220‐250 g) were acutely treated with a low (2 g/kg body weight) or a high (5 g/kg body weight) dose of ethanol as a 30% solution in saline or an equal volume of saline (controls) by gastric intubation. Animals were killed at various times after treatments (3‐72 hr). Messenger RNA levels for different members of hsp70 family (hsp70; 73 kDa heat shock cognate, or hsc73; and 78 kDa glucose‐regulating protein, or grp78) were determined by Northern blot analysis and hybridization with specific complementary deoxyribonuclcic acid (cDNA) probes. The amounts of related proteins were assayed by Western blot analysis with specific antibodies. Autoradiograms and fluorograms were subjected to densitometric scanning. Results: Ethanol (2 g/kg) caused a slight increase in hsc73 and grp78 mRNA levels only in the liver, without enhancing the amount of proteins. Ethanol (5 g/kg) increased the level of hsc73 and grp78 mRNAs and related proteins in the liver. In the brain, the amount of hsc73 mRNA was enhanced, but this did not change hsc73 protein. In addition, we observed an increase in cerebral grp78 transcript and related protein. Hsp70 gene was not induced in the examined tissues by either dose of ethanol. Conclusions: Hepatic and cerebral hsc73 and grp78 genes are responsive to ethanol in vivo, and their activation may signal the cell's effort to counteract the harmful action of ethanol.
Disruption of Operant Oral Self‐Administration of Ethanol, Sucrose, and Saccharin by the AMP/Kainate Antagonist, NBQX, but Not the AMPA Antagonist, GYKI 52466
Authors: Stephens D.N. , Brown G. 
Published: May 2006

Background: AMPAergic transmission has been suggested to be important in mediating the rewarding effects of drugs. We therefore examined the role of non‐NMDA glutamate‐receptors in mediating the reinforcing properties of ethanol in an oral self‐administration paradigm.Methods: The competitive antagonist NBQX (2,3‐dihydroxy‐6‐nitro‐7‐sulfamoylbenzo(f)quinoxaline) and the non‐competitive antagonist, GYKI 52466 (1‐(4‐aminophenyl)‐4‐methyl‐7,8‐methylene‐dioxy‐5H‐2,3‐benzodiazepine), were administered to animals previously trained to self‐administer ethanol, sucrose, or saccharin, on a progressive ratio schedule.Results: GYKI 52466 (5 & 10 mg/kg) had no effect on operant responding for ethanol, but increased spontaneous locomotor activity, whereas the highest doses of NBQX (3 & 6 mg/kg) significantly decreased operant responding and correspondingly decreased the breaking point in responding for ethanol on a progressive ratio schedule. NBQX (but not GYKI 52466) also significantly decreased operant responding for a food reinforcer (sucrose) as well as for a sweet tasting reinforcer (saccharin). Doses of NBQX that disrupted operant performance caused a significant reduction in locomotor activity, indicating that NBQX decreased ethanol self‐administration only at doses which disrupt motor activity.Conclusions: These results suggest non‐NMDA glutamate‐receptors may not have a specific role in the maintenance of responding for an ethanol reinforcer, but may generally disrupt operant performance. Because, unlike GYKI 52466, NBQX possesses an action at central kainate receptors, these results suggest that kainate, but not AMPA (α‐amino 3‐hydroxy‐5‐methyl‐4‐isoxazole propionate) receptors may be important in mediating the reinforcing effects of ethanol.
An A/G Polymorphism in the Promoter of Mitochondrial Aldehyde Dehydrogenase (ALDH2): Effects of the Sequence Variant on Transcription Factor Binding and Promoter Strength
Authors: Chou Wan‐Yin , Stewart Mark J. , Carr Lucinda G. , Zheng Daisy , Stewart Trent R. , Williams Adrienne , Pinaire Jane , Crabb David W. 
Published: May 2006

Introduction:The strong protective effect of the ALDH2*2 mutation on risk of alcoholism suggests that other mutations that reduce mitochondrial aldehyde dehydrogenase (ALDH) activity in the liver might also deter drinking. This study describes a polymorphic locus found in the promoter of the ALDH2 gene that affects expression of reporter constructs. Method: Polymerase chain reaction (PCR)‐based sequencing was used to search for polymorphisms. The ability of the promoter variants to bind transcription factors apolipoprotein A regulatory protein 1 (ARP‐1) and chicken ovalbumin upstream promoter‐transcription factor (COUP‐TF) was tested in gel retardation assays using in vitro synthesized transcription factors. The variant promoters were tested for transcriptional activity using a heterologous promoter system and transient transfection assays. Result: A common polymorphism (A or G) in the human ALDH2 promoter region was found at ‐361 base pair (bp) from the translation start site. This polymorphism was found at different frequencies in African Americans, Caucasians, and Asians. The polymorphism occurs adjacent to the core binding motif for the transcription factors COUP‐TF and ARP‐1. Competition and binding affinity determinations did not show differences in the ability of these two sequences to bind the factors. Reporter genes containing these elements upstream of a basal thymidine kinase promoter had similar activity when transfected into a fibroblast (CV‐1) cell line. However, the reporter containing the G allele was more active than that containing the A allele in hepatoma (H4IIEC3) cells. Conclusions: The ‐361 bp A/G polymorphism is common in all racial groups tested. The G allele was more active than the A allele in a transfection assay. The basis for this difference is not known. If the differences in activity of the promoter constructs were paralleled by differences in ALDH2 enzyme activity in the liver, this polymorphism could affect risk of alcoholism.
Action of Ethanol on Responses to Nicotine From Cerebellar Interneurons and Medial Septal Neurons: Relationship to Methyllycaconitine Inhibition of Nicotine Responses
Authors: Yang Xiaohong , Criswell Hugh E. , Breese George R. 
Published: May 2006

Background: A majority of alcoholics also smoke, suggesting that alcohol and nicotine share a common action on nicotinic cholinergic receptors. Method: Extracellular single‐unit recording was used to investigate the effects of ethanol on responses to nicotine from rat cerebellar interneurons and medial septal neurons. Result: Nicotine produced inhibition from medial septal neurons, but increased neural activity of cerebellar interneurons. When ethanol was applied locally to cerebellar interneurons, the excitatory response to nicotine was enhanced in a dose‐related manner. Nicotine‐induced inhibition from medial septal neurons was reduced by ethanol from the majority of neurons, but a dose relationship for this inhibition by ethanol was not observed. Ethanol affected responses to nicotine from over 90% of all neurons investigated at these sites. Initially, it was established that the nicotinic antagonists, methyllycaconitine (MLA) and α‐bungarotoxin, which affect a nicotinic cholinergic (nACh) receptor with an α7 subunit, had similar actions on responses to nicotine from individual medial septal cells and cerebellar interneurons. When MLA was tested against responses to nicotine from neurons in the two brain regions, MLA antagonized responses to nicotine from only 27% of the neurons rather than the 90% found for ethanol. This latter observation provided evidence that ethanol was affecting neurons with MLA‐insensitive receptors. When the actions of ethanol on responses to nicotine were compared directly with the action of MLA on the same medial septal neurons, both ethanol and MLA caused a greater than 50% antagonism of the response to nicotine, indicative that nACh receptors with the α7 subunit were sensitive to ethanol. Conclusions: Collectively, these data provide evidence that ethanol affects responses to nicotine not only from nACh receptors on medial septal cells and cerebellar interneurons containing an α7 subunit (i.e., MLA‐sensitive receptors), but also from nACh receptor subtypes without this specific nACh receptor subunit (i.e., MLA‐insensitive receptors).
Innate Differences of Neuropeptide Y (NPY) in Hypothalamic Nuclei and Central Nucleus of the Amygdala Between Selectively Bred Rats with High and Low Alcohol Preference
Authors: Hwang Bang H. , Zhang Jing‐Kang , Enters Cindy L. , Lumeng Lawrence , Li T.‐K. 
Published: May 2006

Background: Neuropeptide Y (NPY) is a neuropeptide that has been demonstrated to produce anxiolytic effects when administered centrally. To examine the hypothesis that NPY might play a role in alcohol‐seeking behavior, this study took advantage of the genetic differences of the alcohol‐preferring (P) rats and alcohol‐nonpreferring (NP) rats, as well as the high alcohol‐drinking (HAD) rats and low alcohol‐drinking (LAD) rats, in voluntary alcohol consumption to examine if NPY neurons in the brains differ between these selected lines. Method: The NPY immunoreactivity (NPY‐I) was measured using an established radioimmunohisto‐chemical assay in discrete brain structures including the paraventricular hypothalamic nucleus (PVN), arcuate nucleus (ARC), and central nucleus of the amygdala (CeA). Result: The quantitative data indicated that there was more NPY‐I in the PVN and ARC of P rats than NP rats, whereas there was less NPY‐I in the PVN and ARC of HAD rats than LAD rats. However, the NPY‐I in the CeA was less in both the P and HAD rats than in the NP and LAD rats, respectively. Therefore, the data indicate that there are innate differences in the NPY‐I in the brain between selectively bred rats with high and low alcohol preference.Conclusion:Because both P rats and HAD rats have high alcohol preference, the disparate finding between these two lines of rats suggests that the hypothalamic NPY neurons are probably not associated with alcohol preference. In contrast, consistent findings in the CeA of both P rats and HAD rats suggest that NPY in the CeA of P and HAD rats may contribute to the regulation of alcohol consumption. This is substantiated by a recent report showing that NPY‐knockout mice drink significantly more ethanol, and transgenic mice that overexpress the NPY gene drink less alcohol, than wild‐type mice. Together, the findings support the notion that NPY agonists that would enhance NPY function in the amygdala might be useful for the treatment of anxiety and alcoholism.
Operant Self‐Administration of Sweetened Versus Unsweetened Ethanol: Effects on Blood Alcohol Levels
Authors: Roberts Amanda J. , Heyser Charles J. , Koob George F. 
Published: May 2006

Background:Sweeteners are often added to ethanol solutions to increase ethanol intake. However, literature on studies that use human subjects and laboratory animals suggests that sucrose, other sugars, and carbohydrate‐rich foods alter ethanol absorption and metabolism, which leads to lower blood alcohol levels (BAL) relative to ethanol absorbed alone. This experiment was designed to test whether the addition of the nutritive sweetener sucrose, or the nonnutritive sweetener saccharin, to a 10% ethanol solution, self‐administered in an oral operant paradigm, affected BAL in rats relative to self‐administration of an unsweetened 10% ethanol solution. Methods:All rats were trained to lever press for ethanol by use of a saccharin fading procedure. Half of the rats then received 30‐min sessions in which ethanol + 2% sucrose and water were available and were alternated daily with sessions in which ethanol + 0.2% saccharin and water were available. The other half of the rats went on to receive daily sessions of unsweetened ethanol and water. BAL were taken after these standard daily sessions as well as after a 1‐week period of alcohol deprivation (to enhance ethanol intake). Results:Rats responded for more ethanol + sucrose than unsweetened ethanol, but had lower BAL per gram ethanol consumed in both the baseline test and alcohol deprivation effect test. No effect of saccharin on BAL was detected. An additional experiment that examined the effects of four concentrations of both sucrose and saccharin on self‐administration of ethanol and BAL showed that, whereas rats consumed more ethanol + sucrose than ethanol + saccharin, BAL were significantly lower per gram ethanol consumed in the sucrose group. Conclusions:These results confirm previous reports and suggest that the addition of sucrose to an ethanol solution can result in lower BAL relative to unsweetened ethanol in an oral operant self‐administration paradigm.
Ontogeny of Rapid Tolerance to the Hypnotic Effects of Ethanol
Authors: Silveri Marisa M. , Spear Linda Patia 
Published: May 2006

Background: Alcohol use typically begins during adolescence. Little is known regarding the antecedents and impact of this early alcohol use, although age‐related changes in the neural systems modulating alcohol sensitivity could contribute to the propensity of adolescents to consume alcohol. We have previously observed a marked ontogenetic decline in acute tolerance to ethanol (EtOH), with preweanling pups exhibiting the most acute tolerance (Silveri and Spear, 1998). The objective of this study was to assess whether rapid tolerance shows a similar ontogenetic profile. Methods: In Experiment I of the present study, female and male Sprague‐Dawley preweanling rats at postnatal day (P) 16 or young adults at P56 were examined. On Day 1, preweanlings were pretreated with saline, 1.5,3.5, or 5.0 g/kg EtOH and adults were pretreated with saline or 3.5 g/kg EtOH. This was followed by challenge with 3.5 g/kg EtOH and assessment of ethanol‐induced sleep time on Day 2. In Experiment II, adolescents at P36 were pretreated with saline, 3.5, or 5.0 g/kg EtOH on Day 1 before Day 2 assessment of sleep time after 3.5 g/kg EtOH. Upon awakening, animals were killed and whole brains removed and analyzed for brain alcohol levels (BrALs). Results: Rapid tolerance was observed in P36 and P56 animals, with EtOH‐pretreated animals exhibiting significantly shorter sleep times than age‐matched animals treated with saline. In contrast, no evidence for rapid tolerance was seen after any pretreatment dose at P16. Interestingly, although EtOH‐pretreated adults woke at higher BrALs than saline‐treated adults, this pattern was not evident in the adolescents, which suggests that at this age, metabolic tolerance may play a prominent role in the expression of rapid tolerance. Thus, it seems as though the ability to develop rapid tolerance to EtOH hypnosis emerges during adolescence and continues into adulthood. Conclusions: Together with previous findings that adolescent animals also display substantial acute tolerance to alcohol (Silveri and Spear, 1998), the propensity of adolescents for developing these two forms of tolerance may have important implications for the increased voluntary consumption of alcohol at this age relative to other ages.
Adrenocortical Responses and Family History of Alcoholism
Authors: Wand Gary S. , Mangold Deborah , Ali Mahmood , Giggey Paul 
Published: May 2006

Background: This study was designed to assess whether nonalcoholic offspring from families with a high density of alcohol‐dependent individuals have altered hypothalamic‐pituitary‐adrenal (HPA) axis dynamics compared with nonalcoholic subjects without a family history of alcohol dependence. Methods: Seventy‐eight nonalcoholic subjects aged 18 to 25 were enrolled in the protocol. Thirty‐nine subjects were offspring from families with a high density of alcohol dependence and were designated as family history‐positive (FHP) subjects. Thirty‐nine subjects were biological offspring of nonalcohol‐dependent parents and were designated as family history‐negative (FHN) subjects. Subjects received naloxone hydrochloride (0 and 125 μg/kg) and cosyntropin (0, 0.25 μg, and 250 μg) in double‐blind, randomized order and Cortisol was monitored. A subset of subjects (11 FHP, 11 FHN) was admitted to the General Clinical Research Center to measure serum Cortisol levels every 30 min for 24 hr. Results: FHP subjects had an increased Cortisol response to opioid receptor blockade induced by naloxone. However, no group differences in Cortisol were uncovered during administration of cosyntropin or during monitoring of the Cortisol circadian profile. Conclusion: These observations suggest that differences in the Cortisol dynamics between FHP and FHN subjects are unmasked by opioid receptor blockade directed at the hypothalamus, but not when Cortisol levels are directly provoked at the level of the adrenal gland. In addition, unprovoked Cortisol secretion monitored over a 24‐hr interval cannot distinguish FHP from FHN subjects.
Immune Changes in Alcohol‐Dependent Patients Without Medical Disorders
Authors: Schleifer Steven J. , Keller Steven E. , Shiflett Samuel , Benton Tonya , Eckholdt Haftan 
Published: May 2006

Introduction: We examined a battery of in vitro immune measures in inner city alcohol‐dependent (as determined by the Structured Clinical Interview for DSM‐III‐R (SCID) persons who were without liver or other medical disorders and free of other substance abuse. These subjects were seeking treatment at an ambulatory alcohol treatment center. Methods: Alcohol‐dependent subjects (n = 44) were compared with healthy, nonabusing community subjects (n= 34). Subjects, both male and female, had a mean age of 41 years and were primarily African American. Many were homeless. An extended battery of enumerative and functional immune measures was obtained, as well as information about alcohol consumption. Results: Controlling for age and gender, ANCOVA revealed no differences (p > 0.1) between alcohol‐dependent and control subjects in leukocyte and lymphocyte subsets or in circulating CD56+ (natural killer) cells. There were also no significant differences in responses to the mitogens phytohemagglutinin, con‐canavalin A, or pokeweed mitogen (p > 0.1) or in natural killer cell activity (p> 0.1). There was, however, altered granulocyte function in the alcohol‐dependent sample, with decreased phagocytic activity in the alcohol‐dependent males (p < 0.04) and gender and age dependent differences in the number of circulating granulocytes (p < 0.01). Granulocyte killing of Staphylococcus aureus, however, did not differ between the groups. Conclusions: The findings suggest that although males with chronic alcohol dependence have compromised phagocytic function, chronic alcohol‐dependent subjects who are free of medical disorders do not have substantial abnormalities in many immune system functions.
Hypoperfusion of the Cerebellum and Aging Effects on Cerebral Cortex Blood Flow in Abstinent Alcoholics: A SPECT Study
Authors: Harris Gordon J. , Oscar‐Berman Marlene , Gansler A. , Streeter Chris , Lewis Robert F. , Ahmed Iqbal , Achong Dwight 
Published: May 2006

Background:This study evaluated hypotheses concerning alcoholism, aging, and the relationship between cerebral hypoperfusion and residual deficits in the functioning of cerebellar and neocortical brain systems.Methods:The participants were 10 healthy abstinent alcoholics (9 men, 1 woman) and 12 nonalcoholic controls (10 men, 2 women) ranging in age from 35 to 67 years. Cerebral blood flow was observed through the use of regionally specific computer‐derived quantitative analysis of single photon emission computed tomography (SPECT) perfusion images. Cerebellar perfusion was measured and compared with cerebral cortex perfusion in age‐equivalent subgroups of alcoholics and controls (under 55 years; 55 years and over).Results:In abstinent alcoholics under age 55, cerebellar perfusion ratios were significantly reduced compared with the controls. In alcoholics and nonalcoholic controls 55 years old and older, this relationship was reversed, probably as a result of diminished cortical perfusion with aging in the alcoholics and of cerebellar decline in the controls.Conclusions:The findings support hypotheses that the residual effects of alcoholism include cerebellar brain abnormalities and that aging combined with long‐term alcoholism leads to cerebral cortical decline.