促肾上腺皮质激素对N-甲基-D-天冬氨酸诱发幼鼠痉挛模型应激蛋白表达的影响

目的 分析促肾上腺皮质激素(ACTH)对婴儿痉挛模型应激蛋白表达的影响,为婴儿痉挛症的治疗提供理论依据。方法 将60只新生幼鼠随机分为对照组、N-甲基-D-天冬氨酸(NMDA)组和ACTH组,每组20只。幼鼠出生第11天,ACTH组腹腔注射10 mg/(kg·d) ACTH,其他两组注射等量的生理盐水。幼鼠出生的第15天,NMDA组和ACTH组腹腔注射15 mg/(kg·d) NMDA,对照组注射等量生理盐水。对三组幼鼠痉挛症状进行评分,采用q-PCR法测海马白介素1β(IL-1β)、白介素6(IL-6)和ACTH的mRNA转录水平,Western Blot法测海马促肾上腺皮质激素释放激素(CRH)和促肾上腺皮质激素释放激素1型受体(CRHR1)蛋白表达。结果 NMDA组中幼鼠的痉挛症状评分高于对照组(t=11.236,P<0.001); ACTH组幼鼠的痉挛症状评分低于NMDA组(t=-6.347,P<0.001)。与对照组相比,NMDA组海马IL-1β和IL-6的mRNA转录水平升高(IL-1β: t=6.237,P<0.001;IL-6: t=6.553,P<0.001),ACTH组海马中IL-1β和IL-6的mRNA转录水平低于NMDA组(IL-1β:t=-7.669,P<0.001;IL-6:t=-8.125,P<0.001)。ACTH组海马中ACTH mRNA转录水平高于NMDA组(t=7.758,P<0.001)。与对照组相比,NMDA组海马体CRH和CRHR1蛋白表达上调(CRH: t=7.517,P<0.001;CRHR1: t=7.745,P<0.001),ACTH组海马CRH和CRHR1蛋白表达低于NMDA组(CRH: t=-6.120,P=0.003;CRHR1: t=-6.050,P=0.005)。结论 ACTH可缓解幼鼠的痉挛症状,推测与降低海马体中IL-1β和IL-6的mRNA转录水平,上调ACTH的mRNA转录水平,抑制CRH和CRHR1蛋白表达有关。     

促肾上腺皮质激素释放激素受体的研究进展

促肾上腺皮质激素释放激素及其相关肽通过激活G-蛋白藕联的促肾上腺皮质激素释放激素受体在人体多系统中发挥作用.妊娠和非妊娠子宫肌及子宫底、子宫下段CRH结合能力和功能的不同可能与不同受体亚型表达多少相关.促肾上腺皮质激素释放激素受体拮抗剂的研发为治疗可卡因戒断反应、焦虑症和抑郁症开辟了新方向.     

Corticotropin-releasing factor (CRF) and neuropeptide Y (NPY): Effects on inhibitory transmission in central amygdala,and anxiety- & alcohol-related behaviors

The central amygdala (CeA) is uniquely situated to function as an interface between stress- and addiction-related processes. This brain region has long been attributed an important role in aversive (e.g., fear) conditioning, as well as the negative emotional states that define alcohol dependence and withdrawal. The CeA is the major output region of the amygdala and receives complex inputs from other amygdaloid nuclei as well as regions that integrate sensory information from the external environment (e.g., thalamus, cortex). The CeA is functionally and anatomically divided into lateral and medial subdivisions that themselves are interconnected and populated by inhibitory interneurons and projections neurons. Neuropeptides are highly expressed in the CeA, particularly in the lateral subdivision, and the role of many of these peptides in regulating anxiety- and alcohol-related behaviors has been localized to the CeA. This review focuses on two of these peptides, corticotropin-releasing factor (CRF) and neuropeptide Y (NPY), that exhibit a high degree of neuroanatomical overlap (e.g., in CeA) and largely opposite behavioral profiles (e.g., in regulating anxiety- and alcohol-related behavior). CRF and NPY systems in the CeA appear to be recruited and/or up-regulated during the transition to alcohol dependence. These and other neuropeptides may converge on GABA synapses in CeA to control projection neurons and downstream effector regions, thereby translating negative affective states into anxiety-like behavior and excessive alcohol consumption.     

Gene expression within the extended amygdala of 5 pairs of rat lines selectively bred for high or low ethanol consumption

The objectives of this study were to determine innate differences in gene expression in 2 regions of the extended amygdala between 5 different pairs of lines of male rats selectively bred for high or low ethanol consumption: a) alcohol-preferring (P) vs. alcohol-non-preferring (NP) rats, b) high-alcohol-drinking (HAD) vs. low-alcohol-drinking (LAD) rats (replicate line–pairs 1 and 2), c) ALKO alcohol (AA) vs. nonalcohol (ANA) rats, and d) Sardinian alcohol-preferring (sP) vs. Sardinian alcohol-nonpreferring (sNP) rats, and then to determine if these differences are common across the line–pairs. Microarray analysis revealed up to 1772 unique named genes in the nucleus accumbens shell (AcbSh) and 494 unique named genes in the central nucleus of the amygdala (CeA) that significantly differed [False Discovery Rate (FDR) = 0.10; fold-change at least 1.2] in expression between the individual line–pairs. Analysis using Gene Ontology (GO) and Ingenuity Pathways information indicated significant categories and networks in common for up to 3 or 4 line–pairs, but not for all 5 line–pairs. However, there were almost no individual genes in common within these categories and networks. ANOVAs of the combined data for the 5 line–pairs indicated 1014 and 731 significant (p < 0.01) differences in expression of named genes in the AcbSh and CeA, respectively. There were 4–6 individual named genes that significantly differed across up to 3 line–pairs in both regions; only 1 gene (Gsta4 in the CeA) differed in as many as 4 line–pairs. Overall, the findings suggest that a) some biological categories or networks (e.g., cell-to-cell signaling, cellular stress response, cellular organization, etc.) may be in common for subsets of line–pairs within either the AcbSh or CeA, and b) regulation of different genes and/or combinations of multiple biological systems may be contributing to the disparate alcohol drinking behaviors of these line–pairs.     

Molekulare Grundlagen der Alkoholsucht

Preclinical as well as clinical data strongly imply that relapse and craving for alcohol can be induced through different mechanisms. A first pathway may induce alcohol craving and relapse due to the moodenhancing, positive reinforcing effects of alcohol consumption.This pathway seems to involve opioidergic systems in the ventral striatum.The role of the dopaminergic system may lie in the direction of attention towards reward-indicating stimuli, while the induction of euphoria and positive mood states may be mediated by opioidergic systems.Associative learning may, in turn, transform positive mood states and previously neutral environmental stimuli into alcohol-associated cues that acquire positive motivational salience and induce reward craving.A second and potentially independent pathway may induce alcohol craving and relapse by negative motivational states, including conditioned withdrawal and stress.This pathway seems to involve the glutamatergic system and the corticotropinreleasing hormone (CRH) system.Chronic alcohol intake leads to compensatory neurotransmission and increased CRH release leads to a state of hyperexcitability,which becomes manifest as craving, anxiety, seizures, and autonomic dysregulation. Moreover, cues associated with prior alcohol intake that are not followed by actual drug consumption may induce conditioned with-drawal.     

Leptin rapidly inhibits hypothalamic neuropeptide Y secretion and stimulates corticotropin-releasing hormone secretion in adrenalectomized mice

Leptin may rapidly inhibit food intake by altering the secretion of hypothalamic neuropeptides such as neuropeptide Y (NPY), a stimulator of food intake, and/or corticotropin-releasing hormone (CRH), an inhibitor of food intake. We measured concentrations of NPY and CRH in specific hypothalamic regions [i.e., arcuate nucleus (ARC), paraventricular nucleus (PVN), ventromedial nucleus and dorsomedial nucleus] of 7- to 8-wk-old lean and ob/ob mice at 1 or 3 h after intracerebroventricular leptin administration. No rapid-onset effects of leptin on hypothalamic NPY or CRH concentrations were observed in intact mice. The addition of leptin to hypothalamic preparations from intact mice also did not alter NPY or CRH secretion. Glucocorticoids may oppose leptin actions. Consistent with this, leptin administration to adrenalectomized mice markedly reduced CRH concentrations in the ARC within 3 h after injection. This rapid reduction in CRH concentration in the ARC after leptin administration is more likely due to stimulated CRH release from this region than to decreased synthesis/transport from the PVN because leptin stimulates CRH synthesis in the PVN. Within 20 min after exposure to leptin, NPY secretion from hypothalamic preparations obtained from adrenalectomized mice was lowered by 27% and CRH secretion was elevated by 51%. The current study demonstrates that leptin rapidly influences the secretion of hypothalamic NPY and CRH and that these actions of leptin within the hypothalamus are restrained by the presence of endogenous corticosterone.     

Mmu and D2 receptor antisense oligonucleotides injected in nucleus accumbens suppress high alcohol intake in genetic drinking HEP rats.

Numerous pharmacological and other studies have implicated both Mmu and dopamine receptor subtypes in alcohol consumption. In the genetic drinking rat as well as those chemically induced to drink, evidence has accrued that the abnormal intake of alcohol is underpined by these receptors in the brain. The purpose of this investigation was to demonstrate unequivocally that a biological impairment by antisense oligodeoxynucleotide (ODN) targeted specifically to these two receptor subtypes would disrupt ongoing alcohol drinking. In this project, a new strain of female and male high-ethanol preferring (HEP) rats was used that had free access to preferred concentrations of alcohol over water in a two choice paradigm. A guide cannula for a microinjection needle was first implanted bilaterally above the nucleus accumbens (NAC) of each rat. Following recovery, a dose of either 250 or 500 ng of the Mmu ODN or 500 ng D2ODN was microinjected into the NAC of the rat in a volume of 0.8-1.0 microl. A standard temporal sequence was used in which microinjections were given four times at successive 12-h intervals over a 2-day interval. The control mismatch ODNs corresponding to both the Mmu or D2 receptor antisense were microinjected identically at homologous sites in the NAC. Following the experiments, the brain of each rat was removed and sectioned in the coronal plane for histological analysis so that each microinjection site was identified. The results showed that the Mmu receptor antisense caused a significant dose dependent fall in free access alcohol drinking within 12 to 24 h following the initial microinjection. This decline often persisted for 1 to 2 days in terms of both g/kg intake and proportion of alcohol to water consumed. Similarly, the D2 receptor ODN likewise induced an intense and significant decline in both g/kg and proportion measures of alcohol intake. Since the corresponding mismatch ODN for both Mmu and D2 receptors exerted no effect on either of these measures of alcohol consumption, the specificity of molecular action of the respective antisense molecules on drinking behavior of the HEP rats was confirmed. Thus, these results provide the first unequivocal evidence that the genes for D2 and Mmu receptors are fundamentally involved in abnormal alcohol drinking in the genetically predisposed individual. Finally, important new anatomical evidence is introduced for the critical role of the NAC in the genetic basis of aberrant drinking of alcohol.     

乙醇对大鼠脑纹状体和海马神经递质的影响

[目的]研究乙醇对大鼠脑组织神经递质的影响。[方法]雄性SD大鼠25只，随机分为低剂量组、高剂量组和对照组(分别为8、8、9只)。用相应25．6%(V／V)、51．3％(V／V)乙醇浓度和对照组用蒸馏水，一次灌胃(灌胃体积为1．0ml/100g体重)染毒。1h后处死大鼠，取血、脑纹状体和海马，分别测定血中乙醇浓度、脑纹状体单胺类递质含量及海马中强啡肽A水平。[结果]纹状体多巴胺(DA)含量随乙醇染毒剂量增加而升高，呈剂量一效应关系。低剂量组3，4-双羟苯乙酸(DOPAC)、强啡肽A(dynorphin A，DynA)含量显著升高；高剂量组5-羟色胺(5-HT)含量显著高于低剂量组和对照组。5-HT、5-羟吲哚乙酸(5-HIAA)含量与血中乙醇浓度(BAC)显著相关。[结论]脑组织神经递质的变化，可能是乙醇神经毒性的机制之一。     

Anatomical localization in hippocampus of tetrahydro-beta-carboline-induced alcohol drinking in the rat

Guide cannulae for unilateral or bilateral micro-injection were implanted stereotaxically into the dorsal hippocampus of the male adult Sprague-Dawley rat. Following post-operative recovery, the animal's individual preference for ethyl alcohol in concentrations from 3-30% (v/v) was tested over a 9-day period by a three-bottle, two-choice technique. Following this pre-screen, 3.0 microliter of 1,2,3,4-tetrahydro-beta-carboline (TH beta C) hydrochloride, a benzodiazepine receptor antagonist, was infused in a concentration of 25-200 ng into the hippocampus of each unrestrained rat twice a day for three to six days. After the first two days of infusion, the 9-day preference test for alcohol drinking was begun and continued identically as in the earlier test. A third alcohol preference test during which no injections were given was conducted at an interval of two weeks following the second. The micro-injection of TH beta C into certain sites in the hippocampus enhanced alcohol consumption from 0.5-2.0 g/kg during the 9-day test interval. The magnitude of this elevated intake was dependent on the site of infusion and was more pronounced when intermediate concentrations of 7-12% alcohol were offered to the rat. At sites in coronal planes encompassing AP 3.0 and AP 3.5, the micro-injection of TH beta C enhanced alcohol drinking significantly in 75% of the animals; however, when delivered at sites in coronal planes AP 1.0 through AP 2.5, TH beta C augmented alcohol drinking significantly in 15% of the rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

子痫前期患者血清及胎盘促肾上腺皮质激素释放激素水平的变化及意义

目的:了解子痫前期患者血清和胎盘组织促肾上腺皮质激素释放激素(CRH)的变化及其意义。方法:采用ELISA测定36例子痫前期患者(子痫前期组)和39例正常孕妇(对照组)血清和胎盘血清CRH浓度组织蛋白提取液中CRH浓度,并进行组间比较。结果:子痫前期患者血清CRH浓度为(5.661±2.895 0)pmol/L,与正常妊娠时血清CRH浓度(8.753 9±2.741 0)pmol/L比较呈显著下降(P<0.001),子痫前期患者胎盘组织中CRH相对浓度为(0.314 8±0.083 65)pmol/g蛋白与正常妊娠时(0.317 8±0.110 0)pmol/g蛋白比较则没有显著性差异(P>0.05)。结论:子痫前期患者血清CRH显著降低,是子痫前期的一个重要病理生理变化,可能与疾病的的发生、发展有关。     

Relation of tumor necrosis factor (TNF) gene polymorphisms with serum concentrations and in vitro production of TNF-alpha and interleukin-8 in heavy drinkers.

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) play a role in the pathogenesis of alcoholic hepatitis. The aim of the current study was to investigate the possible relation of TNF gene polymorphisms with TNF-alpha and IL-8 synthesis in heavy drinkers. Nineteen heavy drinkers and 14 healthy control subjects were included in the study. Investigations included (a) polymorphisms in the TNF promoter region at positions -238 (G-->A), -308 (G-->A), -857 (C-->T), and -863 (C-->A), as well as a biallelic Ncol restriction fragment length polymorphism in the first intron of the close TNF-beta gene; (b) serum TNF-alpha and IL-8 concentrations; and (c) TNF-alpha and IL-8 production by phytohemagglutinin A-stimulated peripheral blood mononuclear cells. In comparison with findings for control subjects, heavy drinkers showed higher TNF-alpha production, higher IL-8 production, and higher serum IL-8 concentrations. Increased serum TNF-alpha concentrations were specifically found in heavy drinkers with the -857 (C-->T) substitution (CT heterozygotes), therefore indicating an interaction between alcohol consumption and that polymorphism on serum TNF-alpha concentrations.     

Comparison of the action of the 5-HT2 antagonists amperozide and trazodone on preference for alcohol in rats

Previous studies in the rat demonstrated that the 5-hydroxytryptamine₂ (5-HT₂) antagonist amperozide attenuates the volitional intake of both alcohol and cocaine solutions in a free-choice situation. However, another 5-HT₂ antagonist, ritanserin, has not been found to reduce alcohol drinking consistently in the rat. In this study, trazodone was compared to amperozide for its effect on the volitional consumption of alcohol because, like amperozide, trazodone is a potent 5-HT₂ receptor antagonist but a weak inhibitor of 5-HT reuptake. Male Sprague-Dawley rats were induced to drink alcohol by 10 mg/kg cyanamide injected for 3 days b.i.d. One week later the rats were offered a choice of water and increasing concentrations of alcohol solutions ranging from 3% to 30% v/v in a three-bottle two-choice paradigm. After the concentration of alcohol that produced maximal daily intake was determined for each rat, trazodone or amperozide was injected b.i.d. SC in doses of 1.0 mg/kg or 2.5 mg/kg for three days. Whereas the higher dose of amperozide produced a significant, 55.6% decrease from pretreatment baseline of alcohol intake, trazodone did not alter alcohol preference at either the 1.0- or 2.5-mg/kg dose. These results are discussed in terms of whether the antagonism of 5-HT₂ receptors by amperozide is critical to its attenuating effect on preference for alcohol solutions.     

葡多酚对肝细胞内Ca~(2+)浓度和增殖活性的影响

目的探讨葡多酚(GPC)对正常肝细胞和受乙醇损伤肝细胞内Ca2+浓度与细胞增殖活性的影响。方法将大鼠正常肝细胞和乙醇损伤肝细胞加入不同剂量GPC共同培养,用Fura-2荧光测定肝细胞内Ca2+浓度,用MTT法测定细胞增殖活性。结果①正常对照组和乙醇对照组的Ca2+浓度分别为(108·26±14·17)和(651·24±47·95)nmol/L,二者差异有显著性意义(P<0·05);中、高剂量GPC组均较乙醇对照组显著性降低(P<0·05)。②加入GPC的正常肝细胞内Ca2+浓度依次为:细胞外液含Ca2+组>外液无Ca2+组>正常对照组。③正常肝细胞和乙醇损伤肝细胞的中、高剂量GPC组细胞增殖活性均较正常对照组和乙醇对照组显著性升高(P<0·05)。结论GPC可通过增加细胞外液Ca2+内流和胞内Ca2+库的释放两种途径升高正常肝细胞内Ca2+浓度,提高细胞增殖活性,并可抑制乙醇引发的肝细胞内Ca2+浓度异常升高(超载)和细胞增殖活性损伤。     

Zinc status affects neurotransmitter activity in the paraventricular nucleus of rats

Alterations in neurochemical activity in the paraventricular nucleus (PVN) of the hypothalamus may account for decreased intake of zinc-deficient diets. Male Sprague-Dawley rats were fed zinc-deficient (ZD) or zinc-adequate (ZA) diet for 14 d before samples of extracellular fluid in the PVN were collected by microdialysis or push-pull perfusion. A third set of rats was pair-fed (PF) an amount of ZA diet equal to the intake of ZD rats. Samples were collected over a 2-h period spanning the transition from light to dark. All rats then consumed the zinc adequate diet ad libitum for 3 d before a second set of samples was collected. The increase in extracellular norepineprhrine (NE) during h 1 of the dark period to 147 +/- 13% of baseline (P < 0.05) was apparent only in ZA rats at d 14. After the 3-d repletion period, the increase in NE at dark onset occurred in all three groups. An increase in extracellular neuropeptide Y (NPY) at dark onset to 174 +/- 32% of baseline in rats fed ZA (P < 0.01) was measured in all three groups at both d 14 and 17. Basal NPY concentrations were significantly elevated in PF rats on d 14 (7.45 +/- 2.01 vs. 0.58 +/- 0.23 pmol/L, P = 0.01) and returned to ZA levels by d 17. The activities of the NE and NPY systems in the PVN were altered in rats fed a zinc-deficient diet; however, it is unclear whether the disruption in the NE and NPY neural systems in the PVN results in the altered feeding behavior accompanying zinc deficiency.     

血浆促肾上腺皮质激素释放激素与妊娠期疾病关系的临床研究

目的:探讨治疗早产药物,早产、贫血、肝功能损害及妊娠期胆汁淤积症对妊娠期血浆促肾上腺皮质激素释放激素(CRH)水平的影响。方法:以放射免疫方法测定正常妊娠以及早产等妊娠期疾病时母体CRH水平的变化。结果:各孕周早产孕妇血浆CRH较正常对照孕妇显著升高(P<0.05)。经有效药物治疗后,血浆CRH明显回落。贫血、肝功能损害及足月妊娠合并胆汁淤积症可使血浆CRH水平升高(P<0.05)。孕37周前妊娠合并胆汁淤积症对血浆CRH水平无影响(P>0.05)。结论:妊娠期血浆CRH水平与早产关系密切,有可能成为预测早产的有效指标。以血浆CRH水平预测早产时,应注意排除贫血及肝功能损害的影响。     

Blockade of ethanol reward by the kappa opioid receptor agonist U50,488H

Alcoholism is a pervasive social problem, and thus understanding factors that regulate alcohol (ethanol) reward is important for designing effective therapies. One putative regulatory system includes the kappa opioid receptor (KOR) and its endogenous ligand, dynorphin. Previously, we demonstrated that acute ethanol increased preprodynorphin expression via brain-derived neurotrophic factor (BDNF) in striatal neurons, and that blockade of the KOR attenuated decreases in ethanol intake observed following increased expression of BDNF. As high doses of KOR agonists can generate an aversive state, we hypothesized that endogenous dynorphin may regulate ethanol intake by interfering with the rewarding properties of ethanol. We found that low, nonaversive doses of the KOR agonist U50,488H blocked the rewarding properties of ethanol during conditioning, thus impairing the acquisition of conditioned place preference. Importantly, we demonstrate that U50,488H also inhibited the conditioned increase in locomotor activation normally observed in the ethanol-paired chamber on test day. Taken together, these data indicate that the KOR/dynorphin system may acutely regulate ethanol intake via inhibition of the rewarding properties of ethanol.     

Conceptualizing withdrawal-induced escalation of alcohol self-administration as a learned,plasticity-dependent process

This article represents one of five contributions focusing on the topic “Plasticity and neuroadaptive responses within the extended amygdala in response to chronic or excessive alcohol exposure” that were developed by awardees participating in the Young Investigator Award Symposium at the “Alcoholism and Stress: A Framework for Future Treatment Strategies” conference in Volterra, Italy on May 3–6, 2011 that was organized/chaired by Drs. Antonio Noronha and Fulton Crews and sponsored by the National Institute on Alcohol Abuse and Alcoholism. This review discusses the dependence-induced neuroadaptations in affective systems that provide a basis for negative reinforcement learning and presents evidence demonstrating that escalated alcohol consumption during withdrawal is a learned, plasticity-dependent process. The review concludes by identifying changes within extended amygdala dynorphin/kappa-opioid receptor systems that could serve as the foundation for the occurrence of negative reinforcement processes. While some evidence contained herein may be specific to alcohol dependence-related learning and plasticity, much of the information will be of relevance to any addictive disorder involving negative reinforcement mechanisms. Collectively, the information presented within this review provides a framework to assess the negative reinforcing effects of alcohol in a manner that distinguishes neuroadaptations produced by chronic alcohol exposure from the actual plasticity that is associated with negative reinforcement learning in dependent organisms.     

Suppressing effect of the cannabinoid CB1 receptor antagonist, SR147778, on alcohol intake and motivational properties of alcohol in alcohol-preferring sP rats

AIMS: The present study investigated the effect of the newly synthesized cannabinoid CB(1) receptor antagonist, SR147778, on alcohol intake and the motivational properties of alcohol in selectively bred Sardinian alcohol-preferring (sP) rats. METHODS AND RESULTS: In Experiment 1, the repeated administration of SR147778 (0.3-3 mg/kg twice daily, i.p.) specifically suppressed the acquisition of alcohol drinking behaviour in alcohol-naive rats exposed to the two-bottle "alcohol vs water" choice regimen for 24 h/day. In Experiment 2, an acute administration of SR147778 (2.5-10 mg/kg, i.p.) specifically reduced alcohol intake in alcohol-experienced rats that were given alcohol and water under the two-bottle choice regimen in daily sessions of 4 h. In Experiment 3, an acute administration of SR147778 (0.3-3 mg/kg, i.p.) suppressed the "alcohol deprivation effect", i.e. the extra-intake of alcohol occurring after a period of alcohol abstinence. In Experiment 4, an acute administration of SR147778 (0.3-3 mg/kg, i.p.) specifically suppressed the extinction responding for alcohol, i.e. the maximal number of lever responses reached in the absence of alcohol in rats trained to lever-press for alcohol (measure of the motivational properties of alcohol). In Experiment 5, the combination of 3 mg/kg of SR147778 (i.p.) and 0.5 g/kg of alcohol (i.p.), a dose comparable with those usually consumed by sP rats in each drinking binge, failed to induce any conditioned taste aversion. CONCLUSION: Taken together, these results extend to SR147778 the anti-alcohol profile of the prototype cannabinoid CB(1) receptor antagonist, rimonabant (SR141716), and strengthen the hypothesis that the cannabinoid CB(1) receptor is part of the neural substrate mediating alcohol intake and the motivational properties of alcohol.     

Antagonism by naltrexone of voluntary alcohol selection in the chronically drinking macaque monkey

An opiate receptor antagonist can reduce excessive alcohol drinking in the rat previously given intracerebroventricular (ICV) infusions of a tetrahydroisoquinoline. Recently, it was found that cerebrospinal fluid (CSF) obtained from volunteers or human patients and subsequently injected ICV in macaque monkeys markedly alters the voluntary consumption of ethyl alcohol in certain of these primates. The purpose of the present study was to determine whether an opioid antagonist would affect the pattern of alcohol intake in selected monkeys which drank excessive amounts of alcohol. Initially, the preferred concentration of alcohol was determined individually for each monkey which consistently drank from 3.0-6.0 g/kg alcohol per day. Subsequently, the single concentration, which ranged from 5-15%, was offered together with water during three consecutive periods as follows: (1) 4-day control baseline period; (2) a 3-day interval during which a saline control vehicle or 0.6 or 1.2 mg/kg naltrexone was administered subcutaneously at 0900 and 1700 hours; and (3) a final 4-day post-injection period during which the alcohol-water preference test was continued. The results showed that both doses of naltrexone significantly attenuated voluntary alcohol drinking up to 60% of the baseline intake during the 3 days of its administration. In two monkeys, alcohol drinking continued to be suppressed up to 50% of basal intake during all or a part of the 4-day post-naltrexone interval. These findings suggest that an opiate receptor mechanism in the brain could be partially involved in the action of the chemical constituents of the human's CSF which serve to induce an abnormally high intake of alcohol in the infra-human primate.