Role of the GABAB receptor in alcohol-seeking and drinking behavior

The present paper summarizes experimental data demonstrating the reducing effect of direct agonists and positive allosteric modulators (PAMs) of the γ-aminobutyric acid_B (GABA_B) receptor on different alcohol-related behaviors. Different lines of evidence indicate that direct agonists, including baclofen, effectively suppress acquisition and maintenance of alcohol drinking behavior, relapse-like drinking, and alcohol's reinforcing, rewarding, stimulating, and motivational properties in rats and mice. More recently, the discovery of a positive allosteric modulatory binding site, together with the synthesis of in vivo effective ligands, opened a new avenue of research in GABA_B pharmacology. Accumulating lines of evidence suggest that PAMs retain baclofen's capcity to suppress alcohol consumption and alcohol's reinforcing and motivational properties in rats; these effects occur at doses far from those producing behavioral toxicity.     

Positive allosteric modulation of the GABAB receptor by GS39783 attenuates the locomotor stimulant actions of ethanol and potentiates the induction of locomotor sensitization

Acute ethanol-induced locomotor stimulation and ethanol-induced locomotor sensitization are two behavioral assays thought to model the rewarding effects of ethanol. Recent evidence suggests that GS39783, a GABA_B positive allosteric modulator, may be effective at reducing both the rewarding and reinforcing effects of several drugs of abuse, including ethanol. The goal of this study was to determine if GS39783 was capable of altering acute ethanol-induced stimulation, and the induction and expression of ethanol-induced locomotor sensitization, without effecting basal locomotion levels. Several doses of GS39783 (ranging from 0 to 100 mg/kg, depending on experiment) were tested on adult male DBA/2J mice in four experiments using 3-day basal locomotion and acute ethanol stimulation paradigms, and 14-day induction and expression of ethanol sensitization paradigms. The results of experiment 1 are in agreement with current literature, suggesting that 30 mg/kg doses of GS39783 and lower do not alter basal locomotor activity. In experiment 2, we found that GS39783 significantly decreased acute ethanol stimulation, but only at the 30 mg/kg dose, supporting our hypothesis and other publications suggesting that GABA_B receptors modulate acute ethanol stimulation. Contrary to our hypothesis, GS39783 did not alter the expression of locomotor sensitization. Additionally, repeated administration of GS39783 in conjunction with ethanol unexpectedly potentiated ethanol-induced locomotor sensitization. Further study of GS39783 is warranted as it may be a more tolerable treatment for alcoholism than full agonists, due to its behavioral efficacy at doses that lack sedative side effects. Our results add to current literature suggesting that the GABA_B receptor system is indeed involved in the modulation of ethanol-induced locomotor stimulation and sensitization.     

Protracted withdrawal from ethanol and enhanced responsiveness stress: Regulation via the dynorphin/kappa opioid receptor system

Although recent work suggests that the dynorphin/kappa opioid receptor (DYN/KOR) system may be a key mediator in the stress-related effects of alcohol, the regulation of long-term changes associated with protracted withdrawal from ethanol via the DYN/KOR system has yet to be explored. The objective of the present study was to determine the role of the DYN/KOR system in the regulation of anxiety-related behaviors during an extended period of abstinence from ethanol in animals with a history of ethanol dependence. Male Wistar rats (n = 94) were fed an ethanol or control liquid diet for 25–30 days. Six weeks after its removal, rats were exposed to 20 min of immobilization, and the ability of the KOR antagonist nor-binaltorphimine (nor-BNI) (0–20 mg/kg, intraperitoneal [i.p.]) to attenuate the enhanced responsiveness to stress observed in rats chronically exposed to ethanol was investigated using the elevated plus maze. In addition, the ability of U50,488 (0–10 mg/kg, i.p.) to prime anxiety-like behavior during protracted withdrawal was also examined. Rats with a history of ethanol dependence showed a significant decrease in open-arm exploration after exposure to restraint, indicating an anxiety-like state, compared to similarly treated controls, an effect that was blocked by nor-BNI. nor-BNI also selectively decreased center time and open-arm approaches in ethanol-exposed rats. The highest dose of U50,488 decreased open-arm exploration and the total number of arm entries in ethanol-exposed and control rats. Although lower doses of U50,488 did not affect open-arm exploration in either group, the 0.1 mg/kg dose selectively decreased motor activity in the ethanol-exposed rats when compared to similarly pretreated controls. These findings further support the hypothesis that behaviors associated with withdrawal from ethanol are in part regulated by the DYN/KOR system, and suggest that these effects may be long lasting in nature.     

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.     

Relationship between the serotonin transporter polymorphism and obsessive-compulsive alcohol craving in alcohol-dependent adults: a pilot study

A serotonin deficiency state has been implicated in alcohol-dependent individuals' experience of obsessive-compulsive alcohol craving. Because the serotonin transporter (5-HTT) functions to remove serotonin from the synapse, it is thought that increased reuptake (indicated by the number of high-expressing L_A alleles present in the 5-HTT gene-linked polymorphic region [5-HTTLPR] of the SLC6A4 gene) is associated with an increase in obsessive-compulsive alcohol craving. The current pilot investigation sought to explore this hypothesis by examining the extent to which obsessive-compulsive alcohol craving varies by 5-HTTLPR genotype among participants enrolled in an ongoing pharmacogenetics trial. All participants were screened with a semi-structured diagnostic interview, completed self-report measures of alcohol-related behavior, and underwent peripheral venous blood draw for DNA genotyping. Cross-sectional data obtained at baseline from 176 currently drinking alcohol-dependent individuals were analyzed using multiple regression. Preliminary findings suggest that 5-HTTLPR is not predictive of Obsessive Compulsive Drinking Scale total and factor scores. Although the 5-HTTLPR polymorphism was not related to obsessive-compulsive alcohol craving in this pilot study, additional research is needed to clarify the possible role of serotonergic mechanisms in alcohol craving.     

Reduction of alcohol intake by the positive allosteric modulator of the GABAB receptor, rac-BHFF,in alcohol-preferring rats

Previous research has demonstrated that treatment with the positive allosteric modulator (PAM) of the GABA_B receptor (GABA_B PAM), rac-BHFF, suppressed lever-responding for alcohol and amount of self-administered alcohol in Sardinian alcohol-preferring (sP) rats. The present study was designed to extend the investigation on the anti-alcohol effects of rac-BHFF to alcohol drinking behavior. To this end, sP rats were exposed to the homecage, 2-bottle “alcohol (10%, v/v) vs water” choice regimen, with unlimited access for 24 h/day. rac-BHFF was administered once daily and for 7 consecutive days at the doses of 0, 50, 100, and 200 mg/kg (i.g.). Treatment with rac-BHFF resulted in an immediate, stable, and dose-related reduction in daily alcohol intake; the overall magnitude of reduction in alcohol intake averaged approximately 25%, 40%, and 65% in 50, 100, and 200 mg/kg rac-BHFF-treated rat groups, respectively. An increase in daily water intake fully compensated the reduction in alcohol intake, so that daily total fluid intake was unaffected by treatment with rac-BHFF. Daily food intake tended to be reduced only by the highest dose of rac-BHFF. These results complement closely with previous data indicating that (a) rac-BHFF suppressed operant, oral alcohol self-administration in sP rats and (b) the prototypic GABA_B PAMs, CGP7930 and GS39783, reduced alcohol drinking in sP rats. However, while the reducing effect of CGP7930 and GS39783 on the daily alcohol intake tended to vanish after the first 2–3 days of treatment, the reducing effect of rac-BHFF on daily alcohol intake remained unchanged over the entire 7-day treatment period. These data strengthen the hypothesis that GABA_B PAMs may represent a step forward in the search for GABA_B receptor ligands with therapeutic potential for alcoholism.     

Altered anxiety-like behavior and long-term potentiation in the bed nucleus of the stria terminalis in adult mice exposed to chronic social isolation, unpredictable stress, and ethanol beginning in adolescence

Alcohol and chronic stress exposure, especially during adolescence, can lead to an increased risk in adulthood of developing alcohol use disorders. To date, however, no study has assessed the potential long-term effects of chronic intermittent and unpredictable ethanol (EtOH) exposure in mice chronically stressed beginning in adolescence on brain function and anxiety-like behaviors in adulthood. In particular, alterations in function of the bed nucleus of the stria terminalis (BNST), a brain region heavily implicated in anxiety-related behaviors and altered plasticity following EtOH exposure, may play a key role in the pathological responses to chronic stress and EtOH. In the present study, adolescent and adult C57Bl/6J mice were exposed to a regimen of chronic social isolation and unpredictable stressors and EtOH (or air [sham]; CSI-CUS-EtOH and CSI-CUS-Sham, respectively) for 8-10 weeks. In adulthood, mice were tested for altered anxiety-like behavior (elevated plus maze [EPM] and modified social interaction [SI] test). Following behavioral testing, mice were reexposed to CSI-CUS-EtOH (and CSI-CUS-Sham for controls) for an additional 3 days. Four to six hours following the final EtOH (or air) exposure, field potential recordings of the dorsal-lateral (dl)BNST were performed. Mice first exposed during adolescence to CSI-CUS-EtOH displayed lower levels of anxiety-like behavior on the EPM compared with mice first exposed to CSI-CUS-EtOH during adulthood and control mice only exposed to CSI-CUS-Sham, regardless of age of first exposure. However, mice first exposed to CSI-CUS-EtOH during adulthood displayed lower levels of anxiety-like behavior on the SI test compared with mice first exposed during adolescence and control CSI-CUS-Sham mice. CSI-CUS-EtOH exposure, regardless of age, produced blunted expression of long-term potentiation (LTP) in the dlBNST compared with CSI-CUS-Sham mice. This study demonstrates age-dependent effects of chronic unpredictable ethanol exposure in chronically stressed mice on anxiety-like behaviors during adulthood. Further, CSI-CUS-EtOH exposure results in blunted LTP expression in the adult dlBNST.     

Brain region specific modulation of ethanol-induced depression of GABAergic neurons in the brain reward system by the nicotine receptor antagonist mecamylamine

The mechanisms underlying ethanol-induced activation of the mesolimbic dopamine system are not fully understood, but increased extracellular dopamine in the nucleus accumbens (nAc) has been shown to involve nicotinic acetylcholine receptors (nAChRs). Basal activity of dopaminergic neurons in the ventral tegmental area (VTA) is under the influence of GABAergic neurotransmission, and the aim of this study was to characterize the involvement of nAChRs in mediating acute ethanol effects on GABAergic activity in subregions of the brain reward system. Multi-electrode in vivo recordings were made in the VTA and nAc of awake and behaving C57BL6/J mice receiving intraperitoneal injections of saline or ethanol (2.0 g/kg), combined with, or without, pre-injection of the non-competitive nAChR antagonist mecamylamine (1.0 mg/kg). Ethanol significantly decreased the activity of quinpirole-insensitive slow-spiking and fast-spiking units in both the VTA and the nAc as compared to saline injection. Pre-treatment with mecamylamine inhibited the rate-inhibiting properties of ethanol in the VTA, but not in the nAc. The data presented here show that ethanol depresses the activity of quinpirole-insensitive, putative GABAergic neurons, in the mesolimbic dopamine system of mice, and that nAChRs contribute to this modulation. This finding, taken together with previous microdialysis studies, supports an involvement of GABAergic neurons and nAChRs in ethanol's interaction with the mesolimbic dopamine system.     

Effects of heroin-assisted treatment on alcohol consumption: findings of the German randomized controlled trial

Alcohol has been suggested to be a risk factor for opioid-dependent patients in methadone maintenance treatment (MMT). Literature shows that MMT has limited effects on alcohol use. Nevertheless, a decrease in alcohol use was detected in the Swiss heroin-assisted treatment (HAT) study. In this article, we carry out an in-depth analysis of the German HAT trial with the aim of determining whether alcohol use was affected among patients undergoing HAT and MMT. Analysis was carried out using self-reported data on consumption units of alcohol used (CU), Addiction Severity Index composite scores (ASI CSs), and carbohydrate-deficient transferrin (CDT) measures. Results suggest significant reduction of CU and CDT in both groups, yet larger effects in the HAT group. ASI CS significantly decreased in the HAT but not in the MMT group. The greater benefit of HAT in reducing alcohol use may be due to the greater daily frequency of dispensing heroin coupled with a requirement of sobriety at each dosing occasion.     

The role of gamma-hydroxybutyric acid in the treatment of alcoholism: from animal to clinical studies

Since its discovery nearly 40 years ago, gamma-hydroxybutyric acid (GHB) has attracted several waves of scientific interest due to new developments in the knowledge of its mechanisms of action and ideas for its potential use in clinical practice. Its effects have been claimed to treat different psychiatric conditions, but over time its use has become limited to a few specific situations (e.g. sedating patients in non-painful surgical procedures and narcolepsy). New interest in the drug derives from its potential use in the treatment of alcoholism. Recent studies demonstrated a marked effect of the substance in suppressing ethanol (ETOH) withdrawal symptoms and in reducing craving for alcohol, compared to other available drugs. However, GHB has to be given under very careful supervision because of its side-effects, including the risk of abuse and dependence and possible interference with the metabolic pathways of endogenous GHB and ETOH. This short review discusses these and related issues and we hope that it will stimulate further interest in GHB.     

Effects of stress,acute alcohol treatment,or both on pre-pulse inhibition in high- and low-alcohol preferring mice

Pre-pulse inhibition of the acoustic startle reflex (PPI) is a measure of sensorimotor gating frequently used to assess information processing in both humans and rodents. Both alcohol and stress exposure can modulate PPI, making it possible to assess how stress and alcohol interact to influence information processing. Humans with an increased genetic risk for alcoholism are more reactive to stressful situations compared to those without a family history, and alcohol may have stress-dampening effects for those with high genetic risk. The purpose of the present study was to examine the effects of stress, acute alcohol exposure, or both on PPI in male and female mice selectively bred for high- (HAP2) and low- (LAP2) alcohol preference. Experiment 1 assessed the effects of various doses of acute alcohol on PPI. Experiments 2 and 3 assessed the effect of 10 days of restraint stress on subsequent PPI tested at 30 min (Experiment 2) or 24 h (Experiment 3) following the termination of stress exposure. Experiment 3 also examined the effects of acute alcohol treatment (0.75 g/kg) on PPI in mice previously exposed to stress or no stress. Results indicate that 0.75 and 1.0 g/kg doses of alcohol increased PPI in HAP2 but not LAP2 mice. When PPI was tested 30 min after stress exposure, stressed HAP2 mice showed a trend toward decreased PPI and stressed LAP2 mice showed a trend toward increased PPI. The combination of stress and alcohol treatment did not alter PPI in either line 24 h following the termination of stress exposure, suggesting that alcohol does not ameliorate the effect of stress on PPI. Stressed LAP2 mice had increased basal circulating corticosterone on the final stress exposure day compared to non-stressed LAP2 mice, and no difference was found between stressed and non-stressed HAP2 mice. The results suggest that high genetic risk for alcoholism may be related to increased sensitivity to alcohol and stress effects on PPI, and this sensitivity could signify an endophenotype for increased genetic risk to develop alcoholism.     

The interaction of chronic restraint stress and voluntary alcohol intake: Effects on spatial memory in male rats

Alcohol consumption and exposure to stressful life events activate similar neural pathways and thus result in several comparable physiological and behavioral effects. Alcoholics in treatment claim that life stressors are the leading cause of continued drinking or relapse. However, few studies have investigated the interactive effects of stress and alcohol on cognitive behavior. The effects of restraint stress, alcohol, and stress in combination with alcohol were examined on a spatial memory test, the object placement (OP) task. In addition, intake levels were measured to determine if stress altered general consumption of alcohol. Male Sprague-Dawley rats were assigned to one of four conditions: no alcohol/no stress control (CON), stress alone (STR), alcohol alone (ALC), and STR + alcohol (STR + ALC). Following each restraint stress bout, the STR + ALC and the ALC groups were given access to 8% alcohol for 1 h using the two-bottle choice limited access paradigm. As predicted, the STR + ALC group significantly increased alcohol consumption, while the ALC group had consistent drinking over the 10-day treatment. On the OP task, STR and ALC groups performed at chance levels, whereas the CON and STR + ALC groups significantly discriminated between objects in the new and old locations. These data show that stress increases alcohol intake and the intake of alcohol is associated with reduction of the stress-induced impairment of spatial memory. The data have important implications for the development of alcohol abuse and its treatment.     

多学科合作诊疗系统治疗孕妇心理问题诱发的躯体功能障碍临床研究

目的探讨应用多学科合作模式的生理调控、心理调节、音乐调理(PPM)干预措施(基于产科),治疗孕妇心理问题诱发的躯体功能障碍的临床效果。 方法选择2016年3～4月,在天津市滨海新区大港妇女儿童保健中心、广州市越秀区妇幼保健院、烟台市烟台山医院、天津市滨海新区汉沽妇女儿童保健中心及天津市河北区妇女儿童保健中心孕产妇心身健康门诊,进行产前检查的100例孕妇为研究对象,采取抽签方式进行随机抽样,将受试者分为观察组和对照组各50例。观察组在传统健康教育基础上应用PPM干预措施治疗,对照组仅进行传统健康教育。治疗3周后,采用统计学方法比较两组孕妇治疗后主诉躯体功能障碍主要症状变化、自主神经系统(VNS)功能状态变化及汉密顿焦虑量表(HAMA)评分值差异。两组受试者治疗前VNS功能状态均为紊乱,且两组孕妇年龄、学历、职业、产妇类型及孕龄构成比,以及治疗前HAMA评分值比较,差异均无统计学意义(P>0.05)。本研究遵循的程序符合上述各医疗单位人体试验委员会制定的伦理学标准,得到其伦理委员会批准,征得受试对象知情同意,并与之签署临床研究知情同意书。 结果①观察组孕妇治疗后,多梦、易醒、入睡困难、尿频、恶心、呕吐、便秘、胃胀、胸闷、心悸、口干及肌肉酸痛12项躯体功能障碍主要症状,均较对照组孕妇有显著改善,且差异有统计学意义(P<0.05)。②两组孕妇治疗后,VNS功能状态构成比比较,差异有统计学意义(χ²＝79.704,P＝0.000),观察组孕妇VNS功能状态主要为平衡状态,而对照组孕妇仍主要为紊乱状态。③观察组孕妇治疗后HAMA评分值[(1.9±1.2)分]较对照组[(9.8±2.5)分]显著降低,且差异有统计学意义(t＝－19.490,P＝0.000)。 结论应用多学科合作模式的PPM干预措施(基于产科)治疗孕妇由心理问题诱发的躯体功能障碍,疗效显著;同时对焦虑、抑郁亦起到治疗作用。     

职业应激对行车调度员糖皮质激素受体及免疫功能的影响

目的探讨慢性职业应激对行车调度人员糖皮质激素受体(GR)及免疫功能的影响.方法采用职业应激量表,将接受调查的112名行车调度人员分为重、中、轻度职业应激组.采集外周静脉血,测定血清皮质醇(GCs)含量、GR水平和CD3、CD4、CD8等淋巴细胞表面分子阳性细胞的百分率,以及血清白细胞介素2(IL-2)水平,并对各项指标进行相关分析.结果与轻度职业应激组血清GCs含量[(181.01±53.41)ng/ml]相比,重、中度职业应激组GCs含量明显增高[分别为(295.43±79.06)、(274.34±70.08)ng/ml],差异有显著性(P＜0.05);而外周淋巴细胞GR水平明显低于轻度职业应激组[分别为(4 330.0±1 001.0)、(3 971.6±966.8)、(5 141.3±1 068.5)位点/细胞],差异亦有显著性(P＜0.05);重度职业应激组T细胞CD3表达百分率明显低于轻度职业应激组[分别为(50.21±10.30)%、(56.87±15.36)%],差异有显著性(P＜0.05);重、中度职业应激组CD4百分率明显低于轻度职业应激组[分别为(23.27±10.01)%、(27.06±7.47)%、(33.31±7.77)%];而重、中度职业应激组的CD8百分率则明显高于轻度职业应激组[分别为(28.16±6.47)%、(25.54±6.70)%、(21.91±5.93)%],差异均有显著性(P＜0.05);重、中度职业应激组CD4/CD8比值明显低于轻度职业应激组[分别为(0.86±0.24)、(1.13±0.26)和(1.60±0.37)],同时,重度职业应激组的CD4、CD8的百分率及CD47/CD8比值与中度职业应激组的差异均有显著性(P＜0.05);重、中度职业应激组血清IL-2水平明显低于轻度职业应激组[分别为(0.77±0.05)、(0.80±0.07)、(1.05±0.12)ng/ml],差异有显著性(P＜0.05).相关分析结果表明,血清皮质醇含量与CD8百分率之间具有明显的相关关系(r=-0.612,P＜0.01).结论慢性职业应激可导致人体糖皮质激素水平升高和GR水平下调,对机体免疫功能具有抑制作用.     

Effects of fenfluramine, 8-OH-DPAT, and tryptophan-enriched diet on the high-ethanol intake by rats bred for susceptibility to stress

The swim-test susceptible (SUS) line of rats has been bred in our laboratory for the characteristic of reduced motor activity in the swim test following exposure to an acute stressor. Testing of multiple generations of SUS rats has also revealed that they consume large amounts of ethanol voluntarily. As reported for lines of rats that show a propensity for high-ethanol intake, the SUS rats show evidence of low serotonergic function. Because serotonergic function has often been shown to be involved in the regulation of alcohol consumption, here we examined the effects of manipulations of serotonin transmission on intake of ethanol by SUS rats. Fenfluramine, a serotonin-releasing drug, was injected at various doses (0.625, 1.25, 2.5, and 5.0 mg/kg) twice per day and ethanol intake was measured using a two-bottle free-choice method. The 8-OH-DPAT, a 5?HT_1A agonist, was injected at various doses (0.03125, 0.0625, 0.125, 0.25, 0.5, and 1.0 mg/kg) before a 1-h session of exposure to ethanol (single-bottle test, water available the other 23 h per day). A diet enriched with 3% tryptophan (TRP), the amino acid precursor for serotonin synthesis, was administered in a restricted feeding schedule (5 h per day) with ethanol intake measured the last 4 h. Fenfluramine decreased ethanol intake at all doses tested. The 8-OH-DPAT increased ethanol intake at lower doses, presumably acting at autoreceptors, which inhibit serotonergic neurons, and decreased intake at higher doses, presumably acting at postsynaptic 5-HT_1A receptors. TRP-enriched diet also significantly decreased ethanol intake. Food and water intake were less or unaffected by these three manipulations. With all three manipulations, ethanol intake remained suppressed one or more days after the day of tests that decreased ethanol intake. These data suggest that SUS rats, like many other lines/strains of rodents that consume large amounts of alcohol, show an inverse relationship between serotonin transmission and voluntary intake of ethanol.     

A review of the interactions between alcohol and the endocannabinoid system: Implications for alcohol dependence and future directions for research

Over the past fifty years a significant body of evidence has been compiled suggesting an interaction between the endocannabinoid (EC) system and alcohol dependence. However, much of this work has been conducted only in the past two decades following the elucidation of the molecular constituents of the EC system that began with the serendipitous discovery of the cannabinoid 1 receptor (CB1). Since then, novel pharmacological and genetic tools have enabled researchers to manipulate select components of the EC system, to determine their contribution to the motivation to consume ethanol. From these preclinical studies, it is evident that CB1 contributes the motivational and reinforcing properties of ethanol, and chronic consumption of ethanol alters EC transmitter levels and CB1 expression in brain nuclei associated with addiction pathways. These results are augmented by in vitro and ex vivo studies showing that acute and chronic treatment with ethanol produces physiologically relevant alterations in the function of the EC system. This report provides a current and comprehensive review of the literature regarding the interactions between ethanol and the EC system. We begin be reviewing the studies published prior to the discovery of the EC system that compared the behavioral and physiological effects of cannabinoids with ethanol in addition to cross-tolerance between these drugs. Next, a brief overview of the molecular constituents of the EC system is provided as context for the subsequent review of more recent studies examining the interaction of ethanol with the EC system. These results are compiled into a summary providing a scheme for the known changes to the components of the EC system in different stages of alcohol dependence. Finally, future directions for research are discussed.     

KCa2 channels: Novel therapeutic targets for treating alcohol withdrawal and escalation of alcohol consumption

Small-conductance, calcium-activated potassium (K_Ca2) channels influence neuronal firing properties, intrinsic excitability, and NMDA receptor-dependent synaptic responses and plasticity. In this mini-review, we discuss new evidence that chronic alcohol-associated plasticity critically involves K_Ca2 channels in hippocampus, ventral tegmental area, and nucleus accumbens. K_Ca2 channel activity can modulate the magnitude of excitation of midbrain dopamine neurons induced by acute alcohol exposure. Emerging evidence indicates that K_Ca2 channels regulate neuroadaptations to chronic alcohol that contribute to withdrawal hyperexcitability and escalation of voluntary alcohol consumption. Restoring K_Ca2 channel activity can attenuate the severity of the alcohol withdrawal syndrome in vivo and withdrawal-associated neurotoxicity in vitro. Pharmacological modulation of K_Ca2 channels can bi-directionally influence drinking behavior in rat and mouse models of voluntary alcohol consumption. Collectively, these studies using various rodent models have clearly indicated a central role for K_Ca2 channels in the neuroplasticity of chronic alcohol exposure. In addition, accumulating evidence suggests that K_Ca2 channels are a novel therapeutic target to alleviate the symptoms of alcohol withdrawal and reduce high amounts of alcohol drinking.     

Role of the renin-angiotensin system in the pathogenesis,clinical picture and treatment of diabetic nephropathy

Prevalence of diabetic nephropathy is increasing. Understanding of pathogenesis and clinical picture helps to manage this disease. Recent data of the research of this disease support that the renin-angiotensin system plays a pivotal role in the pathogenesis. Hyperglycaemia activates the renin-angiotensin system and induces transforming growth factor-beta expression. These both lead to glomerulosclerosis and tubulointerstitial fibrosis. Diabetic nephropathy develops earlier and progress faster in patients with DD or ID genotypes of angiotensin-I-converting-enzyme gene. Angiotensinogen and type 1 angiotensin-II-receptor gene mutations may be also predisposing factors for diabetic nephropathy. All these factors can be responsible for the hyperfiltration, albuminuria, salt sensitivity, and hypertension, which are characteristic features of diabetic nephropathy. According to these, one can suppose that inhibitors of the renin-angiotensin system are effective in the prevention and treatment of this disease. Evidence of clinical studies suggests that angiotensin-I-converting-enzyme inhibitors in type 1 diabetes can prevent overt nephropathy, decrease proteinuria, inhibit the loss of the glomerular filtration and decelerate progression. Angiotensin-II-receptor blockers exert the same effect in type 2 diabetic patients, and presumably angiotensin-I-converting-enzyme inhibitors have similar activity in this group of patients. That is why, in the case of intolerance of one class of drugs, the other should be substituted. Combination therapy of angiotensin-I-converting-enzyme inhibitors with angiotensin-II-receptor blockers can be the choice of treatment in the future.