Potential anti-anxiety, anti-addictive effects of LY 354740, a selective group II glutamate metabotropic receptors agonist in animal models

Despite there being a lot of biochemical data about metabotropic glutamate (mGlu) receptors, our knowledge of the behavioural effects of mGlu receptor agonists/antagonists is still inadequate. LY 354740 is a systemically active agonist of group II mGlu receptors. After peripheral administration, LY 354740 produced anxiolytic-like effects in the conflict drinking test in rats and a four-plate test in mice. It was also found that LY 354740 decreased spontaneous locomotor activity in mice, but did not disturb motor coordination. In behavioural models of depression including the despair test and a tail suspension test, LY 354740 did not produce antidepressant-like effects. LY 354740 inhibited the naloxone-induced symptoms of morphine withdrawal in morphine-dependent mice. The above results indicate that agonists of group II mGlu receptors may play a role in the therapy of anxiety and/or drug-dependence states. The brain sites of action of LY 354740 need to be identified and the mechanism of both the above described effects remains to be elucidated.     

Depletion of brain norepinephrine: differential influence on anxiolyic treatment effects

Rationale: Previous studies have demonstrated that anxiolytic-like anticonflict effects can be produced by either (1) acute administration of traditional anti-anxiety compounds (benzodiazepines or barbiturates) or (2) chronic administration of tricyclic (TCA) or monoamine oxidase inhibitor (MAOI) antidepressants. Objective: The present study determined the effects of noradrenergic neuronal depletion on these distinct anticonflict treatments. Methods: After 3 weeks of training in a repeated measures drink suppression conflict paradigm, water-restricted rats consumed 11–14 ml water/session (unpunished responding) and accepted 25–40 shocks/session (punished responding) during control (i.e., non-drug) 10-min test sessions. The noradrenergic neurotoxin DSP4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride; 65 mg/kg, IP] or its vehicle (saline; 1 ml/kg) was administered after 3 weeks of conflict testing. Conflict behavior was then evaluated for 8 weeks post-treatment. In separate groups of DSP4- and vehicle-pretreated subjects, the effects of acute administration (10-min pretreatment) of phenobarbital (5–40 mg/kg) or alprazolam (0.3–2.5 mg/kg) were determined. In a third experiment, the effects of chronic treatment with the TCA desipramine (DMI; 5 mg/kg, twice daily for 8 weeks) or the non-selective MAOI phenelzine (4.0 mg/kg, twice daily for 8 weeks) on conflict behavior were determined in additional groups of DSP4- or vehicle-pretreated subjects. Results: DSP4 treatment produced a modest yet statistically significant decrease in punished responding (i.e., anxiogenic-like effect) relative to vehicle controls. DSP4 pretreatment did not alter the anticonflict effects of acute alprazolam or phenobarbital treatment. In contrast, DSP4 treatment completely abolished the anticonflict effects produced by chronic DMI or chronic phenelzine treatment. Conclusions: Thus, noradrenergic neuronal integrity appears to be required for the anxiolytic-like effects of chronic antidepressant treatment, but not for the anxiolytic-like effects of acute treatment with barbiturates and benzodiazepines. Received: 6 August 1998/Final version: 16 October 1998     

Pharmacological evaluation of a modified conflict procedure: punished drinking in non-water-deprived rats

Rationale: Conflict procedures used to detect anxiolytic-like activity of drugs often rely on maintaining strict schedules of water or food availability. It is ethically and practically desirable to reduce such states of deprivation in animal testing. Objective: The purpose of the present experiment was to develop and pharmacologically characterize a conflict drinking procedure that did not require the use of water-deprived animals. Methods: Rats were tested during daily sessions with alternating unpunished drinking (no tone: lick=sucrose solution) and signaled punished drinking (tone: lick=sucrose+shock) components, and developed individual steady baselines over a brief training period (approximately 3–4 weeks). The drugs tested i.p. were the positive allosteric modulators of γ-amino butyric acid_A (GABA)_A receptors, diazepam (0.03–30 mg/kg), chlordiazepoxide (0.03–30 mg/kg), lorazepam (0.03–10 mg/kg), zolpidem (0.3–10 mg/kg), pentobarbital (1–30 mg/kg), pregnanolone (1–30 mg/kg), and bretazenil (0.03– 10 mg/kg); the 5-hydroxy tryptamine_1A (HT)_1A-mediated anxiolytics, buspirone (1–10 mg/kg) and ipsapirone (1–17 mg/kg); and the negative controls d-amphetamine (0.3–3 mg/kg), haloperidol (0.01–0.3 mg/kg), morphine (0.3–17 mg/kg), and imipramine (0.3–30 mg/kg). Results: The experimental procedure was sensitive to increases in punished drinking by the GABA_A-positive modulators, consistent with their known or putative anxiolytic activity. Further, the 5-HT_1A-mediated anxiolytics increased punished drinking, although to a lesser extent and over a more narrow dose range than did the GABAergic drugs. In contrast, d-amphetamine, haloperidol, morphine, and imipramine failed to increase punished drinking up to doses that decreased unpunished drinking. Conclusions: The present results indicate that water deprivation is not a necessary condition to engender drinking conflict behavior or to obtain pharmacological effects similar to those obtained with other classical conflict procedures. Received: 23 November 1998 / Final version: 15 March 1999     

Relationships of plasma tryptophan availability to course of illness and clinical features of alcoholism: a preliminary study

Rationale: Serotonergic (5-HT) mechanisms may be involved in impulse control (including anti-social behavior) across psychiatric syndromes. Age of onset may differentiate alcoholics on psychopathological characteristics associated with impulse control, especially mood disturbance, hostility, and a broad range of antisocial behaviors. Thus, there may be a predictable relationship between markers of 5-HT function and age of onset-related characteristics. Objective: We tested the hypothesis that there would be a predictable relationship between the ratio of plasma tryptophan to large neutral amino acids (i.e. TRYP/LNAA ratio), a marker of 5-HT function, age of onset and related psychopathological characteristics associated with impulse control. Methods: Fifty-eight male and female DSM-IV diagnosed alcoholics attending an outpatient treatment center completing a comprehensive psychopathological assessment, and from whom blood samples were obtained. Results: Plasma TRYP/LNAA ratio was positively correlated with symptoms of dysphoria, and negatively associated with harm avoidance on Cloninger’s Temperament and Character Inventory. Low tryptophan availability was associated with antisocial-type personality characteristics. Interestingly, the few (nine) subjects who had both early onset alcoholism and antisocial personality disorder had a higher plasma tryptophan but similar TRYP/LNAA ratio to the others. Conclusions: These data suggest that a low plasma TRYP/LNAA ratio is associated with susceptibility to anxiety, antisocial-type personality characteristics, and an early age of onset for alcoholism. In contrast, a high plasma TRYP/LNAA ratio is associated with a later onset of alcoholism and dysphoria. Received: 26 May 1998/Final version: 24 November 1998     

Mild social stress abolishes the effects of isolation on anxiety and chlordiazepoxide reactivity

  Rationale: Social isolation is anxiogenic and may change the effects of anxiolytic drugs. These effects are generally attributed to ”isolation stress”. However, isolation does not affect basal corticosterone levels; thus, it cannot be considered stressful. On the contrary, isolation deprives animals of mild daily stressors that are inherent to social life. Since mild stressors were shown to be anxiolytic in rats, it was postulated that short-term, repeated stressors may abolish the effects of isolation. Objectives: The aim of the present study was to investigate whether short-term, repeated, mild social stress can abolish the consequences of isolation on anxiety and on the effects of chlordiazepoxide. Methods: Rats were housed in groups or in individual cages for 5 days (isolates). Half of isolates were daily submitted to the attacks of a resident rat for 30 min per day, on 4 consecutive days (stressed isolates). On day 5, rats were treated either with vehicle or with chlordiazepoxide and submitted to the elevated plus-maze test. Endocrinological consequences of experimental manipulations were assessed in a different set of rats. Results: Plasma ACTH and corticosterone levels were similar in the three groups. Weight gain was higher, while plasma growth hormone was lower in stressed isolates, both effects being consistent with a mild stress. Isolation had a clear anxiogenic effect. This effect was completely abolished by the daily experience of social stress. Chlordiazepoxide had a significant anxiolytic effect in all three groups. Its effects on classical plus-maze variables did not differentiate the three groups. However, chlordiazepoxide decreased risk assessment activity only in isolates. Conclusions: The lack of appropriate endocrinological changes challenges the concept of ”isolation stress”. However, isolation was anxiogenic in our study and it also induced subtle changes in the effects of chlordiazepoxide. It appears that mild daily stressors have a protective effect against the effects of isolation. Received: 23 May 1998 / Final version: 3 December 1998     

Dose-response relationship for oral idazoxan effects in healthy human subjects: comparison with oral yohimbine

The effects of oral administration of the ₂ adrenergic receptor antagonists idazoxan (20 mg, 40 mg, 80 mg) and yohimbine (20 mg) were compared using a placebo-controlled within-subjects design. Healthy subjects completed 5 test days during which medication effects on mood and anxiety states, physiologic indices, plasma cortisol levels, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were assessed. Idazoxan dose-dependently increased plasma MHPG, plasma cortisol, systolic and diastolic blood pressure, and Panic Attack Symptom Scale scores in healthy subjects. Overall, yohimbine and idazoxan produced a similar pattern of behavioral and neuroendocrine responses. Since idazoxan possesses relatively greater receptor specificity compared to yohimbine, it may be a more useful ₂ antagonist in humans.     

糖尿病合并抑郁和焦虑症的临床观察

目的探讨糖尿病患者合并焦虑、抑郁症的发生率及其对糖尿病的影响。方法采用汉密尔顿焦虑量表(HAMA)和抑郁量表(HAMD)对146例糖尿病患者(患者组)和98名正常人(对照组)进行调查评定,并对其相关因素进行分析。结果①患者组抑郁、焦虑的发生率为41.1%,对照组抑郁、焦虑的发生率为10.2%,两组间有显著性差异(P<0.01);②在糖尿病患者中,抑郁、焦虑与女性、体重指数、糖化血红蛋白、糖尿病慢性并发症及使用胰岛素密切相关。结论抑郁、焦虑在糖尿病患者中发生率较高,对糖尿病的进展及预后具有不良影响。     

福建省畲族中学生心理健康状况

目的了解畲族中学生心理健康状况,以便为少数民族中学生的心理健康教育提供依据.方法以症状自评量表(SCL-90)为测试工具,以当地汉族中学生为对照组,采用随机整群分层抽样研究方法,调查福建省部分畲族中学生的心理健康状况.结果汉畲族中学生在抑郁、恐怖等因子中差异均有显著性,与对照组不同,调查对象的心理健康状况差异不存在显著性.结论畲族中学生总体心理健康水平低于汉族学生.应针对畲族中学生的心理特点进行心理健康的指导和干预工作.     

私立学校初一新生焦虑和抑郁状况

目的探讨私立学校初中新生的情绪状况及性别差异,为开展心理健康教育提供依据.方法采用Zung氏焦虑自评量表(SAS)和抑郁自评量表(SDS),对青岛市某私立学校初一新生228人进行整群抽样测查,匹配市区公立学校初一新生239人作同期对照,并做统计分析.结果观察组有15.79%处于焦虑状态(女生检出率较高),高于对照组(9.21%),差异有显著性(χ2=4.65,P＜0.05);观察组SAS均分高于对照组及常模,其中独生子女SAS均分高于对照组(P＜0.05).观察组中23.25%处于抑郁状态(男生检出率高),明显低于对照组(32.22%)(χ2=4.67,P＜0.05),但SDS均分不低于对照组.焦虑和抑郁同时存在率也以观察组较高(12.28%),与对照组差异有显著性(χ2=4.27,P＜0.05).结论私立学校初一新生存在以女生为主的较高焦虑检出率、以独生子女为主的较高焦虑水平以及以男生为主的抑郁检出率和较高抑郁水平,社会、学校和家庭要根据中学生的年龄和性别特点开展心理健康教育工作.     

妊娠期糖尿病孕妇情绪状态及危险因素分析

目的 :探讨妊娠期糖尿病 ( GDM)孕妇情绪状态及糖尿病的危险因素。方法 :对 4 3例 GDM孕妇和 74例正常孕妇进行对照研究。采集两组孕妇的一般资料 ,并以汉密顿焦虑量表 ( HAMA)、汉密顿抑郁量表 ( HAMD)为工具评定焦虑及抑郁症状。结果 :GDM孕妇焦虑及抑郁症状的发生率均为 2 5 .6 % ( 11/ 4 3) ,焦虑症状的发生率显著高于对照组。GDM孕妇的 HAMA总分及因子分均显著高于对照组。L ogistic回归分析发现 ,孕周、孕妇体重指数、家庭经济状况及 HAMA总分为 GDM的危险因素。结论 :GDM孕妇孕中期焦虑及抑郁症状的发生率较高 ,并且焦虑是 GDM的风险因素。应加强对 GDM孕妇情绪状态变化的检测 ,及时进行心理辅导及心理治疗