Acquisition of conditioned avoidance response in rats under the influence of addicting drugs

Four groups of white rats, aged 8–12 weeks, were treated with morphine, d-lysergic acid diethylamide, dl-amphetamine and ethanol, respectively, while being trained in a conditioned avoidance response (CAR) schedule. Morphine caused deterioration in the acquisition of CAR, as manifested by significant increases in the number of training sessions required for 100% correct CAR and in the reaction time (RT), when compared to those of a control group. The RT decreased after withdrawal of morphine and was associated with a revival of the conditioned emotional responses (CER). LSD and ethanol insignificantly retarded the acquisition of CAR, while withdrawal of LSD caused significant increases in the RT, error and CER. Amphetamine facilitated the acquisition rate associated with increased CER; during withdrawal, the CER was negligible whereas the error increased significantly. In another series of rats, tolerance was seen to morphine and, to a less extent, to ethanol and amphetamine after 8–12 days of continued treatment; whereas the withdrawal effects lasted for 3–4 days only. These effects of the addicting drugs on conditioned learning are discussed in the light of their influence on the emotional responses of the animals and the degree of development of drug-dependence.     

Behavioral and electrophysiological effects of phenylethanolamine and 2-phenylethylamine

The electrophysiological and behavioral effects of phenylethanolamine (OHPEA) and of its precursor 2-phenylethylamine (PEA) were studied in mice and rabbits. In animals pretreated with MAOI, PEA was found to exert strong amphetamine-like effects, EEG alerting, reduction of visual evoked responses, increased locomotor activity, and blockade of tonic seizures induced by electroshock. OHPEA exerted weaker amphetamine-like effects. Inhibition of dopamine--hydroxylase increased most of the effects of PEA. In non-pretreated animals, OHPEA was found to shorten electroshock latency and to prolong the duration of visual evoked responses. PEA (but not OHPEA) potentiated the excitement induced by ⁹-tetrahydrocannabinol in MAOI-pretreated mice. Reserpine pretreatment reduced but did not abolish the CNS effects of OHPEA and PEA. One may speculate that endogenous PEA is more likely to serve as a modulator for ergotropic functions than is endogenous OHPEA.     

宫腔镜手术并发症48例的临床分析

目的：探讨宫腔镜手术并发症的致病原因和应对措施。方法48例宫腔镜手术并发症患者,对患者的病史资料进行回顾性分析。结果48例患者中子宫穿孔15例、宫腔粘连16例、大出血8例、灌流液过度吸收综合征4例、空气栓塞1例、输卵管绝育子宫内膜去除术后综合征4例。其中以宫腔粘连和子宫穿孔的发病率最为显著,所有患者经对症治疗后均顺利痊愈。结论引起宫腔镜手术并发症的主要因素有宫腔内操作复杂、子宫肌壁破坏较深、子宫内膜残留和宫腔灌流压力过高,通过改善施术者的手术能力、行腹腔镜监护和加强围手术期护理,能够有效的降低宫腔镜手术并发症的发生率。     

Cholinergic modulation of an opposed effect of d-amphetamine and methylphenidate on the rearing response

Rats given d-amphetamine (1 mg/kg) engage in frequent, short-duration rearing responses, whereas rats given methylphenidate (1 mg/kg) make less frequent, long-duration responses. The effects on this behavior of mixing d-amphetamine or methylphenidate with scopolamine or physostigmine suggest that this opposed action on rearing response duration is related to cholinergic-catecholaminergic balance. The anticholinergic agent scopolamine produces changes in rearing response duration similar to those produced by d-amphetamine, while the cholinergic agent physostigmine lengthens response duration and further potentiates this effect of methylphenidate.     

Effects of phentolamine,dihydroergocristine and isoxsuprine on the blood pressure and heart rate in normotensive,hypotensive and hypertensive rats

Summary Phentolamine, dihydroergocristine and isoxsuprine were compared for their effects on the blood pressure in anaesthetized normotensive rats, in rats made hypotensive by ganglionic blockade or by pithing and in rats with noradrenaline-induced hypertension. Their ability to inhibit pressor responses elicited by electrical stimulation of the posterior hypothalamus and of the sympathetic outflow from the spinal cord was also investigated.All three drugs appeared very potent in inhibiting noradrenaline-induced hypertension and caused a dose-dependent fall in blood pressure in normotensive rats, which however was less pronounced with dihydroergocristine than with phentolamine and isoxsuprine. In hypotensive rats, dihydroergocristine caused a rise in blood pressure.At higher doses than those required to block noradrenaline-induced hypertension, the three drugs inhibited pressor responses elicited by electrical stimulation and were equally active on peripherally- and centrally-evoked responses.Simultaneous recording of heart rate and blood pressure, both in anaesthetized and in pithed rats, indicated a reflex origin for phentolamine-induced tachycardia and a direct cardiac stimulation for isoxsuprine. Reflex changes of heart rate were not observed with dihydroergocristine.     

Xiao-Xu-Ming decoction extract alleviates LPS-induced neuroinflammation associated with down-regulating TLR4/MyD88 signaling pathway in vitro and in vivo

In the present study, we aimed to investigate the effects of Xiao-Xu-Ming decoction extract (XXM) on lipopolysaccaride (LPS)-induced neuroinflammation invitro and invivo. Invitro, the microglia BV2 cells were treated with 200 ng/mL LPS for 24 h to induce inflammatory responses. Invivo, mice were treated with 5 mg/kg LPS to induce inflammatory responses. The NO level was determined by Griess Reagents. The levels of IL-1β, IL-6, TNF-α and MCP-1 were determined by ELISA. The expressions of Iba-1, TLR4 and MyD88 at the protein levels were determined by Western blotting analysis. The mRNA levels of TLR4 and MyD88 were determined by real-time PCR. Invitro, XXMsignificantly reduced the levels of various pro-inflammatory factors, including NO, IL-1β, IL-6 and TNF-α, induced by LPS in the supernatant of BV2 cells and suppressedexpressions of inflammatory proteins TLR4 and MyD88 induced by LPS in BV2 cells. Invivo, XXM significantly inhibited microglia activation, attenuated LPS-induced inflammatory factors and chemokine production, such as IL-1β, IL-6, TNF-α and MCP-1, andinhibited the expressions of inflammatory proteins including TLR4 and MyD88, in the cortex of LPS-induced mice. Our findings suggested that XXM could attenuate LPS-induced neuroinflammation via down-regulating TLR4/MyD88 signaling pathway.     

Initial response to cigarettes predicts rate of progression to regular smoking: Findings from an offspring-of-twins design

The aim of this study was to examine the association between initial subjective effects from cigarettes and the rate of progression from first cigarette to regular smoking. Latent class analysis (LCA) was applied to subjective effects data from 573 offspring of twins ranging in age from 14 to 32 years. LCA revealed four classes: 1) High on both pleasurable and physiological responses, 2) Cough only response, 3) High on physiological, low on pleasurable responses, and 4) High on pleasurable, low on physiological responses. Classes of responses were then used to predict time from first cigarette to the onset of regular smoking in a Cox proportional hazards model. Time-varying covariates representing relevant psychiatric and psychosocial factors as well as dummy variables representing the offspring-of-twins design were included in the model. Members of classes 1 and 4 transitioned more rapidly to regular smoking than the classes characterized as low on the pleasurable response dimension. Our findings provide evidence that previously reported associations between pleasurable initial experiences and progression to regular smoking hold true as well for the rate at which that transition occurs. Furthermore, the fact that profiles of responses did not fall into global categories of exclusively pleasurable vs. exclusively negative (physiological) responses suggests the importance of considering both dimensions in combination to characterize risk for smoking-related outcomes.     

Effects of acute and chronic nicotine on responses maintained by primary and conditioned reinforcers in rats

There is growing recognition that nonnicotine factors, such as the sensory stimuli associated with smoking, can play a critical role in the maintenance of cigarette smoking. However, little is known about the effects of nicotine on responding maintained by these stimuli, which are assumed to be conditioned reinforcers. The authors used an animal model to examine the acute and chronic effects of nicotine on responses maintained by food and conditioned reinforcers (i.e., lights) and responses in the absence of programmed consequences (i.e., extinction). During the acute phase, 4 male rats received 5 doses of subcutaneous nicotine. One dose of nicotine was then administered for a minimum of 60 days. Food-maintained and extinction responses did not significantly increase during the acute phase; however, food-maintained responses did increase during the chronic phase. Relative to vehicle, intermediate doses increased responses maintained by conditioned reinforcers during both phases. The results suggest that nicotine enhances responding maintained by conditioned reinforcers and possibly by food.     

Effects of chlorpromazine and chlordiazepoxide on discriminated lever-press avoidance behavior and intertrial responding in mice

Mice of the BALB/c strain show high levels of intertrial responding during discriminated lever-press avoidance training. Chlorpromazine reduces intertrial responses only at dose levels depressing avoidance behavior. Mice trained under chlordiazepoxide show, instead, performances characterized by high levels of avoidance responding and low levels of intertrial responding.     

Postnatal methyl mercury exposure: effects on ontogeny of renal and hepatic ornithine decarboxylase responses to trophic stimuli

The effects of postnatal methyl mercury exposure on the ontogeny of renal and hepatic responsiveness to trophic stimuli were examined. Increased ornithine decarboxylase (ODC) activity was used as an index of tissue stimulation. In the rat, renal ODC responsiveness to growth hormone, angiotensin, vasopressin, isoproterenol, and serotonin was absent at birth and matured 3 to 4 weeks later. However, pups exposed to methyl mercury showed marked, ODC responses to these same agents as early as 10 to 19 days of postnatal age, accompanied by a significant renal hypertrophy. In contrast to the kidney, the liver of normally developing rats was responsive to trophic factors even in the neonate. In this tissue, there was no consistent effect of neonatal methyl mercury treatment on ODC responses at any developmental stage tested; although absolute liver weights were reduced, liver/body weight ratio was not affected. These results demonstrate that postnatal methyl mercury exposure causes a precocious onset of ODC responses to trophic agents specifically in the kidney. Altered responsiveness may mediate some of the effects of this organomercurial on overall renal development and function.     

The reliability of 5-hydroxytryptamine induced platelet aggregation responses in schizophrenic patients treated with neuroleptic drugs.

1 The reliability of 5-hydroxytryptamine induced platelet aggregation responses in psychiatric patients treated with neuroleptic drugs was investigated by examining the effects of a number of technical factors which could account for the variability of responses observed in some patients. 2 Variation in incubation time, temperature, aggregometer stirrer speed, and in the time interval between withdrawal of the blood sample and testing, had no significant effects on the consistency of responses. 3 Dilution of platelet rich plasma (PRP) led to enhanced platelet aggregation responses becoming non-enhanced. 4 Overcentrifugation of blood samples during the preparation of PRP caused a decrease in the incidence of enhanced platelet aggregation responses observed in chronic schizophrenic patients receiving chlorpromazine. 5 The reliability of platelet aggregation responses as indices of the action of neuroleptic drugs in psychiatric patients remains doubtful.     

Effects of chlorpromazine and d-amphetamine on observing responses during a fixed-interval schedule

Pigeons were trained to peck a response key that briefly produced stimuli correlated with the passage of time in a fixed-interval schedule of food presentation for pecks on another response key. Pecks on the key that produced food were most likely near the end of each fixed interval, whereas pecks on the key that produced the discriminative stimuli were most likely to occur during the middle portion of each fixed interval. Chlorpromazine (3.0–30.0 mg/kg) and d-amphetamine (0.03–3.0 mg/kg) produced inverted U-shaped dose-effect curves with response rate on the food-producing key as the dependent variable, and monotonically decreasing functions were obtained for the discriminative-stimulus producing responses. A rate-dependency interpretation adequately described the drug effects on the temporal distribution of pecks on the food-producing key, but was not consistent with the disruption of the temporal distribution of pecks on the key that produced the discriminative stimuli. The pecks on the discriminative-stimulus producing key had some of the properties of schedule-induced, or adjunctive, behavior. The effects of amphetamine and chlorpromazine on the rate of adjunctive behaviors may not be predictable from control rates.     

Differential expression and functional role of cannabinoid genes in alcohol users

Background

Genetic factors account for about fifty percent of the risk for alcoholism and alcohol dependence (AD) has been reported to be influenced by cannabinoid receptors (CBRs) and the endocannabinoid system (ECS). Previous studies have focused on cannabinoids and alcohol-related effects in the CNS; however, the role CBRs play on alcohol effects in the immune system has not been elucidated yet. Since alcohol can affect immune responses and have detrimental effects on immune cells such as dendritic cells (DCs), we hypothesize that alcohol can exert its effects on DCs by modulating changes in CBRs, which in turn can regulate important DC functions such as cytokine production.

Methods

Therefore, we studied the expression of CNR1 and CNR2, and the novel cannabinoid G protein-coupled receptor (GPCR) 55 (GPR55) in human monocyte-derived dendritic cells (MDDCs) from alcohol users. CNR1, CNR2, and GPR55 genes were measured by qRT-PCR and protein by flow cytometry. MDDCs from alcohol users show significantly higher levels of CNR2 and GPR55 compared to MDDCs from non-users. These findings were further confirmed using MDDCs treated with alcohol. Inflammatory cytokines were measured in EtOH-treated and non-treated cells by antibody array.

Results

Functional effects of CBRs on MDDCs were shown by CB2 and GPR55 siRNA transfection. Transfected EtOH-treated cells showed significantly higher levels of proinflammatory cytokine production as measured by IL-1β expression. Our results provide insights into alcohol mechanisms of DC regulation and show, for the first time, that alcohol is inducing CNR2 and GPR55 in human DCs.     

A novel synthetic derivative of squamosamide FLZ inhibits the high mobility group box 1 protein-mediated neuroinflammatory responses in murine BV2 microglial cells

High mobility group box 1 (HMGB1) is a critical pro-inflammatory cytokine that contributes to the pathogenesis of various human diseases. FLZ, a squamosamide derivative, has been demonstrated to have neuroprotective effects in Parkinson’s disease models and shows strong anti-inflammatory activity, while the precise mechanism remains unclear. Here, we investigated the anti-inflammatory mechanism of FLZ on HMGB1-mediated inflammatory responses. The effects of FLZ on HMGB1 release from microglial cells induced by lipopolysaccharide were first explored by Western blot assay and ELISA. Then, co-immunoprecipition was used to study FLZ’s effect on the interaction between HMGB1 and its receptor TLR4. Finally, we employed HMGB1 to simulate pro-inflammatory responses and then studied the inhibitory effects of FLZ on its bioactivity. FLZ has a significant inhibitory effect on HMGB1 release while it exerts no inhibitory effect on the binding between HMGB1 and TLR4. After the recognition of HMGB1 by TLR4, NF-κB signaling pathway is activated. FLZ could efficaciously alleviate HMGB1-induced inflammatory responses via the suppression of TLR4/MyD88/NF-κB signaling pathway. FLZ could inhibit HMGB1 release as well as HMGB1-induced inflammatory responses, HMGB1 might be one of the FLZ anti-inflammatory targets, and interfering at this inflammatory mediator may have benefit effects on neurodegenerative disorders, such as Parkinson’s disease.

     

响应面法优化桂龙凝胶膏剂提取工艺

目的 优选桂龙凝胶膏剂的提取工艺.方法 采用响应面法,以乌头总碱提取率和干膏得率为指标进行试验,考察乙醇浓度、乙醇用量、提取时间对桂龙凝胶膏剂提取工艺的影响.结果 最佳提取工艺为：乙醇浓度为81.48%,乙醇用量为15.94倍,提取时间为65.62min,提取2次,乌头总碱提取率和干膏得率分别为0.1372mg·g-1和26.16%.结论 优选的提取工艺稳定可行,为桂龙凝胶膏剂的制备提供了实验依据.     

Effect of in vivo desensitization to leukotriene B4 on eosinophil infiltration in response to C5a in guinea-pig skin.

1. The effect of in vivo desensitization to leukotriene B4 (LTB4) on eosinophil infiltration in response to recombinant C5a was examined in guinea-pig skin. 2. LTB4 (10-300 ng) and C5a (1-10 micrograms) caused a dose-dependent increase in the levels of eosinophil peroxidase activity (a measure of eosinophil infiltration) 4 h after injection into guinea-pig skin. Leukotriene B4 and C5a were approximately equipotent on a molar basis. Platelet activating factor (0.01-10 micrograms) also caused eosinophil accumulation but was much less active than LTB4 or C5a. 3. 20-Hydroxy-LTB4 caused a dose-dependent desensitization of eosinophil responses to LTB4 (ED50 = 1.6 micrograms kg-1, s.c.) and partially reduced responses to C5a. At a dose of 20-hydroxy-LTB4 (10 micrograms) which inhibited responses to LTB4 completely, responses to C5a were reduced by 56.5 +/- 1.8% (n = 5). The structurally related metabolite of 20-hydroxy-LTB4, 20-carboxy-LTB4, which does not cause desensitization to the effects of LTB4, did not inhibit eosinophil infiltration in response to C5a. 4. The LTB4 receptor antagonist, SC-41,930 (10 mg kg-1, p.o.), also inhibited eosinophil accumulation in response to C5a by 63.0 +/- 3.9% (n = 5) at a dose which inhibited responses to LTB4 by 86.5 +/- 1.9% (n = 5). 5. These data indicate that eosinophil infiltration in response to C5a may, in part, be mediated by the generation of secondary chemotactic factors such as LTB4.     

The role of metabolism in carbon tetrachloride-mediated immunosuppression: in vivo studies

The role of metabolic bioactivation for carbon tetrachloride-mediated suppression of humoral responses was investigated in B6C3F1 mice. Subchronic studies with CCl4 demonstrated that this chlorinated hydrocarbon markedly suppressed T-dependent antibody responses following 7 consecutive days of administration at doses between 500 and 5000 mg/kg. No significant difference in the magnitude of suppression was observed between the ip and oral routes of exposure. Thirty-day ip administration of CCl4 at doses as low as 25 mg/kg also resulted in a significant inhibition of T-dependent antibody responses. The results from both the 7-day and the 30-day studies indicate that a greater than 50% suppression of antibody responses could not be achieved even at doses of CCl4 as high as 5000 mg/kg. In vivo studies utilized the cytochrome P450 competitive inhibitor, aminoacetonitrile (AAN), in an effort to block the effects of exposure to CCl4. Both the hepatotoxicity, as measured by serum glutamic pyruvic transaminase levels, and the suppression of the T-dependent antibody response to sRBC were reversed by treatment with AAN. Conversely, induction of cytochrome P450, by pretreatment of mice with ethanol prior to treatment with CCl4, resulted in the potentiation of the immunosuppressive effects of CCl4. AAN and ethanol administered alone had no effect on antibody responses. In order to assess the effect of CCl4 treatment on cytochrome P450 activity at doses which cause immunosuppression, measurements of total microsomal protein and specific substrate activities were determined. Significant decreases were observed in both total hepatic microsomal protein as well as in aminopyrine N-demethylase activity, aniline hydroxylase activity, and aryl hydrocarbon hydroxylase activity following treatment with CCl4 for 7 days at doses ranging from 5 to 1000 mg/kg. All of the cytochrome P450 parameters that were measured, following CCl4 treatment, demonstrated very flat dose-response curves which appeared to parallel the effects of CCl4 on antibody responses.     

Cardiovascular and behavioural effects of centrally administered tachykinins in the rat: characterization of receptors with selective antagonists.

1. The effects of intracerebroventricular (i.c.v.) injection of selective and potent NK1 (RP 67580), NK2 (SR 48968) and NK3 (R 486, [Trp7, beta-Ala8]NKA(4-10)) receptor antagonists were assessed on the cardiovascular and behavioural responses elicited by the i.c.v. injection of substance P (SP), neurokinin A (NKA) or [MePhe7]neurokinin B ([MePhe7]NKB) in the conscious freely moving rat. 2. SP, NKA and [MePhe7]NKB (5-650 pmol) evoked dose-dependent increases in mean arterial blood pressure (MAP) and heart rate (HR) with the rank order of potency SP > NKA > [MePhe7]NKB. The cardiovascular responses were accompanied by excessive face washing, grooming and wet dog shakes. 3. The cardiovascular effects and face washing behaviour induced by SP (25 pmol) were significantly reduced by the pre-injection (i.c.v., 5 min earlier) of RP 67580 (6.5 nmol). However, this antagonist failed to affect the central effects of 25 pmol NKA or [MePhe7]NKB. 4. The cardiovascular and behavioural responses (except for wet dog shakes) elicited by NKA (25 pmol) were significantly reduced by 6.5 nmol SR 48968. However, the latter antagonist had no effect on the SP or [MePhe7]NKB-mediated responses. 5. Both cardiovascular and behavioural effects produced by either SP or NKA (25 pmol) were completely abolished when rats were pretreated with a combination of RP 67580 (6.5 nmol) and SR 48968 (6.5 nmol), yet this combination of antagonists failed to modify the central effects of [MePhe7]NKB. 6. R 486 (6.5 nmol) inhibited the cardiovascular effects as well as wet dog shakes produced by [MePhe7]NKB, but it was inactive against the responses induced by either SP or NKA.(ABSTRACT TRUNCATED AT 250 WORDS)     

4-Hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (PI-OH): a new potentiator of sympathomimetic amines on the rat anococcygeus muscle.

1. The potentiating effects of racemic 4-hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (PI-OH), cocaine, desipramine and nomifensine on the concentration-response curves of the rat anococcygeus muscle to noradrenaline (NA) and field stimulation were examined. 2. PI-OH and cocaine concentration-dependently potentiated the responses of anococcygeus muscle to NA and field stimulation, but the activity of PI-OH was stronger than that of cocaine on both responses. 3. At high concentrations the potentiating activities of desipramine and nomifensine were less, a fact that was explained by their postsynaptic inhibitory properties; the actions of nomifensine and desipramine as antagonists against NA were competitive and non-competitive, respectively. 4. It is concluded that PI-OH may be an ideal potentiator of the response to NA in adrenergically-innervated tissues because it has no side effects such as postsynaptic inhibition.