The effect of α-amanitin on passive and active avoidance acquisition in mice

-Amanitin, a specific and potent inhibitor of form II DNA-dependent RNA polymerase, produced greater than 98% inhibition of the enzyme in mouse brain within 2 h of intracerebroventricular (icv.) injection. Mice were given one trial passive avoidance training and retested on the task 4 h later. Mice treated with -amanitin 2 h before training or immediately after training demonstrated a retention deficit when compared to non-injected or saline injected controls.Active avoidance was trained for 1 h using a Sidman schedule with a drumturning response. Performance during the last 15 min of training was compared to performance in the first 15 min of a retesting session, 4 h after training. -Amanitin, 2 h prior to training reduced the number of responses, per cent escapes and per cent avoidances in the retesting session. Post-training injection of -amanitin significantly reduced the number of responses and per cent avoidances.Rotarod and spontaneous motor activity were not affected by -amanitin. Whole body temperature was slightly and transiently reduced in icv. administration of -amanitin.     

A comparative study on the effects of the benzodiazepine midazolam and the dopamine agents, apomorphine and sulpiride, on rat behavior in the two-way avoidance test

In recent years, studies in behavioral pharmacology have shown the involvement of dopaminergic mechanisms in avoidance behavior as assessed by the two-way active avoidance test (CAR). Changes in dopaminergic transmission also occur in response to particularly threatening challenges. However, studies on the effects of benzodiazepine (BZD) drugs in this test are still unclear. Given the interplay of dopamine and other neurotransmitters in the neurobiology of anxiety and schizophrenia the aim of this work was to evaluate the effects of systemic administration of midazolam, the dopaminergic agonist apomorphine, and the D₂ receptor antagonist sulpiride using the CAR, a test that shows good sensitivity to typical neuroleptic drugs. Whereas midazolam did not alter the avoidance response, apomorphine increased and sulpiride reduced them in this test. Escape was not affected by any drug treatments. Heightened avoidance was not associated with the increased motor activity caused by apomorphine. In contrast with the benzodiazepine midazolam, activation of post-synaptic D₂ receptors with apomorphine facilitates, whereas the D₂ receptor antagonism with sulpiride inhibited the acquisition of the avoidance behavior. Together, these results bring additional evidence for a role of D₂ mechanisms in the acquisition of the active avoidance.     

Comparison of the effects of acute and subchronic administration of atipamezole on reaction to novelty and active avoidance learning in rats

The effects of an α₂-adrenoceptor antagonist, atipamezole, on exploratory behaviour in a novel environment, spontaneous motor activity and active avoidance learning were studied after acute injection and continuous infusion (0.1 mg/kg h) for 24 h and 6–9 days in rats. The effects of atipamezole on biogenic amines and their main metabolites in brain were studied after an acute injection (0.3 mg/kg s.c.) and continuous infusion (0.1 mg/kg h) for 24 h and 10 days. The level of central α₂-adrenoceptor antagonism and the drug concentration in blood and in the brain were measured after continuous infusion for 24 h and 10 days. In behavioural tests, atipamezole had no effect on spontaneous motor activity at any of the doses studied. However, after both acute administration and continuous 24-h infusion, atipamezole decreased exploratory behaviour in a staircase test, but no longer after 6 days of continuous infusion. Acute administration of atipamezole impaired performance in active avoidance learning tests causing a learned helplessness-like behaviour. When the training was started after 7 days of continuous infusion, atipamezole significantly improved active avoidance learning. There was a significant increase in the metabolite of noradrenaline (NA), 3-methoxy-4-hydroxyphenylethyleneglycol sulphate (MHPG-SO₄), after 24 h but not any longer after 10 days of continuous atipamezole infusion, although the extent of central α₂-adrenoceptor antagonism was unchanged and the atipamezole concentration present in brain was even elevated at 10 days compared to levels after 24-h infusion. In conclusion, these results reveal that acute and sub-chronic atipamezole treatments have different and even opposite effects on behaviour in novel, stressful situations. After acute treatment, atipamezole potentiates reaction to novelty and stress, causing a decrease in exploratory activity and impairment in shock avoidance learning. After subchronic treatment, there was no longer any effect on exploratory behaviour and, in fact, there was an improvement in the learning of a mildly stressful active avoidance test. The changes in behaviour occurred in parallel with attenuation in the MHPG-SO₄-increasing effect, thus the suppressed behaviour in the present test conditions after acute atipamezole injection is associated with a major increase in central NA release. The results support the role of α₂-adrenoceptors and noradrenergic system in reactions both to novelty and stress and have possible implications in cognitive functions as well as in depression. Received: 6 August 1998 / Accepted: 4 January 1999     

Forebrain serotonin and avoidance learning: Behavioural and biochemical studies on the acute effect of p-chloroamphetamine on one-way active avoidance learning in the male rat

The acute effects of p-chloroamphetamine (PCA) on one-way active avoidance learning and on central monoamine concentrations were examined in the male rat. The 5-HT specificity of the acute behavioural effect of PCA was examined in several experiments. PCA (0.08–5 mg/kg IP) injected 30–60 min before testing produced a dose-related impairment of both avoidance acquisition and retention. Pretreatment with the selective serotonin (5-HT) uptake inhibitors fluoxetine and zimelidine, but not the noradrenaline (NA) uptake inhibitor desipramine, resulted in a blockade of the avoidance deficit. Degeneration of brain 5-HT neurons by a high neurotoxic dose of PCA (2 × 10 mg/kg IP) 7 days prior to the administration of PCA also blocked the avoidance deficit. There was also a complete blockade of the PCA-induced avoidance deficit by pretreatment with metergoline, a central 5-HT receptor blocking agent. A 2.5 mg/kg dose of PCA examined 60 min after injection produced regional changes in the 5-HT levels preferentially in the forebrain region with significant reductions in the cerebral cortex, hippocampus and striatum while marginal effects were observed in the hypothalamus, midbrain and spinal cord. PCA failed to reduce dopamine and noradrenaline concentrations in the time- and dose-range of the avoidance deficit. Thus, the avoidance learning impairment appears to be specifically related to the acute release of endogenous 5-HT from presynaptic nerve endings possibly in the forebrain resulting in stimulation of postsynaptic 5-HT receptors. These findings indicate that 5-HT neurons in the forebrain play a role in active avoidance learning possibly by an involvement in memorial and/or retrieval processes.     

The effects of chronic amphetamine administration on the acquisition and extinction of an active and passive avoidance response in mice

Long-term amphetamine treatment had no effect on the acquisition or retention of an active or passive avoidance response. In both tasks, however, mice withdrawn from chronic amphetamine administration showed a resistance to extinction relative to control animals. These findings were related to the effects of long-term amphetamine administration on attentional processes. Possible neurochemical mechanisms governing the attentional deficits induced by chronic exposure to amphetamine were discussed.     

Effects of acute and chronic administration of antidepressant drugs on the central cholinergic nervous system: Comparison with anticholinergic drugs

The purpose of this investigation was to study the effects of antidepressant drugs on the central cholinergic system of the rat after acute and chronic administration. Drugs (antidepressants and non-antidepressants) were first divided into highly potent, moderately potent or weak anticholinergic categories based upon the ability of each compound to displace [³H]-QNB ([³H]quinuclidinyl benzilate from synaptosomal membranes. One antidepressant drug and one non-antidepressant drug, with similar anticholinergic properties, were chosen as representative agents of each category of anticholinergic potency. Acute administration of amitriptyline or atropine (highly potent anticholinergics) increased the level of high affinity uptake of choline in the hippocampus and striatum. Imipramine and thioridazine (moderately potent anticholinergics) increased the uptake of choline only in the striatum. After acute administration, the effects of nomifensine and d-amphetamine (weak anticholinergics) differed on striatal uptake of choline. Following 30 days pretreatment with any drug, an acute challenge dose of that drug no longer altered the uptake of choline in either region. After chronic administration, amitriptyline increased the density of muscarinic receptors in the cortex whereas atropine increased the density of receptors in the cortex, hippocampus and striatum. The other agents did not alter receptor parameters in the regions examined. Since the central cholinergic actions of the antidepressants were similar to the central actions of the non-antidepressants, it is concluded that the effects of the antidepressants on the central cholinergic nervous system are more closely related to the side effects of these agents than to their therapeutic mechanism of action.     

The effects of acute administration of propranolol and practolol on the uptake,content, release,and turnover of noradrenaline in the rat heart in vivo

Summary The effect of the acute administration of (±)-, (+)-, and (–)-propranolol and practolol, respectively, on the cardiac turnover of noradrenaline was studied in male Wistar rats kept under controlled conditions of environmental lighting. Propranolol caused no or only minor effects on the turnover in concentrations of 0.001–0.1 mmoles/kg, whereas higher doses (0.2–0.4 mmoles/kg) decreased the noradrenaline turnover in rat hearts concomitantly with toxic signs from the CNS. The endogenous noradrenaline content was not changed by any concentration of propranolol. Practolol (0.1–0.4 mmoles/kg) did not influence the cardiac noradrenaline turnover, but, like an indirectly acting sympathomimetic drug, released noradrenaline.Supported by a grant of the Deutsche Forschungsgemeinschaft.     

The effect of amitriptyline and mianserine (Org. GB94) on food motivated behaviour of rats trained in a runway: Possible correlation with biogenic amine concentration in the limbic system

Rats on a 23 h food deprivation schedule were trained to run down a straight runway for a food reward. Neither amitriptyline nor mianserine had an effect on the running time for the food reward during the period of continuous reinforcement. However both antidepressants delayed the extinction of this response. It seems unlikely that this effect on extinction was due to an altered motivation for the food reward as amitriptyline significantly decreased the food intake of the experimental animals while mianserine increased the food intake throughout the period of the experiment. The observation that both these antidepressants reduce the speed of extinction of rewarded behaviour may be explicable in terms of observed changes in the concentration of biogenic amines in the limbic system.This article has been delayed due to an error in the editorial office for which we apologizeTo whom offprint requests should be sent     

Effect of acute and prolonged tianeptine administration on the 5-HT transporter: electrophysiological,biochemical and radioligand binding studies in the rat brain

In the present study, in vivo extracellular unitary recordings, in vitro [³H]5-HT uptake and [³H]cyanoimipramine binding assays were used to assess the effect of acute and prolonged administration of the putative antidepressant tianeptine, on the 5-hydroxytryptamine (5-HT) transporter. Microiontophoretic application of tianeptine onto dorsal hippocampus CA₃ pyramidal neurons, as well as its intravenous administration (2 mg/kg), increased their firing frequency. Following intracerebroventricular administration of 5,7-dihydroxytryptamine, the activation induced by the microiontophoretic application of tianeptine remained unchanged, thus suggesting that the 5-HT carrier is not involved in this effect. Furthermore, in spite of its activating effect on CA₃ pyramidal neuron firing frequency, the intravenous administration of tianeptine did not alter the time of recovery of these neurons from microiontophoretic applications of 5-HT, an index of 5-HT uptake activity. In keeping with this observation, the acute administration of tianeptine did not change the effectiveness of the 5-HT reuptake blocker paroxetine (1 mg/kg, i.v.) in prolonging the suppressant effect of microiontophoretically-applied 5-HT. However, in rats that had received tianeptine for 14 days (20 mg/kg/day, s.c.), the recovery time from the suppressant effect of microiontophoretic applications of 5-HT was reduced by 40% and the effectiveness of paroxetine (1 mg/kg, i.v.) was decreased. These effects were no longer observed following a 48 h washout period. In a second series of experiments, the ability of tianeptine to interfere with the uptake blocking capacity of paroxetine was assessed in vitro, using hippocampal slices obtained from rats that had been treated with tianeptine for 14 days (20 mg/kg/day, s.c.; by minipump). The effectiveness of paroxetine to block [³H]5-HT uptake was unchanged in slices obtained from rats still bearing the osmotic minipump at the time of the sacrifice, as well as from those which had undergone a 48 h washout period. To assess whether prolonged administration of tianeptine would induce adaptive changes on 5-HT uptake sites, [³H]cyanoimipramine-binding parameters were measured following a 48 h washout period. Affinity values remained unchanged while density values were significantly increased in cortex (+22%) but not in hippocampus (+12%). It is concluded that, i) the activation of CA₃ pyramidal neurons observed following acute tianeptine administration cannot be attributed to its 5-HT uptake enhancing properties and ii) the prolonged administration of tianeptine induces adaptive changes on cortical but not on hippocampal 5-HT transporters.Deceased 10 May 1994     

三七总皂苷联合三苯氧胺对人乳腺癌细胞的抑制作用及对PI3K-AKT-mTOR信号通路的影响

目的 探讨三七总皂苷(PNS)联合三苯氧胺(TAM)对人乳腺癌细胞的抑制作用及对PI3 K-AKT-mTOR信号通路的影响.方法 70只裸鼠于右胸部皮下接种乳腺癌LCC2细胞,选取造模成功的66只裸鼠随机分为6组,每组11只,分别为模型对照组、单纯5 mg· kg-1TAM组、100 mg·kg-1 PNS组、200 mg·kg-1 PNS组、5 mg·kg-1 TAM+100 mg·kg-1 PNS组、5 mg·kg-1TAM +200mg·kg-1 PNS组、连续给药30 d,每周记录裸鼠体质量,肿瘤抑制率,给药结束后分离瘤体并称重,观察瘤体病理组织学结果,采用免疫组化法检测HER-2,谷胱甘肽S转移酶(GST-л)及天冬氨酸蛋白水解酶(Caspase-3)的表达情况.结果 与TAM组相比较,5 mg·kg-1 TAM+ 100 mg·kg-1 PNS组和5 mg·kg-1 TAM +200 mg·kg-1PNS组肿瘤抑制率均大于单纯TAM组(P＜0.05),5 mg·kg-1 TAM+ 100 mg·kg-1 PNS组和5 mg·kg-1 TAM+ 200 mg·kg-1 PNS组HER-2及GST-л表达水平显著低于单纯TAM组(P＜0.05),Caspase-3表达显著高于单纯TAM组(P＜0.05).结论 PNS能显著增加TAM抗乳腺癌的作用,其机制可能与调控mTOR信号通路有关.