Effects of vinpocetine in scopolamine-induced learning and memory impairments

Scopolamine-induced memory dysfunctions are related to reduced cholinergic transmission. In our experiments scopolamine (3.0 mg/kg i.p.) inhibited acquisition and induced retrograde amnesia in a one-trial step- through passive avoidance task in mice. We have studied the effect of vinpocetine (Cavinton^R), in the amnesic states mentioned above compared to that of vincamine, nicergoline (Sermion^R), and papaverine, to assess its activity on learning and memory processes impaired by scopolamine. Vinpocetine decreased the disrupting effect of scopolamine on acquisition and prevented and restituted the memory loss with 21.0 and 7.0 mg/kg i.p. peak effect dose, respectively. It facilitated the recall of memory traces damaged by scopolamine. Vincamine (3.5–63.7 mg/kg i.p.) showed a favorable effect in two of the four tests (reversal of amnesia and recall). Nicergoline (5–40 mg/kg i.p.) exerted moderate activity, and papaverine (10–40 mg/kg i.p.) was ineffective in the situations tested. Our findings indicate that vinpocetine directly or indirectly influences the cholinergic system, which may explain its previously reported beneficial effect in electroconvulsive shock- and hypoxia-induced experimental amnesic states, and its therapeutic activity in human mental and cognitive disorders.     

Beneficial effects of Brassica juncea on cognitive functions in rats

Abstract

Context. Brassica juncea (BJ; Linnaeus) Czern & Coss (Brassicaceae), commonly known as Indian mustard, are enriched in redox-active polyphenols with antidiabetic activities. Diverse other health benefits of this edible plant have been described in classical Ayurvedic texts.

Objective: The reported experiments were designed to assess therapeutic potential of a methanol extract of BJ leaves for treatment of cognitive disorders associated with diabetes or caused by central cholinergic dysfunctions.

Materials and methods: Elevated plus-maze and active- and passive-avoidance tests were used to assess anti-amnesic potentials of BJ (100, 200 and 400?mg/kg/day, p.o., for 10 days) in alloxan diabetic or scopolamine-challenged rats. Treatment effects on brain acetylcholinesterase (AChE), superoxide dismutase (SOD) and catalase (CAT) activities were quantified in behavioral tested animals.

Results: Anti-amnesic efficacy of all three tested BJ doses against scopolamine-induced amnesia was almost equal in all behavioral tests. Such efficacy of the extract in diabetic rats was increased always with its increasing doses. All treatments of BJ dose dependently decreased the elevated level of AChE, and significantly increased the SOD and CAT levels in brain homogenates of scopolamine-challenged and diabetic rats. Minimal effective oral daily doses of BJ in all tests were 100?mg/kg/day for 10 consecutive days.

Discussion and conclusion: Our observation indicates that BJ could be a therapeutic option for treatment of cognitive disorders associated with diabetes, or caused by cholinergic deficit and brain oxidative status. They also indicate that the bioactive constituents or mode of actions involved in observed effects of the extract in scopolamine-challenged or diabetic rats are most probably not the same.     

Shared genes influence sensitivity to the effects of ethanol on locomotor and anxiety-like behaviors, and the stress axis

RATIONALE: In rodents, a common response to many drugs of abuse, including ethanol (EtOH), is locomotor stimulation. It has been proposed, although debated, that EtOH-induced locomotor stimulation may represent an animal model of EtOH's euphoric effects. Another possibility is that this behavioral phenotype may represent an altered state of anxiety, and/or stress axis activation. OBJECTIVES: Mouse lines selectively bred for sensitivity (FAST) or resistance (SLOW) to EtOH's low dose locomotor stimulant effects were tested for differential sensitivity to EtOH's anxiolytic and/or stress axis activating effects, with the goal of detecting genetic correlations. METHODS: Saline- and EtOH-treated FAST and SLOW mice were tested on the elevated plus maze and the light-dark box, two widely used measures of anxiety-related behavior in rodents. In addition, serum corticosterone (CORT) levels were measured at various time points following injection of saline or ethanol. RESULTS: Behavioral data from both anxiety tests showed that FAST mice were less sensitive to EtOH's anxiolytic effects than were SLOW mice. Moreover, late recovery of elevated serum CORT levels following mild saline injection stress, as well as reduced CORT release in response to EtOH, suggested that FAST mice may possess a less responsive stress axis. CONCLUSIONS: These results provide evidence that sensitivity to the effects of EtOH on locomotor behavior, anxiety-like behavior, and the stress axis share some genetic influence.     

Differential severity of anxiogenic effects resulting from a brief swim or underwater trauma in adolescent male rats

Clinical studies have shown a link between early-life adversity and severity of adulthood responses to a traumatic stress event (post-traumatic stress disorder, PTSD). Despite a need for basic research, few rodent models are available to test the lasting impacts of early-life traumatic stressors. Underwater trauma (UWT) has been used previously to model traumatic stress; however, effects of this procedure have only been characterized in adulthood. Susceptibility of younger animals to physiological or psychological damage from a forced submersion procedure is unknown. A procedure involving swimming may be a stressful stimulus outside of the underwater component of the experience, as well. The acute effects of a 1-minute sham exposure (empty water tank), swim‐only, and UWT (40 s swim followed by 20 s underwater) were compared in adolescent rats at postnatal day 37. No effects on blood oxygenation or lung tissue were observed. Stepwise decreases in open arm behavior were observed on the elevated plus maze (EPM) in swim‐only rats, while UWT rats showed an immediate, lasting decrease in open arm behavior. UWT rats showed a significant decrease in basal corticosterone one week after trauma. These results show that while water immersion is a stressor, UWT causes a distinct syndrome of traumatic stress response in adolescent rats.     

Beneficial effects of the sigma1 receptor agonists igmesine and dehydroepiandrosterone against learning impairments in rats prenatally exposed to cocaine

In utero cocaine (IUC) exposure results in offspring rats in complex neurochemical and behavioral alterations, particularly affecting learning and memory processes. We examined here the impact of IUC exposure on memory functions in male and female offspring rats and report that selective sigma₁ (σ₁) receptor agonists are effective in reversing the deficits. Dams received a daily cocaine, 20 mg/kg ip, injection between gestational days E17 to E20. Learning was examined in offspring between day P30 and P41 using delayed alternation in the T-maze, water-maze learning and passive avoidance. Both male and female rats prenatally exposed to cocaine showed delayed alternation deficits and impairments of acquisition of a fixed platform position in the water maze, as shown by higher acquisition latencies and diminutions of time spent in the training quadrant during the probe test. The acquisition of a daily changing platform position also demonstrated impaired working memory. Finally, passive avoidance deficits were observed. Pretreatment with the synthetic σ₁ agonist igmesine (0.1–1 mg/kg ip) or the neuroactive steroid dehydroepiandrosterone (DHEA 10–40 mg/kg ip) reversed the prenatal cocaine-induced learning deficits in offspring rats for each test. The σ₁ antagonist BD1063 (1 mg/kg ip) failed to affect performances alone but blocked the igmesine and DHEA effects, confirming the involvement of the σ₁ receptor. IUC exposure thus results in marked memory deficits, affecting spatial and nonspatial short- and long-term memories in juvenile male and female offspring rats. The activation of the σ₁ neuromodulatory receptor allows a complete behavioral recovery of the memory functions in prenatally cocaine-exposed rats.     

Nootropic activity of Celastrus paniculatus seed

The effect of Celastrus paniculatus Willd. (Celastraceae) seed aqueous extract on learning and memory was studied using elevated plus maze and passive avoidance test (sodium nitrite induced amnesia rodent model). The aqueous seed extract was administered orally in two different doses to rats (350 and 1050?mg/kg) and to mice (500 and 1500?mg/kg). The results were compared to piracetam (100?mg/kg, p.o.) used as a standard drug. Chemical hypoxia was induced by subcutaneous administration of sodium nitrite (35?mg/kg), immediately after acquisition training. In elevated plus maze and sodium nitrite-induced amnesia model, Celastrus paniculatus extract has showed statistically significant improvement in memory process when compared to control. The estimation of acetylcholinesterase enzyme in rat brain supports the plus maze and passive avoidance test by reducing acetylcholinesterase activity which helps in memory performance. The study reveals that the aqueous extract of Celastrus paniculatus seed has dose-dependent cholinergic activity, thereby improving memory performance. The mechanism by which Celastrus paniculatus enhances cognition may be due to increased acetylcholine level in rat brain.     

Beneficial effects of an Andrographis paniculata extract and andrographolide on cognitive functions in streptozotocin-induced diabetic rats

Context Andrographolide containing Andrographis paniculata (Burm. F.) Wall. Ex Nees (Acanthaceae) extracts is often used for treatments of diabetes and other inflammatory disorders commonly accompanying cognitive and other psychiatric disorders.

Objective To compare the efficacies of a standardised A. paniculata extract (AP) and pure andrographolide on cognitive functions, oxidative stress and cholinergic function in diabetic rats.

Materials and methods Streptozotocin-induced diabetic Charles Foster albino rats treated orally with a hydro-methanolic A. paniculata leaf extract (50, 100 and 200?mg/kg/day), or with pure andrographolide (15, 30 and 60?mg/kg/day) for 10 consecutive days, were subjected to Morris water maze test. After the test, acetylcholinesterase, superoxide dismutase (SOD), and catalase (CAT) activities and lipid peroxidation (LPO) in brain tissues were assessed.

Results Acetylcholinesterase activity in pre-frontal cortex and hippocampus of diabetic rats was 2.1 and 2.6 times higher compared to nondiabetic rats. LPO was 1.6 times higher and decreased SOD (56.3%) and CAT (44.9%) activities in pre-frontal cortex of diabetic rats compared to nondiabetic rats. AP or andrographolide treatments dose dependently attenuated cognitive deficits, reduced acetylcholinesterase activity, oxidative stress, improved diabetic hyperglycemia and insulin deficiency. All observed effects of AP were quantitatively almost equal to those expected from its analytically quantified andrographolide content.

Discussion and conclusion Reported observations are the very first ones suggesting beneficial effects of andrographolide against diabetes associated cognitive deficits, increased acetylcholinesterase activity and deteriorated antioxidative status. Efforts to exploit A. paniculata extracts enriched in andrographolide as preventive measures against such disorders can be warranted.     

One-trial tolerance to the effects of chlordiazepoxide on the elevated plus maze may be due to locomotor habituation,not repeated drug exposure

The phenomenon of one-trial tolerance to the effects of chlordiazepoxide hydrochloride (CDP) in the elevated plus maze was re-examined. Unlike previous experiments, pre-exposure to the maze resulted in habituation and a consequential reduction in time spent on the open arms. The habituation effect was measured by recording the actual distance travelled by the rats in the maze and this was found to be significantly reduced by pre-exposure. Pre-exposure to the maze in the presence of CDP resulted in a reduced response to its anxiolytic-like effects (increasing time on the open arms compared to vehicle control rats). However, although the time spent on the open arms was reduced by pre-exposure, CDP significantly increased the time spent on the open arms by rats pre-exposed under a non-drugged state. These results suggest that rats do not become tolerant to the effects of CDP, but rather the reduced response to CDP after pre-exposure is due to habituation of exploratory behaviour.     

In vivo investigation of the neuroprotective property of Convolvulus pluricaulis in scopolamine-induced cognitive impairments in Wistar rats

Aim:

To investigate the neuroprotective effect of Convolvulus pluricaulis aqueous extract (AE) against scopolamine (1 mg/kg body weight (bwt))-induced neurotoxicity in the cerebral cortex of male Wistar rats.

Materials and Methods:

The study was carried out on male Wistar rats (age matched, weight 250 ± 20 g). The present study investigated cognitive-enhancing property of AE using Elevated plus maze (EPM) (transfer latency [TL]) and Morris water maze (MWM). Besides evaluating the effect of extract on neurochemical enzymes, in vivo antioxidant and free radical scavenging activities were also screened. All the measured parameters were compared with rivastigmine tartrate (1 mg/kg bwt) which was taken as standard.

Results:

Pretreatment of rats with AE (150 mg/kg bwt) significantly reduced scopolamine-induced increase in the TL in EPM, whereas in MWM, administration of extract improved the impairment of spatial memory induced by scopolamine. The activity of acetylcholinesterase (AChE) was significantly inhibited by extract within the cortex and hippocampus. Reduced activities or contents of glutathione reductase, superoxide dismutase, and reduced glutathione within the cortex and hippocampus induced by scopolamine were elevated by the extract. Taken together, it could be postulated that extract may exert its potent-enhancing activity through both anti-AChE and antioxidant action.

Conclusion:

AE possesses neuroprotective potential, thus validating its use in alleviating toxic effects of scopolamine.     

Transgenerational consequences of adolescent morphine exposure in female rats: effects on anxiety-like behaviors and morphine sensitization in adult offspring

Rationale and objective Opiate abuse in adolescent girls has increased in the past decade; however, few animal studies have examined the potential consequences of opiate use occurring at this time. The purpose of the present study was to determine whether exposing female rats to morphine during the peripubertal period can alter the adult behavior of their offspring. Methods Beginning at 30 days of age, female rats were injected subcutaneously (s.c.) twice daily with either morphine sulfate or saline. The initial morphine dose of 2.5 mg/kg was increased by 2.5 mg/kg daily for a total of 20 days. Ten days after the final drug treatment, all subjects were mated. Their subsequent offspring were then tested as adults on the elevated plus maze, in a novel environment or were examined in a morphine locomotor sensitization paradigm. Results Adult female offspring of dams exposed to morphine during puberty spent less time in the open arms of the elevated plus maze and displayed decreased exploration in a novel environment. Female offspring also demonstrated a more rapid induction of morphine sensitization. Finally, male offspring demonstrated a significant enhancement in the expression of morphine sensitization. Conclusions Chronic morphine exposure during adolescence can have significant transgenerational effects on adult offspring. Future studies will be needed to determine how these changes are transferred to the offspring and whether these effects are specific to drug exposure that occurs during the peripubertal period. This work was supported by the National Institute on Health grant DA14613 awarded to E.M. Byrnes     

Anxiogenic and stress-inducing effects of peripherally administered acetaldehyde in mice: similarities with the disulfiram-ethanol reaction

Peripheral accumulation of acetaldehyde, the first metabolite of ethanol, produces autonomic responses in humans called “flushing”. The aversive characteristics of flushing observed in some populations with an isoform of aldehyde dehydrogenase (ALDH2) less active, are the basis for treating alcoholics with disulfiram, an ALDH inhibitor. Although ethanol and centrally formed acetaldehyde have anxiolytic effects, peripheral accumulation of acetaldehyde may be aversive in part because it is anxiogenic.

Objectives

We investigated the effect of direct administration of acetaldehyde on behavioral measures of anxiety and on hormonal markers of stress in mice. The impact of disulfiram on the anxiolytic actions of ethanol was evaluated. Acetate (a metabolite of acetaldehyde) was also studied.

Methods

CD1 male mice received acetaldehyde (0, 25, 50, 75 or 100 mg/kg) at different time intervals and were assessed in the elevated plus maze and in the dark-light box. Corticosterone release after acetaldehyde administration was also assessed. Additional experiments evaluated the impact of disulfiram on the anxiolytic effect of ethanol (0 or 1 mg/kg), and the effect of acetate on the plus maze.

Results

Direct administration of acetaldehyde (100 mg/kg) had an anxiogenic effect at 1, 11 or 26 min after IP administration. Acetaldehyde was ten times more potent than ethanol at inducing corticosterone release. Disulfiram did not affect behavior on its own, but blocked the anxiolytic effect of ethanol at doses of 30 and 60 mg/kg, and had an anxiogenic effect at the highest dose (90 mg/kg) when co-administered with ethanol. Acetate did not affect any of the anxiety parameters.

Conclusions

Peripheral administration or accumulation of acetaldehyde produces anxiogenic effects and induces endocrine stress responses. This effect is not mediated by its metabolite acetate.     

Comparison of the elevated plus and elevated zero mazes in treated and untreated male Sprague-Dawley rats: Effects of anxiolytic and anxiogenic agents

The elevated plus and zero mazes (Plus and Zero, respectively) are used to assess behavior related to anxiety in rodents but direct comparisons of the two tests are lacking for rats. We compared the two methods in adult male Sprague-Dawley rats. Untreated rats in the Zero spent more time in open zones and exhibited more head dips than in the Plus whereas start latency and closed area entries were lower in the Zero than in the Plus. Diazepam (1 mg/kg) exposure increased time in the open in both mazes. Restraint (60 min prior to testing), yohimbine (2.5 mg/kg), and caffeine (100 mg/kg) had the opposite effect, significantly decreasing time spent in open zones in both mazes. No sexual dimorphism in behavior was seen in either maze in untreated rats. Although more open area time was evident in untreated animals in the Zero, after drug challenge both mazes detected anxiolytic and anxiogenic effects equally. Zero maze data can be analyzed directly because no center region exists; otherwise the two methods appear comparable following challenge.     

Memory-enhancing effect of a cerulein analogue following peripheral administration in the rat

Our previous studies demonstrated that cerulein (CER) has a potent preventive action on amnesia induced by electroconvulsive shock, administration of scopolamine, puromycin, anisomycin, NMDA receptor antagonists, and protein kinase C inhibitors. The present study was aimed at finding more effective CER analogues which could enhance memory processes. Five CER analogues were synthesized and the potencies in passive and active avoidance responses and in the Morris water pool test were examined in the rat. Among the preparations, des-Gln²-[Leu⁵, Nle⁸]-CER was found to possess particularly potent effects on memory acquisition and/or storage. The effects were apparent in less than 1 μg/kg single subcutaneous (s.c.) injection for at least 120 hr in passive avoidance response and 15 days in active avoidance response. Memory impairments induced by scopolamine and puromycin were well improved in passive avoidance response. In the Morris water maze test, disordered behaviors caused by scopolamine and protein kinase C inhibitor were totally restored to the normal state by s.c. injection of this CER analogue. © 1992 Wiley-Liss, Inc.     

Behavioral effects of saredutant, a tachykinin NK2 receptor antagonist, in experimental models of mood disorders under basal and stress-related conditions

The present study was made to investigate the role of tachykinin NK2 receptors in the expression of stress-related behaviors in animals. Under basal conditions, intraperitoneal (i.p.) administration of the selective tachykinin NK2 receptor antagonist, saredutant (1 and 3 mg/kg) or diazepam (1 mg/kg) exerted anxiolytic-like effects in rodents, as they reduced grooming score of Wistar male rats tested in the novelty-induced grooming sampling test (NGT) and increased percentage of time and entries in open arms of Swiss male mice tested in the elevated plus maze (EPM) test. After previous exposure to stress-related conditions, as induced by a 2-min forced swim made 5 min prior to the EPM test, saredutant but not diazepam, exhibited anxiolytic-like effects in mice. To study the antidepressant-like activity of tachykinin NK2 receptor antagonist under basal conditions, different groups of rats were injected i.p. with saredutant (2.5, 5 and 10 mg/kg) or the tricyclic antidepressant, clomipramine (50 mg/kg) and tested in the forced swim test (FST), a widely used antidepressant-responsive test. The influence of stress-related conditions was studied in rats subjected to electric foot-shocks (1 mA, 1 s) 24, 5 and 1 h prior to FST, after drugs injection. In the FST, clomipramine decreased the immobility time only under basal conditions, but not after application of acute foot-shocks. To the contrary, saredutant-treated rats also exhibited more active behavior in FST after previous exposure to stressors. These results give further support to the hypothesis that tachykinin NK2 receptors may be a therapeutic target for pharmacological treatment of stress-related diseases, such as anxiety and depression.     

Beneficial effects of the sigma1 receptor agonists igmesine and dehydroepiandrosterone against learning impairments in rats prenatally exposed to cocaine

In utero cocaine (IUC) exposure results in offspring rats in complex neurochemical and behavioral alterations, particularly affecting learning and memory processes. We examined here the impact of IUC exposure on memory functions in male and female offspring rats and report that selective sigma₁ (σ₁) receptor agonists are effective in reversing the deficits. Dams received a daily cocaine, 20 mg/kg ip, injection between gestational days E17 to E20. Learning was examined in offspring between day P30 and P41 using delayed alternation in the T-maze, water-maze learning and passive avoidance. Both male and female rats prenatally exposed to cocaine showed delayed alternation deficits and impairments of acquisition of a fixed platform position in the water maze, as shown by higher acquisition latencies and diminutions of time spent in the training quadrant during the probe test. The acquisition of a daily changing platform position also demonstrated impaired working memory. Finally, passive avoidance deficits were observed. Pretreatment with the synthetic σ₁ agonist igmesine (0.1–1 mg/kg ip) or the neuroactive steroid dehydroepiandrosterone (DHEA 10–40 mg/kg ip) reversed the prenatal cocaine-induced learning deficits in offspring rats for each test. The σ₁ antagonist BD1063 (1 mg/kg ip) failed to affect performances alone but blocked the igmesine and DHEA effects, confirming the involvement of the σ₁ receptor. IUC exposure thus results in marked memory deficits, affecting spatial and nonspatial short- and long-term memories in juvenile male and female offspring rats. The activation of the σ₁ neuromodulatory receptor allows a complete behavioral recovery of the memory functions in prenatally cocaine-exposed rats.     

Antidepressant and anxiolytic effects of amentoflavone isolated from Cnestis ferruginea in mice

The root decoction of Cnestis ferruginea (CF) Vahl DC (Connaraceae) is used in traditional African medicine in the management of psychiatric disorders. This study presents the antidepressant and anxiolytic effects of amentoflavone (CF-2) isolated from the root extract of C. ferruginea.The antidepressant effect was studied using the forced swimming (FST) and tail suspension tests (TST) while the hole-board, elevated plus maze (EPM) and light/dark tests were used to evaluate the anxiolytic effect. Acute treatment with CF extract and amentoflavone significantly (p < 0.001) reduced the duration of immobility in FST and TST with peak effects observed at 100 and 50 mg/kg respectively in comparison to control treated. Antidepressant effects of CF and amentoflavone were significantly higher (p < 0.05) when compared to imipramine in FST but comparable to the fluoxetine treated group in TST.The pretreatment of mice with metergoline (4 mg/kg, i.p., a 5-HT2 receptor antagonist), prazosin (62.5 μg/kg, i.p., an α1-adrenoceptor antagonist), and yohimbine (1 mg/kg, i.p., an α2-adrenoceptor antagonist), but not sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist), cyproheptadine (3 mg/kg, i.p., a 5-HT2 receptor antagonist), atropine (1 mg/kg, i.p., a muscarinic receptor antagonist) 15 mins before the administration of amentoflavone (50 mg/kg; p.o.) significantly prevented its antiimmobility effect in the FST.CF extract and CF-2 significantly (p < 0.05) attenuated anxiety by increasing the number of head-dips in the hole-board test, the time spent on the open arms in the EPM, and the exploration of the light chamber in the light/dark test. Pretreatment with flumazenil (3 mg/kg, i.p., ionotropic GABA receptor antagonist) 15 min before oral administration of amentoflavone (25 mg/kg) significantly reduced the time spent in the open arms in EPM. It is concluded from the results obtained that amentoflavone produces its antidepressant effect through interaction with 5-HT2 receptor and α1-, and α2-adrenoceptors while the anxiolytic effect involved the ionotropic GABA receptor.     

Naltrexone potentiates the anxiolytic effects of chlordiazepoxide in rats exposed to novel environments

Rationale: Both novelty and naloxone have been reported to modify the anxiolytic-like effect of benzodiazepines in the elevated plus maze. In addition, it has been largely demonstrated that novelty alters endogenous opioid activity. Objectives: The present study was designed to examine a possible interaction between novelty and naltrexone effects on the behavior of chlordiazepoxide-treated rats in two animal models of anxiety. Methods: Thirty minutes after acute intraperitoneal treatment with saline or naltrexone and saline or chlordiazepoxide, male Wistar rats were exposed for the first time to the elevated plus maze apparatus or the social interaction arena for the quantification of the percentage of time spent in the open arms or the time of active social interaction, respectively. The effects of naltrexone and/or chlordiazepoxide on the plus maze and the social interaction tests were also evaluated after previous exposure to the respective apparatus. Results: Naltrexone dose dependently increased the percentage of time spent in the open arms of the elevated plus maze in chlordiazepoxide-treated (5 mg/kg i.p.) rats exposed for the first time to the apparatus. Similarly, naltrexone (5 mg/kg i.p.) increased the time spent in active social interaction by chlordiazepoxide-treated rats exposed to an unfamiliar arena. In both experiments, naltrexone had no effect when administered alone. When both the plus maze and the social interaction tests were conducted after previous exposure to the respective apparatus, naltrexone did not modify the behavior of chlordiazepoxide- or saline-treated rats. Conclusions: These data suggest that the anxiolytic-like effects of chlordiazepoxide can be modified by opioid mechanisms in novel environments. Received: 12 February 1999 / Final version: 19 June 1999     

Effect of pharmacological daytime doses of melatonin on human mood and performance

Previous studies have used the elevated plus maze to test for anxiolytic drugs in rats. The present study demonstrates that guinea-pigs handled daily from birth exhibit similar behaviour to rats on the plus maze. Pretreatment with diazepam (1.0 mg/kg) significantly increased the time the animals spent in the open arms and amount of entries into the open arms. Using intra-cortical microdialysis on exposure of the guinea-pig to the elevated plus maze resulted in increased extracellular 5-HT in the frontal cortex. Diazepam reduced, but not significantly, the increase in extracellular 5-HT and produced an anxiolytic profile of behaviour. Pretreatment with the benzodiazepine antagonist flumazenil (10.0 mg/kg) fully antagonised the behavioural effects of diazepam. Flumazenil also reduced the effect of diazepam on the increase in extracellular 5-HT observed on exposure of the guinea-pig to the elevated plus maze. Flumazenil alone decreased basal extracellular cortical 5-HT but had no effect on behaviour in the elevated plus maze. The results show that an increase in extracellular 5-HT occurs in the guinea-pig exposed to aversive conditions. While it remains to be determined whether the anxiolytic effects of diazepam in the guinea-pig are causally associated with decreased extracellular 5-HT, it is of interest that the selective benzodiazepine antagonist also prevented the increase in basal extracellular 5-HT produced by the exposure to the elevated plus maze but had no effect on behaviour. Results indicate that there is no simple relationship between inhibition of 5-HT release and the anxiolytic action of benzodiazepines.     

The effects of phencyclidine (PCP) on anxiety-like behavior in the elevated plus maze and the light-dark exploration test are age dependent, sexually dimorphic, and task dependent

Previous research in our laboratory revealed sexually dimorphic effects of prior exposure to phencyclidine (PCP) on elevated plus maze behavior. In an attempt to examine the developmental time course of this effect and determine the extent to which it generalizes to other anxiety paradigms, young adult (61-64 days old) and adult (96-107 days old) male and female rats were treated with PCP (15 mg/kg) or saline. Following a two week withdrawal period, animals were tested in either the elevated plus maze (EPM) or a light-dark exploration (LD) test. In adults, both tests revealed a sexually dimorphic effect driven by PCP-induced decreases in anxiety in females as indicated by increased time spent in the open arms of the EPM and in the lit compartment of the LD test and increased anxiety in males as indicated by decreased time spent in the lit compartment of the LD. In young animals, PCP pretreatment decreased open arm exploration in the elevated plus maze, indicating increased anxiety. However, PCP increased time spent in the light compartment in the light-dark exploration test, indicating decreased anxiety. Corticosterone levels measured 15 min after the onset of the EPM failed to reveal an association between the behavioral effects of PCP and corticosterone levels. The results in adults substantiate the previously observed sexually dimorphic effect of PCP on elevated plus maze behavior in adults and indicate that the effect generalizes to another anxiety paradigm. The results in the younger animals suggest an age dependent effect of PCP on anxiety in general and indicate that behaviors in the elevated plus maze and the light-dark exploration test reflect dissociable psychobiological states.     

高架﹢/〇迷宫实验:经典状态焦虑动物模型相关性研究

目的探讨高架﹢迷宫实验(elevated plus maze,EPM)与高架〇迷宫实验(elevated zero maze,EZM)作为经典状态焦虑动物模型的相关性。方法昆明小鼠(4周龄,♂/♀)依次进行EPM、EZM,实验间隔1周,采用摄像系统记录5min行为变化,包括进入时间及进入次数;最终纳入实验参数有:开臂区进入时间百分率(Otime%)和两臂区进入总次数(Entries);采用描述性分析、聚类分析、因子分析、相关分析及一致性检验进行EPM与EZM行为模式、结构维度及相关性研究。结果t检验结果显示,与EPM相比,EZM Otime%(♂/♀/♂+♀)均降低,而Entries(♂/♂+♀)均升高,且差异有统计学意义;Fiedman检验结果显示,EPM/EZM实验参数Otime%(♂/♀/♂+♀)、Entries(♂/♀/♂+♀)重复测量片段间差异均有统计学意义;Wilcoxon检验结果显示,与EPM相比,EZM Otime%在1st min(♂/♀/♂+♀)、2nd min(♂/♀/♂+♀)、3rd min(♀/♂+♀)均降低,而Entries在1st min(♂/♂+♀)、4th min(♂/♀/♂+♀)、5th min(♂+♀)均升高,且差异有统计学意义。聚类分析结果显示,EPM/EZM实验参数可分组为EPM类和EZM类(♂/♀/♂+♀)。因子分析结果显示,EPM/EZM实验参数可提取为EPM因子和EZM因子(♂/♀/♂+♀)。相关分析结果显示,EPM和EZM实验参数Otime、Entries均具有一般或者较差相关性(♂/♀/♂+♀)。一致性检验结果显示,EPM和EZM实验参数Otime%(♂/♀/♂+♀)具有一般一致性。结论尽管EPM/EZM作为状态焦虑动物模型具有相类似内在原理,但是因为其外在环境(结构)差异性,导致EPM/EZM具有不同行为模式,分属不同结构维度,且仅具有一般相关性和一致性,而稳定性实验参数则首选Otime%。