Gingko biloba extract diminishes stress-induced memory deficits in rats

Exposure to chronic restraint stress in rats and psychosocial stress in humans has been shown to alter cognitive functions such as learning and memory and has been linked to the pathophysiology of mood and anxiety disorders. Antianxiety or sedative agents used in the management of stress have several disadvantages and undesired effects. Therefore, in this study, we investigated efficacy of a natural medicine, the extract of Ginkgo biloba (EGB 761), in prevention and treatment of the post-stress memory dysfunctions. The results showed that chronic restraint stress (2 h for 21 days) or an 'equivalent' dose of exogenous corticosterone (5 mg/kg) impaired nonspatial memory as measured by an object recognition test. In control rats, EGB 761 improved spatial and nonspatial memory in Morris water maze and object recognition tests. Preventive doses of EGB 761 (100 mg/kg) normalized cognitive deficits, seen in rats chronically stressed or treated with corticosterone in object recognition test, and improved memory processes in these rats measured by Morris water maze test. There was no influence of our treatments on locomotor exploratory activity and anxiety measured in open field and elevated 'plus' maze tests, making a contribution of unspecific motor and emotional effects of the used drugs to their performance in the memory tests improbable.     

Effects of an extract of Ginkgo Biloba (EGB 761) on "learned helplessness" and other models of stress in rodents

The effects of repeated oral administration of an extract of Ginkgo Biloba (EGB 761) on various behavioral models of stress in rodents were investigated. The models in rats included "learned helplessness," shock-suppressed licking (Vogel conflict test) and forced swimming-induced immobility ("behavioral despair"). The models in mice included shock-suppressed exploration (four plates test), spontaneous exploration (staircase test) and food consumption in a novel situation (emotional hypophagia). Further tests in rats examined the effects of EGB 761 on memory (passive avoidance test) and responsiveness to shock to determine whether the preventive effects observed with EGB 761 in the learned helplessness procedure were due either to drug-induced impairment of memory or to reduced shock sensitivity. In all experiments EGB 761 was administered over 5 days at daily doses of 50 and 100 mg/kg PO. In some experiments (Vogel test, four plates test, staircase test, emotional hypophagia) the effects of acute administration were also investigated. The results showed that repeated administration of EGB 761 (50 and 100 mg/kg/day) before exposure to unavoidable shock (preventive treatment) clearly reduced the subsequent avoidance deficits in the learned helplessness procedure but was less effective when first administered after "helplessness" induction (curative treatment). EGB 761 did not affect performance in the passive avoidance task or alter the animals' response to electric shock, suggesting that the effects observed in the learned helplessness procedure were not due to impaired memory or reduced shock sensitivity. Anxiolytic-like activity was also seen in the emotional hypophagia test in mice where repeated administration of EGB 761 increased the amount of food consumed.(ABSTRACT TRUNCATED AT 250 WORDS)     

St John's wort (Hypericum perforatum) diminishes cognitive impairment caused by the chronic restraint stress in rats.

In this study we tested the hypothesis that St John's wort (Hypericum perforatum) may counteract stress-induced memory impairment. Object recognition test and Morris water maze were used to determine whether administration of H. perforatum (350 mg kg(-1) for 21 days), standardized to 0.3% hypericin content, protects against non-spatial and/or spatial memory impairments due to chronic restraint stress (2h daily for 21 days). A group of rats administered the exogenous corticosterone at the dose of 5 mg kg(-1) daily for 21 days, yielding its similar plasma levels as these observed in stress was run in parallel. In the first experiment all rats were tested for recognition memory in the object recognition test. On the following day, the animals were tested in open field and elevated "plus" maze to control for the contribution of respectively, motor and emotional effects of our treatments to the memory tests. In the second experiment, new group of stressed animals was tested for spatial memory in the water maze. We observed that H. perforatum prevented the deleterious effects of both chronic restraint stress and long-term corticosterone on learning and memory as measured in both, the object recognition and the water maze tests. The herb not only prevented stress- and corticosterone-induced memory impairments, but it significantly improved recognition memory (p<0.01) in comparison to control. These results suggest that H. perforatum has a potential to prevent stress memory disorders.     

Alleviation by Hypericum perforatum of the stress-induced impairment of spatial working memory in rats

It is recognized that chronic stress is an important risk factor for the development of several cognitive impairments involving working memory. Working memory refers to the memory in which the information to be remembered changes from trial-to-trial and should be assessed in a task able to detect retrieval of that information. In the present study, we tested the hypothesis that preventive administration of Hypericum perforatum (also named St John’s wort) may counteract the working memory impairments caused by repeated stress. Specifically, we attempted to characterize the preventive action of long-lasting treatment with St John’s wort (350 mg/kg, p.o.) on the spatial working memory impairments caused by chronic restraint stress (2 h daily for 21 days) or durable medication with exogenous corticosterone (5 mg/kg, s.c.) in male Wistar rats. Spatial working memory was tested in Barnes maze (BM) and in the Morris water maze (MWM). We found that H. perforatum prevented the deleterious effects of both chronic restraint stress and prolonged corticosterone on working memory measured in both tests. The herb significantly improved hippocampus dependent spatial working memory in comparison with control (p < 0.01) and alleviated some other negative effects of stress on cognitive functions.     

Acute stress impairs spatial memory in male but not female rats: influence of estrous cycle

We investigated how sex and estrous cycle influenced spatial recognition memory in the Y-maze after exposure to acute restraint stress. In Experiment 1, intact male and female rats were restrained for 1 h and then 2 h after the start of restraint, rats were trained on the Y-maze. After a 4 h delay, hippocampal-dependent spatial recognition memory was assessed. Acute stress produced opposite patterns between the sexes with spatial memory being impaired in males and facilitated in females. Serum corticosterone measures indicated that both sexes showed a robust corticosterone response after restraint and a moderate corticosterone response after Y-maze exposure. Serum corticosterone levels in response to restraint and Y-maze were not statistically different between the sexes. Experiment 2 examined the influence of the estrous cycle on spatial memory ability after acute stress. Acute stress facilitated spatial memory in females compared to controls, regardless of the estrous cycle phase (estrus and proestrus). Moreover, females in proestrus showed higher serum corticosterone levels during restraint compared to females in estrus. No differences in corticosterone levels were observed at baseline or following 2 h of recovery from restraint. These data show important differences in how sex and estrous cycle influence cognitive functions following acute stress.     

The in vivo synaptic plasticity mechanism of EGb 761-induced enhancement of spatial learning and memory in aged rats

It has not been uniform to date that the Ginkgo biloba extracts enhance cognitive function in aged animals, and the mechanisms of action remain difficult to elucidate. In this study, the Morris water maze task and electrophysiological methods were used to study the effects of repeated daily administration of EGb 761, a standardized extract from G. biloba leaves, on hippocampal-dependent spatial learning and memory and synaptic plasticity of aged rats. The adult subjects perform the Morris water maze task better than aged rats, as a cellular mechanism, the hippocampal long-term potentiation (LTP) elicited from adult animals is robust (139.29+/-2.7%). In addition, the spatial learning and memory of aged rats that had been fed on an EGb 761-supplemented diet (60 mg kg(-1)) for 30 days were significantly better than those of control aged rats. The magnitude of LTP (116.63+/-3.6%) recorded in vivo from the hippocampus CA1 area of aged rats was significantly enhanced by EGb 761 (60 mg kg(-1)). In conclusion, the spatial learning and memory of aged rats is worse than that of young subjects, and EGb 761, acting as a 'cognitive enhancer', has benefit on synaptic plasticity and cognition in aged rats. The present data further confirmed that enhancement of synaptic plasticity of the hippocampus might ameliorate the deficit in spatial learning and memory in aged rats.     

Cannabinoids Ameliorate Impairments Induced by Chronic Stress to Synaptic Plasticity and Short-Term Memory

Repeated stress is one of the environmental factors that precipitates and exacerbates mental illnesses like depression and anxiety as well as cognitive impairments. We have previously shown that cannabinoids can prevent the effects of acute stress on learning and memory. Here we aimed to find whether chronic cannabinoid treatment would alleviate the long-term effects of exposure to chronic restraint stress on memory and plasticity as well as on behavioral and neuroendocrine measures of anxiety and depression. Late adolescent rats were exposed to chronic restraint stress for 2 weeks followed each day by systemic treatment with vehicle or with the CB1/2 receptor agonist WIN55,212-2 (1.2 mg/kg). Thirty days after the last exposure to stress, rats demonstrated impaired long-term potentiation (LTP) in the ventral subiculum-nucleus accumbens (NAc) pathway, impaired performance in the prefrontal cortex (PFC)-dependent object-recognition task and the hippocampal-dependent spatial version of this task, increased anxiety levels, and significantly reduced expression of glucocorticoid receptors (GRs) in the amygdala, hippocampus, PFC, and NAc. Chronic WIN55,212-2 administration prevented the stress-induced impairment in LTP levels and in the spatial task, with no effect on stress-induced alterations in unconditioned anxiety levels or GR levels. The CB1 antagonist AM251 (0.3 mg/kg) prevented the ameliorating effects of WIN55,212-2 on LTP and short-term memory. Hence, the beneficial effects of WIN55,212-2 on memory and plasticity are mediated by CB1 receptors and are not mediated by alterations in GR levels in the brain areas tested. Our findings suggest that cannabinoid receptor activation could represent a novel approach to the treatment of cognitive deficits that accompany a variety of stress-related neuropsychiatric disorders.     

Imidazoline2 (I2) receptor- and alpha2-adrenoceptor-mediated modulation of hypothalamic-pituitary-adrenal axis activity in control and acute restraint stressed rats

Central noradrenaline regulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis and the neuroendocrine response to stress. alpha2-adrenoceptors and imidazoline2 (I2) receptors modulate the activity of the central noradrenergic system. The present set of experiments investigated the role of alpha2-adrenoceptors and I2 receptors in the regulation of HPA axis activity under basal conditions and during exposure to the acute psychological stress of restraint. Three separate experiments were carried out in which rats were given an i.p. injection of either saline vehicle, the combined alpha2-adrenoceptor antagonist and I2 receptor ligand idazoxan (10 mg/kg), the selective I2 receptor ligand BU224 (2.5 or 10 mg/kg) or the selective alpha2-adrenoceptor antagonist RX821002 (2.5 mg/kg) with or without restraint stress. Drugs were administered immediately prior to restraint of 60 min duration. Blood was sampled pre-injection, 30, 60 and 240 min post-injection and plasma corticosterone was measured by radioimmunoassay. In experiment 1, idazoxan increased plasma corticosterone levels in naive animals and potentiated the corticosterone response to acute restraint stress. In experiment 2, BU224 administration increased plasma corticosterone levels in a dose-related manner in naive rats. The results of experiment 3 indicated that RX821002 also elevated plasma corticosterone levels in naive rats, however, only BU224 potentiated the corticosterone response to restraint stress. These studies suggest that both alpha2-adrenoceptors and I2 receptors play a role in modulating basal HPA axis activity and that I2 receptors may play a more important role than alpha2-adrenoceptors in modulating the HPA axis response to the acute psychological stress of restraint.     

Facilitative effects of EGb 761 on olfactory recognition in young and aged rats

The aim of the present study was to evaluate the effects of chronic and acute treatment by the Gingko biloba extract, EGb 761 (IPSEN, France) on olfactory short-term memory in rats, using a spontaneous recognition procedure. The effects of a daily EGb 761 treatment (30 or 60 mg/kg) over a period of 30 days (Experiment 1) were evaluated in young male rats. Those of a single injection of EGb 761 were assessed either in young male rats at 60 or 120 mg/kg (Experiment 2) or in aged female rats at 60 mg/kg (Experiment 3). Results showed that, at the highest dose (60 mg/kg), chronic EGb 761 treatment enhanced the recognition performances, allowing recognition at delays at which control animals did not show any recognition. Acute treatment enhanced recognition at both doses tested. The results of the third experiment showed that EGb 761 had an overall enhancement effect on the performances of aged rats. In summary, our results provide evidence for a short-term memory enhancement effect of EGb 761 in both young and aged rats.     

BGC20-761, a novel tryptamine analog, enhances memory consolidation and reverses scopolamine-induced memory deficit in social and visuospatial memory tasks through a 5-HT6 receptor-mediated mechanism

Inhibition of 5-HT(6) receptors has been shown to improve memory consolidation, thus we tested whether a novel tryptamine analog with high affinity for 5-HT(6) receptors, BGC20-761 (5-methoxy-2-phenyl-N,N-dimethyltryptamine, PMDT), can enhance long-term memory. BGC20-761 (10 mg/kg i.p.) alone had no effect on social recognition in young rats, however, at doses of 5 mg/kg and 10 mg/kg i.p, BGC20-761 dose-dependently reversed a deficit of social recognition induced by scopolamine (0.4 mg/kg i.p.), an anticholinergic drug that impairs memory. BGC20-761 (10 mg/kg i.p.), scopolamine (0.2 mg/kg i.p.) or BGC20-761 + scopolamine had no effects on novel object discrimination in young rats (2 months). In mature rats (6 months), recognition of the novel object was improved following administration of BGC20-761. Scopolamine had no effect in object recognition. However, the addition of scopolamine disrupted the memory-enhancing effect of BGC20-761. Based on the high affinity of BGC20-761 for 5-HT(6) receptors, these cognitive enhancing effects are most likely mediated by 5-HT(6) receptor inhibition. The difference in effects of BGC20-761 in young vs. mature rats may reflect the status of memory consolidation in these different age ranges.     

Single dose of H3 receptor antagonist - ciproxifan - abolishes negative effects of chronic stress on cognitive processes in rats

Rationale

The role of histamine neurons in stress evoked cognitive impairments remains unclear. Previous research has indicated that the blockade of H(3)-type histamine receptors may improve attention and memory in naïve rodents.

Objectives

The purpose of this study was to determine if ciproxifan, (cyclopropyl-(4-(3-1H-imidazol-4-yl) propyloxy) phenyl) ketone, an H(3) receptor antagonist, could alleviate cognitive deficits observed in chronically stressed rats.

Methods

Specifically, we attempted to characterize the preventive action of single dose of ciproxifan (3 mg/kg, i.p.) against an impairment caused by chronic restraint stress (2 h daily for 21 days) on recognition memory tested in an object recognition task and on the long-term memory tested in a passive avoidance test.

Results

We found that administration of ciproxifan potently prevented deleterious effects of chronic restraint stress, when administered prior to learning, or immediately after learning, or before retrieval on both the recognition (p<0.001) and the passive avoidance behavior (p<0.001).

Conclusions

These data support the idea that modulation of H(3) receptors represents a novel and viable therapeutic strategy in the treatment of stress evoked cognitive impairments.     

Effect of Ginkgo biloba extract,EGb 761, on the cellular immune response in a hypothalamic-pituitary-adrenal axis activation model in the rat

We evaluated the effects of Ginkgo biloba extract (EGb 761) on the cellular immune response of rats with immunosuppression induced by activation of the hypothalamic-pituitary-adrenal (HPA) axis. Groups of five rats were subjected to chronic stress by the application of daily electric shocks (ES) over 7 days. This stress produced a significant decrement in the delayed-type hypersensitivity response (DTH) to dinitrofluorobenzene (DNFB), and a decrease in the proliferation index of splenocytes. Treatment with oral doses of the phytopharmaceutical EGb 761 (100 mg/kg per day over 7 days) restored both the DTH response to DNFB and the proliferation index. EGb 761 has stress-alleviating properties through its moderation of corticosterone levels. It also possesses antioxidant activity that may contribute to its effects on the immune response. Our observations indicate that the phytopharmaceutical EGb 761 possesses immunostimulatory properties.     

Pre-training administration of tianeptine, but not propranolol, protects hippocampus-dependent memory from being impaired by predator stress.

Extensive research has shown that the antidepressant tianeptine blocks the adverse effects of chronic stress on hippocampal functioning. The current series of experiments extended this area of investigation by examining the influence of tianeptine on acute stress-induced impairments of spatial (hippocampus-dependent) memory. Tianeptine (10 mg/kg, ip) administered to adult male rats before, but not after, water maze training blocked the amnestic effects of predator stress (occurring between training and retrieval) on memory. The protective effects of tianeptine on memory occurred in rats which had extensive pre-stress training, as well as in rats which had only a single day of training. Tianeptine blocked stress effects on memory without altering the stress-induced increase in corticosterone levels. Propranolol, a beta-adrenergic receptor antagonist (5 and 10 mg/kg, ip), in contrast, did not block stress-induced amnesia. These findings indicate that treatment with tianeptine, unlike propanolol, provides an effective means with which to block the adverse effects of stress on cognitive functions of the hippocampus.     

Effects of water-soluble low-molecular-weight beta-1, 3-D-glucan (branch beta-1, 6) isolated from Aureobasidium pullulans 1A1 strain black yeast on restraint stress in mice

It is well known that different stress paradigms are able to rapidly induce corticosterone production and immune function through the activation of the hypothalamic-pituitary-adrenal axis. It has been reported that glucocorticoids suppress natural killer (NK) activity and interleukin (IL)-1 production and, on the other hand, that IL-1 and IL-6 stimulate the release of corticotrophin-releasing-hormone from the rat hypothalamus. Moreover, it has been reported that IL-12 plays a central role in the initiation of cell-mediated immunity, directly and via its induction of interferon (IFN)-gamma and activation of NK cells. In this study, we examined the effects of water-soluble low-molecular-weight beta-glucan isolated from Aureobasidium pullulans 1A1 strain on the corticosterone levels and immune function, such as NK activity and IL-6 and IL-12 production, using a restraint stress-induced mouse model. The water-soluble low-molecular-weight beta-glucan at a dose of 50 or 100 mg kg(-1) inhibited the increases in the blood corticosterone level and the reduction of NK activity induced by restraint stress. Furthermore, the water-soluble low-molecular-weight beta-glucan (100 mg kg(-1)) prevented the reduction of IL-6 and IL-12 production by splenocytes caused by restraint stress. These findings suggest that the inhibitory actions of water-soluble low-molecular-weight beta-glucan on the increase in corticosterone level and reduction of NK activity induced by restraint stress may be associated with the abrogation of the IL-6 and IL-12 reduction caused by the stress. Thus, water-soluble low-molecularweight beta-glucan may be an effective dietary supplement for the prevention of stress.     

Acute and repeated restraint stress have little effect on pyridostigmine toxicity or brain regional cholinesterase inhibition in rats.

Pyridostigmine, a carbamate cholinesterase (ChE) inhibitor, has been used for decades in the treatment of the autoimmune disorder myasthenia gravis and was used prophylactically to protect soldiers from possible organophosphorus nerve agent exposures during the Persian Gulf War. Pyridostigmine is a charged, quaternary compound and thus would not be expected to easily pass the blood-brain barrier. Some studies have suggested, however, that stress may alter blood-brain barrier integrity and allow pyridostigmine to enter the brain. We evaluated the effects of acute and repeated restraint stress on functional signs of cholinergic toxicity (i.e., autonomic dysfunction and involuntary movements) and brain regional cholinesterase inhibition following either acute or repeated pyridostigmine exposures. The acute, oral maximum-tolerated dosage (MTD) of pyridostigmine was estimated at 30 mg/kg. Peak ChE inhibition in whole blood occurred from 0.5 to 4 h after MTD exposure, whereas minimal (<20%) brain ChE inhibition was noted. For acute restraint studies, rats were either (1) restrained for 90 min and then given pyridostigmine (30 mg/kg, po), (2) given pyridostigmine and immediately restrained for 60 min, or (3) restrained for 3 h, given pyridostigmine, and restrained for an additional 60 min. In all cases, rats were evaluated for cholinergic toxicity (SLUD signs and involuntary movements) and sacrificed 1 h after pyridostigmine treatment. Plasma corticosterone was significantly elevated immediately after a single 60-min session of acute restraint stress, but returned to control levels by 1 and 3 h later. Pyridostigmine-induced toxicity was not enhanced nor was brain ChE inhibition altered by acute restraint stress. Blood-brain barrier permeability, assessed by accumulation of horseradish peroxidase in brain regions following intracardiac injection, was not increased by restraint stress. For repeated restraint studies, rats were given pyridostigmine (0, 3, or 10 mg/kg/day) immediately prior to daily restraint (60 min) for 14 consecutive days. Plasma corticosterone was elevated at 1 and 7 days but not at 14 days. Pyridostigmine-treated rats in both dosage groups exhibited slight signs of toxicity for the first 3-5 days, after which cholinergic signs dissipated. Repeated restraint had little effect on functional signs of pyridostigmine toxicity, however. Whole blood and diaphragm ChE were markedly reduced 1 h after the last treatment, but stress had no influence on ChE inhibition in either peripheral or central tissues. The results suggest that acute and repeated restraint stress have little effect on pyridostigmine neurotoxicity or apparent entry of pyridostigmine into the brain.     

8-OH-DPAT increases corticosterone but not other 5-HT1A receptor-dependent responses more in females

The 5-HT1A receptor subtype agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (50-1000 micrograms/kg s.c.) dose dependently increased rat plasma corticosterone. Tube restraint for 30 min also increased plasma corticosterone; this effect was completely blocked by (-)-pindolol (1 mg/kg i.p.). Increases of corticosterone following either 8-OH-DPAT injection or restraint were significantly greater in female animals. The restraint stress-induced changes but not those due to 8-OH-DPAT were decreased by pretreatment with the tranquiliser chlordiazepoxide (10 mg/kg i.p.). In anaesthetized rats, restraint no longer significantly affected corticosterone levels but 8-OH-DPAT caused increases which (though much attenuated) were significantly greater in the females. Dose-dependent increases of plasma corticosterone also resulted on infusing 8-OH-DPAT (500-1500 ng) into the paraventricular nucleus of the hypothalamus; increases were significantly greater in the females. As mentioned in the discussion, these results may be relevant to the greater incidents of depression in women and the possible role of adrenal corticoids in the illness.     

Effects of neonatal methamphetamine treatment on adult stress-induced corticosterone release in rats

In rats, neonatal (+)-methamphetamine (MA) exposure and maternal separation stress increase corticosterone during treatment and result in learning and memory impairments later in life. Early-life stress also changes later responses to acute stress. We tested the hypothesis that neonatal MA exposure would alter adult corticosterone after acute stress or MA challenge. Rats were treated with MA (10 mg/kg × 4/day), saline, or handling on postnatal (P) days 11-15 or 11-20 (days that lead to learning and memory impairments at this dose). As adults, corticosterone was measured before and after 15 min forced swim (FS) or 15 min forced confinement (FC), counterbalanced, and after an acute MA challenge (10 mg/kg) given last. FS increased corticosterone more than FC; order and stress type interacted but did not interact with treatment; treatment interacted with FS but not with FC. In the P11-15 regimen, MA-treated rats showed more rapid increases in corticosterone after FS than controls. In the P11-20 regimen, MA-treated rats showed a trend toward more rapid decrease in corticosterone after FS. No differences were found after MA challenge. The data do not support the hypothesis that neonatal MA causes changes in adult stress responsiveness to FS, FC, or an acute MA challenge.     

Modafinil-induced modulation of working memory and plasma corticosterone in chronically-stressed mice

The original aims of our study were to investigate the dose-effect relationship of modafinil administration on working memory performance, in parallel with the measurement of plasma corticosterone in chronically-stressed mice, as compared to control mice. Memory performance was evaluated by spontaneous alternation in a T-maze. Vehicle or modafinil (8, 16 or 32 mg/kg) were administered after or without chronic stress (immobilization and exposure to light) for 15 min/day over a period of consecutive 14 days. Immediately after behavioral testing, blood was sampled to measure plasma corticosterone levels. Under non-stress conditions, corticosterone significantly increased with 16 and 32 mg/kg modafinil administration. Interestingly, optimal working memory performance was revealed at the 16 mg/kg dose. Moreover, no correlation was evidenced between working memory performance and plasma corticosterone level in modafinil-treated animals. Under stress conditions, corticosterone level was lowered at 8 mg/kg and remained unchanged at 16 and 32 mg/kg modafinil. An optimal working memory performance was evidenced at 8 mg/kg, which indicated a decrease in the efficiency threshold of modafinil under stress. Furthermore, an inverse correlation emerged between working memory performance and corticosterone level. Our study evidenced for the first time the interaction between stress and memory, in the emotional modulation of working memory performance, as a function of the administered dose of modafinil.     

Chronic unpredictable stress, but not chronic predictable stress, enhances the sensitivity to the behavioral effects of cocaine in rats

RATIONALE: Chronic unpredictable stress, in which the type and timing of stress exposures are varied, alters protein levels in the mesolimbic DA system in a manner previously shown to be associated with enhanced behavioral responsiveness to cocaine. Chronic exposure to the same or predictable stress (restraint) does not. Thus, we examined the effects of chronic unpredictable and chronic predictable (restraint) stress on the locomotor activating and place conditioning effects to low cocaine doses. OBJECTIVE: To test whether chronic unpredictable stress enhances the sensitivity to the behavioral effects of cocaine. METHODS: Rats were exposed to 10 days of chronic unpredictable stress, of chronic predictable (restraint) stress, or were not stressed. One day following cessation of stress exposure, locomotor activity to cocaine (0 or 7.5 mg/kg) was assessed for 4 consecutive days and corticosterone levels on the last day were determined. In other experiments, the effects of the chronic stress procedures on cocaine (0.5 and 7.5 mg/kg) place conditioning using an unbiased procedure were assessed. RESULTS: Chronic unpredictable, but not chronic predictable, stress transiently increased the locomotor activating effects of cocaine and this was correlated positively with corticosterone levels. Chronic unpredictable, but not chronic predictable, stress also enhanced the place conditioning effects of cocaine: increased place preference was seen with the low dose and a pronounced place aversion occurred with the high dose. CONCLUSIONS: These data demonstrate that chronic unpredictable stress enhances the behavioral effects of cocaine, including its aversive effects, whereas chronic predictable stress (restraint) is without effect.     

Role of histaminergic mechanisms in the regulation of some stress responses in rats.

The involvement of histaminergic mechanisms in the regulation of some stress responses was studied in rats. The brain neuronal histamine (HA) depletor, alpha-fluoromethyl histidine (alpha-FMH), at doses (50 or 100 mg/kg) which markedly lower brain HA, significantly attenuated the gastric ulcer formation and the elevation in plasma corticosterone in response to cold restraint stress (CRS). alpha-FMH also appreciably reduced gastric mucosal HA content. The H1-antagonist, pheniramine (25 mg/kg), attenuated both the gastric mucosal and endocrine response to CRS, while the effects of the H2-antagonist, cimetidine (200 mg/kg), were on the plasma corticosterone levels. These results are discussed in light of complex HA-ergic mechanisms in the maintenance of physiological homeostasis during stress.