Showing papers in "Pharmacology, Biochemistry and Behavior in 2003"

Plants used in Chinese and Indian traditional medicine for improvement of memory and cognitive function.

Abstract: In traditional practices of Ayurvedic and Chinese medicine, numerous plants have been used to treat cognitive disorders, including neurodegenerative diseases such as Alzheimer's disease (AD). An ethnopharmacological approach has provided leads to identifying potential new drugs from plant sources, including those for cognitive disorders. Many drugs currently available in Western medicine were originally isolated from plants, or are derived from templates of compounds isolated from plants. Some anticholinesterase (anti-ChE) alkaloids isolated from plants have been investigated for their potential in the treatment of AD, and are now in clinical use. Galantamine, isolated from several plants including Lycoris radiata Herb., which was used in traditional Chinese medicine (TCM), is licensed in the United Kingdom for the treatment of mild to moderate AD. Various other plant species have shown pharmacological activities relevant to the treatment of cognitive disorders, indicating potential for therapeutic use in disorders such as AD. This article reviews some of the plants and their active constituents that have been used in traditional Ayurvedic medicine and TCM for their reputed cognitive-enhancing or antiageing effects. Plants and their constituents with pharmacological activities that may be relevant for the treatment of cognitive disorders, including enhancement of cholinergic function in the central nervous system (CNS), anti-inflammatory and antioxidant activities, are discussed.

Plants and the central nervous system

Abstract: This review article draws the attention to the many species of plants possessing activity on the central nervous system (CNS). In fact, they cover the whole spectrum of central activity such as psychoanaleptic, psycholeptic and psychodysleptic effects, and several of these plants are currently used in therapeutics to treat human ailments. Among the psychoanaleptic (stimulant) plants, those utilized by human beings to reduce body weight [Ephedra spp. (Ma Huang), Paullinia spp. (guarana), Catha edulis Forssk. (khat)] and plants used to improve general health conditions (plant adaptogens) were scrutinized. Many species of hallucinogenic (psychodysleptic) plants are used by humans throughout the world to achieve states of mind distortions; among those, a few have been used for therapeutic purposes, such as Cannabis sativa L., Tabernanthe iboga Baill. and the mixture of Psychotria viridis Ruiz and Pav. and Banisteriopsis caapi (Spruce ex Griseb.) C.V. Morton. Plants showing central psycholeptic activities, such as analgesic or anxiolytic actions (Passiflora incarnata L., Valeriana spp. and Piper methysticum G. Forst.), were also analysed.Finally, the use of crude or semipurified extracts of such plants instead of the active substances seemingly responsible for their therapeutic effect is discussed.

Salvia for dementia therapy: review of pharmacological activity and pilot tolerability clinical trial.

Abstract: S. lavandulaefolia Vahl. (Spanish sage) extracts and constituents have demonstrated anticholinesterase, antioxidant, anti-inflammatory, oestrogenic and CNS depressant (sedative) effects all of which are currently relevant to the treatment of Alzheimer's disease (AD). The essential oil inhibits the enzyme acetylcholinesterase (AChE) from human brain tissue and bovine erythrocyte and individual monoterpenoid constituents inhibit AChE with varying degrees of potency. In vivo AChE inhibition of select brain (striatal and hippocampal over cortical) AChE was obtained following oral administration of the essential oil to rats. In a study in healthy volunteers essential oil administration produced significant effects on cognition. In a pilot open-label study involving oral administration of the essential oil to patients with AD, a significant increase in diastolic and systolic blood pressure was observed in two patients, however this may have been due primarily to preexisting hypertension and there were no abnormalities in other vital signs or blood samples during the trial period. Although an open label trial is not free from practice effects or rater-caregiver expectations, statistically significant differences between baseline and 6 weeks treatment were a reduction in neuropsychiatric symptoms and an improvement in attention.

Synergistic and antagonistic interactions of anticholinesterase terpenoids in Salvia lavandulaefolia essential oil

Abstract: In vitro anticholinesterase activities of eight commercially available terpenoid constituents of Salvia lavandulaefolia have been investigated. These included 1,8-cineole, camphor, alpha-pinene, beta-pinene, borneol, caryophyllene oxide, linalool and bornyl acetate. Dose-dependent inhibition of acetylcholinesterase (AChE) by these chemical constituents was determined using the method of Ellman [Biochem. Pharmacol. 7 (1961) 88]. The IC50 value of 1,8-cineole was 0.06+/-0.01 mg/ml similar to that of the essential oil (0.05+/-0.01 mg/ml). Analyses of the expected inhibitions based on the prediction of a zero interactive response of a combination at its naturally occurring ratios were carried out in comparison with observed inhibition. Minor synergy was apparent in 1,8-cineole/alpha-pinene and 1,8-cineole/caryophyllene oxide combinations, with interaction indexes not exceeding 0.5. In contrast, a combination of camphor and 1,8-cineole was antagonistic with an interaction index of 2. A combination of all eight compounds was zero interactive. A combination of six constituents, excluding 1,8-cineole and camphor, was used to compare the method of expected response of a combination with a method of summation. These findings reveal that the inhibitory activity of the oil results from a complex interaction between its constituents, which produce both synergistic and antagonistic responses between the component terpenes. Understanding such interactions is important in comparing species on the basis of chemical composition.

Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress

Abstract: Withania somnifera (WS) Dunal is classified in Ayurveda, the ancient Hindu system of medicine, as a rasayana, a group of plant-derived drugs reputed to promote physical and mental health, augment resistance of the body against disease and diverse adverse environmental factors, revitalise the body in debilitated conditions and increase longevity. These attributes are remarkably similar to the properties ascribed to adaptogens like Panax ginseng (PG) in contemporary medicine. As such, the adaptogenic activity of a standardised extract of WS roots was investigated against a rat model of chronic stress (CS). The stress procedure was mild, unpredictable footshock, administered once daily for 21 days to adult male Wistar rats. CS induced significant hyperglycaemia, glucose intolerance, increase in plasma corticosterone levels, gastric ulcerations, male sexual dysfunction, cognitive deficits, immunosuppression and mental depression. These CS induced perturbations were attenuated by WS (25 and 50 mg/kg po) and by PG (100 mg/kg po), administered 1 h before footshock for 21 days. The results indicate that WS, like PG, has significant antistress adaptogenic activity, confirming the clinical use of the plant in Ayurveda.

Effect of Centella asiatica on pentylenetetrazole-induced kindling, cognition and oxidative stress in rats

Abstract: Cognitive impairment in epileptics may be a consequence of the epileptogenic process as well as antiepileptic medication. Thus, there is a need for drugs, which can suppress epileptogenesis as well as prevent cognitive impairment. In the present study, the effect of aqueous extract of Centella asiatica (CA) (100 and 300 mg/kg), an Indian medicinal plant known to possess antiepileptic, cognitive-enhancing and antioxidant property, was evaluated on the course of kindling development, kindling-induced learning deficit and oxidative stress markers in pentylenetetrazole (PTZ) kindled rats. Male Wistar rats were injected PTZ (30 mg/kg ip) once every alternate day (48+/-2 h) until the development of the kindling. Passive avoidance test and spontaneous locomotor activity were carried out 24 and 48 h after the last administration of PTZ, while the oxidative stress parameters (malondialdehyde [MDA] and glutathione) were carried out in the whole brain upon completion of the behavioral assessment. The administration of CA (300 mg/kg orally) decreased the PTZ-kindled seizures and showed improvement in the learning deficit induced by PTZ kindling as evidenced by decreased seizure score and increased latencies in passive avoidance behavior. However, low dose of the CA (100 mg/kg) showed improvement only in the learning deficit due to the kindling and failed to improve the seizure score. The findings suggest the potential of aqueous extract of CA as adjuvant to antiepileptic drugs with an added advantage of preventing cognitive impairment.

Environmental enrichment lowers stress-responsive hormones in singly housed male and female rats.

Abstract: Structural and social aspects of an environmental system can influence the physiology and behavior of animals occupying that system. This study examined the physiological effects of environmental enrichment (EE) with Kong Toys and Nestlets on stress-responsive hormones of the hypothalamic-pituitary-adrenal (HPA) axis under basal and mild stress conditions in singly housed, jugular vein-cannulated, male and female rats. Animals of both sexes housed with EE had significantly lower baseline adrenocorticotropic hormone (ACTH) and corticosterone (CORT) concentrations compared to those housed without EE. ACTH responses to the mild stress of saline injection were significantly lower in female rats housed with EE. Interaction with the Kong Toys and Nestlets appears to have provided the rats with a diversion from monotonous cage life, resulting in lower HPA axis activity before and after mild stress. These results are important because low, stable baselines are essential for accurately discerning pharmacological and other influences on the HPA axis.

Ginseng: potential for the enhancement of cognitive performance and mood

Abstract: Ginseng has been used medicinally in the Far East for several millennia and is currently one of the most widely taken herbal products throughout the world. It has been attributed with a plethora of physiological effects that could potentially benefit cognitive performance or mood. Studies involving animals show that ginseng and its constituent ginsenosides can modulate indices of stress, fatigue, and learning. However, there is a lack of adequately controlled research showing behavioural effects following chronic administration to humans. Recent research has demonstrated that single doses of ginseng most notably engender cognitive benefits in terms of improved memory, but can also be associated with 'costs' in terms of attention task deficits following less mnemonically beneficial doses. A single dose of ginseng has also been shown to modulate cerebroelectrical (EEG) activity. It is suggested that ginseng would benefit from rigorous research further delineating its acute effects and exploring the relationship between acute effects and those seen during and following chronic administration regimens.

Hypericum perforatum extract demonstrates antioxidant properties against elevated rat brain oxidative status induced by amnestic dose of scopolamine.

Abstract: This study was designed to investigate if the impairment of learning and memory induced by acute administration of scopolamine (1.4 mg/kg ip) in rats is associated with altered brain oxidative stress status. The passive avoidance paradigm was used to assess retrieval memory of rats after scopolamine treatment. Following retrieval testing, biochemical assessments of malondialdehyde (MDA), glutathione peroxidase (GSHPx), glutathione (GSH), and superoxide dismutase (SOD) levels/activities as oxidative stress indices were performed. This study also investigated the effect of acute administration of Hypericum perforatum extract (4.0, 8.0, 12.0, and 25.0 mg/kg ip), containing flavonoids with documented antioxidant activity, on brain oxidative status of naive rats treated with amnestic dose of scopolamine. Results showed that administration of 1.4 mg/kg of scopolamine impaired retrieval memory of rats and that such amnesia was associated with elevated MDA and reduced GSH brain levels. In naive rats, which have not been exposed to conditioned fear, scopolamine administration also increased MDA and reduced GSH levels, although with an increase in brain GSHPx activity. Pretreatment of the animals with Hypericum extract (4, 8, and 12 mg/kg) resulted in an antioxidant effect through altering brain MDA, GSHPx, and/or GSH level/activity. Since oxidative stress is implicated in the pathophysiology of dementia, the findings of this study may substantiate the value of scopolamine-induced amnesia in rats as a valid animal model to screen for drugs with potential therapeutic benefit in dementia. Exposure of animals to conditioned fear may be suggested to impair the balance between the rate of lipid peroxidation and the activation of GSHPx as a compensatory antioxidant protective mechanism. It is also concluded that low doses of Hypericum extract, demonstrating antioxidant activity, may be of value for demented patients exhibiting elevated brain oxidative status. Since depression commonly coexists with dementia, Hypericum extract as a drug with documented antidepressant action may also be a better alternative than several other antidepressant medications that have not been evaluated to test their effect on brain oxidative status during amnesia.

Anxiogenic effects during withdrawal from acute ethanol in adolescent and adult rats.

Abstract: Elevated signs of anxiety are observed in adult rodents during withdrawal from chronic as well as acute ethanol exposure. To determine whether adolescents, in addition to their insensitivity to a number of acute ethanol effects, might likewise be hyposensitive to these anxiogenic manifestations of withdrawal from an acute ethanol challenge, the behavior of adolescent and adult male Sprague-Dawley rats was assessed in an elevated plus maze (EPM) 18 h following intraperitoneal challenge with 4 g/kg ethanol. Adult but not adolescent animals demonstrated evidence of anxiety in the plus maze during acute ethanol withdrawal. To ensure that this finding did not merely reflect age differences in ethanol clearance, clearance times at each age were determined, with additional adolescents tested at the same time postclearance as the adults were previously. Adolescents still failed to demonstrate anxiogenic signs of withdrawal. Suppression of activity during the withdrawal test, however, was evident in animals of both ages. A relative resistance to the anxiogenic effects associated with acute ethanol withdrawal during adolescence could serve as a permissive factor for development of binge drinking patterns among human adolescents.

Improved cognitive function in postmenopausal women after 12 weeks of consumption of a soya extract containing isoflavones

Abstract: We previously reported that a high soya diet improved memory and frontal lobe function in young volunteers, and since soya isoflavones are agonists at oestrogen receptors, they may improve these functions in postmenopausal women. Thirty-three postmenopausal women (50-65 years) not receiving conventional hormone replacement therapy (HRT) were randomly allocated in a double-blind parallel study to receive a soya supplement (60 mg total isoflavone equivalents/day) or placebo for 12 weeks. They received a battery of cognitive tests and completed analogue rating scales of mood and sleepiness, and a menopausal symptoms questionnaire before the start of treatment and then after 12 weeks of treatment. Those receiving the isoflavone supplement showed significantly greater improvements in recall of pictures and in a sustained attention task. The groups did not differ in their ability to learn rules, but the isoflavone supplement group showed significantly greater improvements in learning rule reversals. They also showed significantly greater improvement in a planning task. There was no effect of treatment on menopausal symptoms, self-ratings of mood, bodily symptoms or sleepiness. Thus, significant cognitive improvements in postmenopausal women can be gained from 12 weeks of consumption of a supplement containing soya isoflavones that are independent of any changes in menopausal symptoms, mood or sleepiness.

Ethanol effects on three strains of zebrafish: model system for genetic investigations.

Abstract: The effects of acute and chronic ethanol administration on the wild-type (WT), long-fin striped (LFS), and blue long-fin (BLF) strains of zebrafish were investigated. In the LFS strain, acute exposure to 0.25% (v/v) ethanol inhibited the startle reaction and increased both the area occupied by a group of subjects and the average distance between each fish and its nearest neighbor. Similar effects were found in the WT fish although higher concentrations of ethanol were required. No effects on the behavior of the BLF fish were observed with up to 1.0% (v/v) ethanol. Brain alcohol levels were comparable among the three strains precluding a pharmacokinetic explanation for the behavioral results. In LFS zebrafish, behavioral tolerance was observed after 1 week of continual exposure to ethanol. Conversely, chronic ethanol exposure of the WT fish for up to 2 weeks did not result in the development of tolerance, but rather appeared to increase the disruptive action of the drug. The present results suggest the observed strain differences in the effects of ethanol reflect genotypic differences in both the response of the central nervous system (CNS) to ethanol as well as the ability of the CNS to adapt to ethanol exposure. Although preliminary, the present study indicates that the zebrafish is an excellent model system to investigate the genetic determinants involved in regulating the responses to ethanol.

6-methylapigenin and hesperidin: new valeriana flavonoids with activity on the CNS.

Abstract: Valerian is an ancient tranquillizing drug obtained from the underground organs of several Valeriana species. Its active principles were assumed to be terpenoids in the form of valepotriates and/or as components of the essential oil. However, unknown active compounds were not discarded and synergic effects were suspected. We have recently isolated 6-methylapigenin (MA) from Valeriana wallichii and proved that it is a benzodiazepine binding site (BDZ-bs) ligand [Planta Med. 68 (2002) 934]. The present paper is the first report of the presence of 2S(−)-hesperidin in valeriana and describes that it has sedative and sleep-enhancing properties. MA, in turn, was found to have anxiolytic properties and was able to potentiate the sleep-enhancing properties of hesperidin (HN). MA and HN are new members of the growing family of natural flavonoids with activity on the CNS, and their properties suggest that they are promising drug leads in the field.

The psychopharmacology of huperzine A: an alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer's disease.

Abstract: Huperzine A (HupA), extracted from a club moss (Huperzia serrata), is a sesquiterpene alkaloid and a powerful and reversible inhibitor of acetylcholinesterase (AChE). It has been used in China for centuries for the treatment of swelling, fever and blood disorders. It has demonstrated both memory enhancement in animal and clinical trials and neuroprotective effects. Recently it has undergone double-blind, placebo-controlled clinical trials in patients with Alzheimer's disease (AD), with significant improvements both to cognitive function and the quality of life. Most of the clinical trials are from China, but HupA and derivatives are attracting considerable interest in the West, where AD is a major and growing concern. Furthermore, both animal and human safety evaluations have demonstrated that HupA is devoid of unexpected toxicity. Other interesting aspects of HupA pharmacological profile relate to its neuroprotective properties: it has been shown in animal studies that HupA can be used as a protective agent against organophosphate (OP) intoxication and that it reduces glutamate-induced cell death.

Clitoria ternatea and the CNS.

Abstract: The present investigation was aimed at determining the spectrum of activity of the methanolic extract of Clitoria ternatea (CT) on the CNS. The CT was studied for its effect on cognitive behavior, anxiety, depression, stress and convulsions induced by pentylenetetrazol (PTZ) and maximum electroshock (MES). To explain these effects, the effect of CT was also studied on behavior mediated by dopamine (DA), noradrenaline, serotonin and acetylcholine. The extract decreased time required to occupy the central platform (transfer latency, TL) in the elevated plus maze (EPM) and increased discrimination index in the object recognition test, indicating nootropic activity. The extract was more active in the object recognition test than in the EPM. The extract increased occupancy in the open arm of EPM by 160% and in the lit box of the light/dark exploration test by 157%, indicating its anxiolytic activity. It decreased the duration of immobility in tail suspension test (suggesting its antidepressant activity), reduced stress-induced ulcers and reduced the convulsing action of PTZ and MES. The extract exhibited tendency to reduce the intensity of behavior mediated via serotonin and acetylcholine. The effect on DA- and noradrenaline-mediated behavior was not significant. In conclusion, the extract was found to possess nootropic, anxiolytic, antidepressant, anticonvulsant and antistress activity. Further studies are necessary to isolate the active principle responsible for the activities and to understand its mode of action.

Salvia lavandulaefolia (Spanish sage) enhances memory in healthy young volunteers.

Abstract: Sage (Salvia) has a longstanding reputation in British herbal encyclopaedias as an agent that enhances memory, although there is little evidence regarding the efficacy of sage from systematized trials. Based on known pharmacokinetic and binding properties, it was hypothesised that acute administration of sage would enhance memory in young adult volunteers. Two experiments utilised a placebo-controlled, double-blind, balanced, crossover methodology. In Trial 1, 20 participants received 50, 100 and 150 μl of a standardised essential oil extract of Salvia lavandulaefolia and placebo. In Trial 2, 24 participants received 25 and 50 μl of a standardised essential oil extract of S. lavandulaefolia and placebo. Doses were separated by a 7-day washout period with treatment order determined by Latin squares. Assessment was undertaken using the Cognitive Drug Research computerised test battery prior to treatment and 1, 2.5, 4 and 6 h thereafter. The primary outcome measures were immediate and delayed word recall. The 50 μl dose of Salvia essential oil significantly improved immediate word recall in both studies. These results represent the first systematic evidence that Salvia is capable of acute modulation of cognition in healthy young adults.

Behavioral effects and anatomic correlates after brain injury: a progesterone dose-response study.

Abstract: Evidence suggests that progesterone enhances functional recovery in rats after medial frontal cortical contusions; however, a high dose of progesterone exacerbates tissue loss in a stroke model when administered chronically (7-10 days) prior to injury [Stroke 31 (2000) 1173)] This study attempts to determine progesterone's dose-response effects on behavioral performance and GABA-A receptor expression following a cortical contusion Male rats received injections of 0, 8, 16, or 32 mg/kg progesterone in 225% 2-hydroxypropyl-beta-cyclodextrin following cortical impact Lesion 8 mg/kg and lesion 16 mg/kg groups displayed less thigmotaxis in the Morris water maze (MWM) than 0 and 32 mg/kg groups and were not significantly impaired relative to shams on other water maze measures Increased variability in the 32 mg/kg group during somatosensory neglect testing was the only evidence indicating that a high dose of progesterone was disruptive to a few animals These results suggest that low and moderate doses of progesterone are optimal for facilitating recovery of select behaviors and that postinjury progesterone treatment permits a wider dose range than preinjury treatment Progesterone did not affect lesion size, but a strong negative correlation was observed between thalamic GABA-A receptor density and water maze performance Future studies could explore causes for this relationship

Gender differences in the intravenous self-administration of mu opiate agonists.

Abstract: Gender differences have been observed in a number of aspects of the pharmacology of opiates, including their antinociceptive activity, discriminative stimulus properties, the generation of physical dependence, and their positive reinforcing properties. The current experiments were carried out to rigorously examine whether gender differences exist in the intravenous (IV) self-administration of opiates in an operant conditioning paradigm. Both dose-response analyses and the determination of the strength of the reinforcing properties of opiates using a "breakpoint" analysis were examined. We found strong gender differences in the IV self-administration of two mu opiate agonists-heroin and morphine. At a standard fixed ratio (FR) of responding, females consumed significantly greater amounts of heroin and morphine than did males in a dose-dependent fashion. In addition, females also showed much higher breakpoints than did males: the highest FR breakpoint achieved in females was more than double that observed in males and the frequency distribution of breakpoints was shifted significantly to the right in females when compared to males. These data collectively show that mu opiate agonists may serve as reinforcing agents in females over a broader dose range than males and that they also self-administer considerably more opiates on a milligram per kilogram basis. Finally, we conclude that they will also expend much greater effort in an operant conditioning task to obtain opiate reinforcement.

Noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant.

Abstract: Antidepressants and physical exercise have been shown to increase the transcription of hippocampal brain-derived neurotrophic factor (BDNF) Much evidence regarding the initial actions of antidepressant medications as well as exercise leads to the hypothesis that noradrenergic (NE) and/or serotonergic (5-HT) activation is a key element in the BDNF transcriptional elevation common to both interventions Currently, we used short-term beta-adrenergic, 5-HT(1A), or 5-HT(2A/C) receptor blockade to characterize the influence of NE and 5-HT systems on BDNF transcription during physical exercise and antidepressant treatment In situ hybridization revealed that beta-adrenergic blockade significantly blunted the BDNF mRNA elevations due to exercise, and also inhibited the modest elevations in the CA3 and dentate gyrus following short-term treatment with tranylcypromine In contrast, 5-HT(2A/C) blockade only minimally altered exercise-induced BDNF mRNA levels, but inhibited up-regulation of BDNF transcription via tranylcypromine Finally, 5-HT(1A) blockade did not inhibit exercise-induced BDNF mRNA elevations, but significantly enhanced levels above those achieved with exercise alone in the CA4 These results suggest that NE activation via beta-adrenergic receptors may be essential for both exercise and antidepressant-induced BDNF regulation 5-HT(1A) and 5-HT(2A/C) activation, on the other hand, appear to be most important for antidepressant-induced BDNF regulation, but may also participate significantly in exercise-induced regulation in the CA4

Amphetamine-sensitized rats show sugar-induced hyperactivity (cross-sensitization) and sugar hyperphagia.

Abstract: The goal was to determine the locomotor and consummatory effects of sugar in amphetamine-sensitized rats. Following a 30-min locomotor activity baseline using a photocell cage, male rats were administered either 3.0 mg/kg amphetamine or saline i.p. daily for 6 days. On the final day of injections, locomotor activity was measured again to affirm amphetamine sensitization. Experiment 1: Seven days later, half of each group was offered 10% sucrose or water for 1 min in the home cages, followed by a 30-min locomotor activity test to determine whether or not the animals had become hyperactive in response to sugar. Results showed that amphetamine-sensitized animals were hyperactive following a taste of sugar, but not water. Experiment 2: All subjects were then given access to 10% sucrose for 1 h daily for five consecutive days. Results showed that the amphetamine-sensitized group consumed more sucrose across the 5-day measurement period. These results suggest that sugar may be acting on the same system as amphetamine to trigger hyperactivity, and that alterations in this system caused by repeated doses of amphetamine can instigate an appetite for sugar that persists for at least a week.

Attenuated adrenocortical and blood pressure responses to psychological stress in ad libitum and abstinent smokers.

Abstract: Chronic smoking may alter physiological systems involved in the stress response. This study was designed to examine the effects of ad libitum smoking and abstinence on adrenocortical and cardiovascular responses to acute psychological stress in dependent cigarette smokers. We evaluated differences among abstinent smokers, smokers who continued to smoke at their normal rate, and nonsmokers in salivary cortisol concentrations, systolic and diastolic blood pressure (BP), heart rate (HR), and mood reports. Measurements were obtained during rest and in response to acute psychological stress (public speaking) in one session (stress session) and during continuous rest in a control session. Thirty-eight smokers (21 women) and 32 nonsmokers (18 women) participated. Smokers were assigned to either abstain from smoking the night prior to and the day of each session, or to continue smoking at their normal rate before each session. All groups showed significant stress-induced changes in BP and HR. Smokers, regardless of their assigned condition, showed attenuated systolic BP responses to the public-speaking stressor when compared to nonsmokers. While resting cortisol levels were greater among smokers than nonsmokers, no cortisol response to the acute stressor was demonstrated in either ad libitum or abstinent smokers. These results indicate that chronic smoking diminishes adrenocortical and cardiovascular responses to stress, and that short-term abstinence does not correct these alterations.

Chronic treatment with antipsychotics in rats as a model for antipsychotic-induced weight gain in human

Abstract: Several clinical reports have demonstrated that most antipsychotics of the new generation, but not the typical antipsychotic haloperidol, induce weight gain in schizophrenic patients. Since weight gain induces serious health complications in humans, it is crucial to test upcoming antipsychotic compounds in an animal model of weight gain. With the aim of evaluating whether the rat can be used as a model for antipsychotic-induced weight gain, we have investigated the effect of chronic treatment (3 weeks) with one antipsychotic drug inducing weight gain in clinic (olanzapine) and one antipsychotic not inducing weight gain in clinic (haloperidol), on food and water intake and body weight gain in rats. We included both female and male rats in this study. To reduce spontaneous high food intake in rats, and to be able to evaluate the treatment effect on a potential increase of food intake or metabolic changes, we allowed animal to receive only low-palatability chow. In male rats, none of the two compounds induced weight gain, but in female rats, both compounds induced weight gain. Consequently, the effect observed in rats does not match the clinical situation, and Wistar rats in this set-up cannot be considered a relevant model for antipsychotic-induced weight gain in humans.

Adaptogenic effect of Bacopa monniera (Brahmi)

Abstract: As stress is linked to many diseases, research on an effective antistress agent (adaptogen) from plants has gained importance. We report the investigations on the adaptogenic property of a standardized extract of Bacopa monniera against acute (AS) and chronic stress (CS) models in rats. Panax root powder (Panax quinquefolium) was taken as a standard. Male SD rats, weighing 180-200 g, exposed to immobilization stress for 150 min once only for AS and for seven consecutive days in CS, were fed with B. monniera or Panax root powder daily for 3 days in AS and for 7 days in CS, 45 min prior to each exposure of stress. Rats were sacrificed immediately after stress, the blood was collected, and the plasma was separated out for biochemical estimation. Adrenals, spleen, and thymus were dissected for organ weight and stomach for ulcer score. AS exposure significantly increased the ulcer index, adrenal gland weight, plasma glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine kinase (CK) but significantly decreased the spleen weight. Pretreatment with B. monniera at 40 mg/kg po significantly reduced the AS-induced increase in the ulcer index, adrenal gland weight, plasma glucose, AST, and CK. A dose of 80 mg/kg po significantly reversed the AS-induced changes in adrenal gland weight, spleen weight, plasma glucose, ALT, and AST. Panax root powder, 100 mg/kg po, significantly reversed the AS-induced changes in spleen weight, plasma ALT, AST, and CK. CS exposure resulted in a significant increase in the ulcer index, adrenal gland weight, plasma AST, and CK with a significant decrease in the thymus and spleen weight, plasma triglyceride, and cholesterol. Pretreatment with low dose of B. monniera extract at 40 mg/kg significantly reversed changes in ulcer index and plasma AST only, whereas the pretreatment with higher dose significantly reversed CS-induced changes in ulcer index, adrenal gland weight, CK, and AST. Panax root powder significantly reversed CS-induced increase in ulcer index, adrenal gland weight, CK, and AST. On the basis of our result, it is concluded that the standardized extract of B. monniera possesses a potent adaptogenic activity.

Effects of dopamine antagonists on the timing of two intervals.

Abstract: Rats were trained on a two-interval (12 and 36 s) temporal production task (the peak procedure). Test sessions were conducted in which either the D1 antagonist SCH-23390 (SCH; 0.02, 0.04, 0.06 mg/kg) or the D2 antagonist haloperidol (HAL; 0.05, 0.1, 0.2 mg/kg) were injected prior to testing. Both drugs affected the amount of responding, but only HAL affected timing. Under HAL, both intervals were overestimated, consistent with a HAL-induced decrease in clock speed. Drug-induced decreases in response output were more profound for the long interval than the short. In addition, there was evidence of HAL- and SCH-induced delays in response initiation that were more severe for the long interval, perhaps owing to its status as a weaker conditioned stimulus. D 2003 Published by Elsevier Science Inc.

The NO-cGMP-K+ channel pathway participates in the antinociceptive effect of diclofenac, but not of indomethacin.

Abstract: The aim of this study was to examine if the peripheral antinociceptive effects of diclofenac and indomethacin involve the sequential participation of NO and cGMP synthesis followed by potassium channel opening. The peripheral antinociceptive effects of diclofenac, indomethacin, pinacidil (a potassium channel opener) and atrial natriuretic peptide (ANP, which increases cGMP content in a NOindependent manner) were assayed using the formalin test in the rat. All compounds produced significant local antinociception. Diclofenac effect was reverted by N G -L-nitro-arginine methyl ester (L-NAME, an inhibitor of NO synthesis), by 1 H-(1,2,4)-oxadiazolo (4,2-a) quinoxalin-1-one (ODQ, an inhibitor soluble guanylyl cyclase), and by the potassium channel blockers glibenclamide, tolbutamide, charybdotoxin and apamin. Pinacidil effect was blocked by glibenclamide, tolbutamide, charybdotoxin and apamin, strongly suggesting that potassium channel opening results in antinociception. ANP effect was inhibited by the potassium channel blockers, but not by L-NAME, suggesting that potassium channel opening is a consequence of an increased cGMP content. Indomethacin was effective, but at doses higher than those of diclofenac, and could not be blocked by L-NAME nor by potassium channel blockers. The present results suggest that the Larginine–NO–cGMP–potassium channel pathway is involved in the peripheral antinociceptive effect of diclofenac, but not of indomethacin, and thus provide evidence for differences in mechanisms of action among nonsteroidal antiinflammatory drugs (NSAIDs). D 2003 Elsevier Inc. All rights reserved.

Adolescent and adult female rats differ in sensitivity to nicotine's activity effects.

Abstract: More than 90% of cigarette smokers begin smoking during adolescence. This between-subjects repeated-measures experiment examined: (1) nicotine's acute effects on activity in adolescent and adult female Sprague-Dawley rats (Drug Phase I); (2) the effects of age of initial nicotine exposure on activity when nicotine was not administered (Interim Phase); and (3) the effects of age of initial nicotine exposure on later responses to nicotine (Drug Phase II). The experiment consisted of three separate phases. In Drug Phase I, animals were administered either 0 (saline), 0.01, 0.10, 0.50, or 1.0 mg/kg nicotine via subcutaneous injections for 12 days and horizontal activity was measured daily. During the Interim Phase (no drug phase), activity was measured but nicotine was not administered. During Drug Phase II, the same animals were administered the same nicotine dosages as in Drug Phase I for 12 days and activity was measured daily. Drug Phase I revealed dose-response differences between adolescent and adult female rats. In addition, animals initially exposed to nicotine in adolescence exhibited greater sensitivity to nicotine's activity-increasing effects than did females initially exposed to nicotine in adulthood (i.e., Drug Phase II).

Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment

Abstract: 18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener that decreases drug self-administration in several animal models, may be a potential treatment for multiple forms of drug abuse. In animal models, 18-MC reduced intravenous morphine, cocaine, methamphetamine and nicotine self-administration, oral alcohol and nicotine intake, and attenuated signs of opioid withdrawal, but had no effect on responding for a nondrug reinforcer (water) and produced no apparent toxicity [Brain Res. 719 (1996) 29; NeuroReport 11 (2000) 2013; Pharmacol. Biochem. Behav. 58 (1997) 615; Psychopharmacology (Berl.) 139 (1998) 274; NeuroReport 9 (1998) 1283; Ann. N. Y. Acad. Sci. 914 (2000) 369]. Consistent with a relationship among drug sensitization, mesolimbic dopamine, and drug-seeking behavior, 18-MC also blocked the sensitized dopamine responses to morphine and cocaine in the nucleus accumbens. An extensive series of receptor studies showed that 18-MC was most potent and somewhat selective as an antagonist at α3β4 nicotinic receptors. Low-dose combinations of 18-MC with other drugs known to have this same action (e.g., mecamylamine, dextromethorphan, bupropion) decreased morphine, methamphetamine, and nicotine self-administration in rats at doses that were ineffective if administered alone. Together, the data support the hypothesis that diencephalic pathways having high densities of α3β4 nicotinic receptors modulate mesocorticolimbic pathways more directly involved in drug reinforcement. Antagonists of α3β4 nicotinic receptors may represent a totally novel approach to treating multiple addictive disorders, and 18-MC might be the first of a new class of synthetic agents acting via this novel mechanism and having a broad spectrum of activity.

The effects of habitual caffeine use on cognitive change: a longitudinal perspective

Abstract: The efficiency of higher cortical functions, such as memory and speed of complex information processing, tends to decrease with advancing age in normal healthy individuals. Recently, a high habitual intake of caffeine was found associated with better verbal memory performance and psychomotor speed in several cross-sectional population studies. We tested the hypothesis that habitual caffeine intake can reduce or postpone age-related cognitive decline in healthy adults. For this purpose, the cognitive performance of all participants in the Maastricht Aging Study (MAAS), aged between 24 and 81 years, was reassessed after 6 years. Information on the intake of caffeine-containing beverages was available from the baseline questionnaire. After 6 years, 1376 (75.6%) individuals were available for reassessment. After correction for demographic characteristics, baseline performance and health status, there were small albeit significant associations between the overall estimated caffeine intake at baseline and the 6-year change in complex motor speed (motor choice reaction time). The earlier found association between caffeine intake and verbal memory performance was not apparent in this longitudinal study. These results imply that the longitudinal effect of habitual caffeine intake is limited and will not promote a substantial reduction in age-related cognitive decline at a population level.

Protective effect of Nardostachys jatamansi in rat cerebral ischemia.

Abstract: The protective effect of Nardostachys jatamansi (NJ) on neurobehavioral activities, thiobarbituric acid reactive substance (TBARS), reduced glutathione (GSH), thiol group, catalase and sodium–potassium ATPase activities was studied in middle cerebral artery (MCA) occlusion model of acute cerebral ischemia in rats. The right MCA of male Wistar rats was occluded for 2 h using intraluminal 4–0 monofilament and reperfusion was allowed for 22 h. MCA occlusion caused significant depletion in the contents of glutathione and thiol group and a significant elevation in the level of TBARS. The activities of Na + K + ATPase and catalase were decreased significantly by MCA occlusion. The neurobehavioral activities (spontaneous motor activity and motor coordination) were also decreased significantly in MCA occlusion group. All the alternations induced by ischemia were significantly attenuated by 15 days pretreatment of NJ (250 mg/kg po) and correlated well with histopathology by decreasing the neuronal cell death following MCA occlusion and reperfusion. The study provides first evidence of effectiveness of NJ in focal ischemia most probably by virtue of its antioxidant property.

The glycine transporter-1 inhibitors NFPS and Org 24461: a pharmacological study.

Abstract: The in vitro and in vivo pharmacology of two glycine transporter-1 (GlyT1) inhibitors, N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-propyl]sarcosine (NFPS) and R,S-(+/-)N-methyl-N-[(4-trifluoromethyl)phenoxy]-3-phenyl-propylglycine (Org 24461), was studied. NFPS and Org 24461 inhibited the uptake of [3H]glycine in hippocampal synaptosomal preparation with IC(50) values of 0.022 and 2.5 microM. Neither NFPS nor Org 24461 (0.1 microM) showed significant binding to alpha-1, alpha-2, and beta-adrenoceptors, D(1) and D(2) dopamine receptors, and 5-HT(1A) and 5-HT(2A) serotonin receptors in membranes prepared from rat brain or to cloned 5-HT(6) and 5-HT(7) receptors. At 10 microM concentrations, binding affinity was measured for NFPS to 5-HT(2A) and 5-HT(2C) serotonin receptors and alpha-2 adrenoceptors and for NFPS and Org 24461 to 5-HT(7) serotonin receptors. Glycine (0.1 mM) and sarcosine (5 mM) increased [3H]glycine efflux from superfused rat hippocampal slices preloaded with [3H]glycine. NFPS and Org 24461 (0.1 mM) did not influence [3H]glycine efflux, however, they inhibited glycine-induced [3H]glycine release. These findings indicate that NFPS and Org 24461 selectively inhibit glycine uptake without being substrates of the transporter protein. Several antipsychotic tests were used to characterize antipsychotic effects of NFPS and Org 24461 in vivo. These compounds did not alter apomorphine-induced climbing and stereotypy in a dose of 10 mg/kg p.o. in mice and did not induce catalepsy in a dose of 10 mg/kg i.p. in rats. The ID(50) values of NFPS were 21.4 mg/kg and higher than 30 mg/kg i.p. for inhibition of phencyclidine (PCP)- and D-amphetamine-induced hypermotility in mice and these values were 2.5 and 8.6 mg/kg i.p. for Org 24461. NFPS and Org 24461 did not exhibit anxiolytic effects in light-dark test in mice, in the meta-chlorophenylpiperazine (mCPP)-induced anxiety test (minimal effective dose or MED was higher than 3 mg/kg i.p.) and in the Vogel conflict drinking test in rats (MED was higher than 10 mg/kg i.p.). Both NFPS and Org 24461 (1-10 mg/kg i.p.) reversed PCP-induced changes in EEG power spectra in conscious rats. These data support the view that GlyT1 inhibitors may have potential importance in treatment of negative symptoms of schizophrenia.