Learning enhancement and behavioral arousal induced by yohimbine

Learning of a food motivated delayed reinforcement autoshaping task was investigated in rats treated with water vehicle or the prototypical anxiogenic agent and alpha 2-adrenergic antagonist yohimbine (0.5 or 1.5 mg/kg, i.p. 30 min before behavioral testing). Unconditioned exploratory rearing activity was monitored concomitantly with acquisition of a lever touch response. The low dose of yohimbine enhanced learning, but it also increased unconditioned behavioral arousal. The high dose retarded acquisition, but when it was withdrawn the animals learned but exploratory activity increased beyond control levels prior to acquisition. Learning thus appeared to be related to the behavioral arousal produced by yohimbine, suggesting that learning enhancement by anxiogenic substances is not due to a direct effect on processes intrinsic to information storage and retrieval; rather, anxiogenic substances may be important modulators of vigilance and performance variables.     

Inhibition of sodium appetite by lipopolysaccharide: involvement of alpha2-adrenoceptors

Lipopolysaccharide (LPS), an endotoxin from the wall of Escherichia coli, produces a general behavioral inhibition and affects several aspects of fluid-electrolyte balance. LPS inhibits thirst; however, it is not clear if it also inhibits sodium appetite. The present results show that LPS (0.3-2.5 mg/kg body wt) injected intraperitoneally produces a dose-dependent reduction of sodium appetite expressed as 0.3 M NaCl intake induced by sodium depletion (furosemide plus removal of ambient sodium for 24 h). The high doses of LPS (1.2-2.5 mg/kg) also produced transient hypothermia at the beginning of the sodium appetite test; however, no dose produced hyperthermia. LPS also increased the stomach liquid content (an index of gastric emptying) after a load of 0.3 M NaCl given intragastrically by gavage to sodium-depleted rats. The α(2)-adrenoceptor antagonist yohimbine (5 mg/kg ip) abolished the effect of LPS on 0.3 M NaCl intake, without changing the effect of LPS on gastric emptying. Injection of RX-821002 (160 nmol), another α(2)-adrenoceptor antagonist, in the lateral cerebral ventricle (LV) also reversed the inhibition of sodium appetite produced by LPS. Yohimbine intraperitoneally or RX-821002 in the LV alone had no effect on sodium intake. Although yohimbine plus LPS produced a slight hypotension, RX-821002 plus LPS produced no change in arterial pressure, suggesting that the blockade of the effects of LPS on sodium intake by the α(2)-adrenoceptor antagonists is independent from changes in arterial pressure. The results suggest an inhibitory role for LPS in sodium appetite that is mediated by central α(2)-adrenoceptors.     

Partial reversal of behavioral action of the agonist D-Trp-6-LH-RH by naloxone in mice

The effects of the superactive agonist analog D-Trp-6-LH-RH were investigated in several neuropharmacological tests: inhibition of picrotoxin-induced seizures, open-field behavior, hot-plate and tail-flick tests, assessment of catalepsy and apomorphine-induced cage-climbing. In most tests, D-Trp-6-LH-RH was administered subcutaneously (sc.) at the dose of 100 micrograms/kg. The opiate involvement in the peptide action was checked by using naloxone HCl (NX) in a dose of 1 mg/kg intraperitoneally (ip.), with the exception of the analgesic tests where the dose was 0.5 mg/kg. The analog significantly suppressed the open-field parameters of ambulation, rearing and grooming; except for grooming, these actions were fully antagonized by NX. Similarly, NX pretreatment restored to the control levels the latencies of seizure parameters increased by D-Trp-6-LH-RH. The hot-plate latencies did not change after pretreatment with NX but the opiate antagonist was fully able to antagonize the analgesic effect of the peptide in the tail-flick test. The cataleptogenic effect and the inhibition of apomorphine-induced cage-climbing demonstrated after D-Trp-LH-RH were not antagonized by NX.     

Melatonin Protects Against Diazinon-Induced Neurobehavioral Changes in Rats

Diazinon is an organophosphorous pesticide with a prominent toxicity on many body organs. Multiple mechanisms contribute to diazinon-induced deleterious effects. Inhibition of acetyl-cholinesterase, cholinergic hyperstimulation, and formation of reactive oxygen species may play a role. On the other hand, melatonin is a pineal hormone with a well-known potent antioxidant activity and a remarkable modulatory effect on many behavioral processes. The present study revealed that oral diazinon administration (25 mg/kg) increased anxiety behavior in rats subjected to elevated plus maze and open-field tests possibly via the induction of changes in brain monoamines levels (dopamine, norepinephrine, and serotonin). Additionally, brain lipid peroxides measured as malondialdehyde (MDA) and tumor necrosis factor alpha (TNF-α) levels were elevated, while the activity of brain glutathione peroxidase enzyme was reduced by diazinon. Co-administration of oral melatonin (10 mg/kg) significantly attenuated the anxiogenic activity of diazinon, rebalanced brain monoamines levels, decreased brain MDA and TNF-α levels, and increased the activity of brain glutathione peroxidase enzyme.     

The treatment of malaria.

At least four doses of quinine followed by a single dose of mefloquine or by a single dose of sulfadoxine-pyrimethamine are two highly effective regimens for chloroquine-resistant falciparum malaria. Mefloquine alone is valuable in ambulant patients. Chloroquine-sensitive falciparum malaria can be treated with a course of chloroquine. Vivax and all other types of malaria should be treated with sequential chloroquine and primaquine. Quinine, by intravenous infusion, is the most effective drug for severe falciparum malaria. The optimum intravenous dose varies between 5 mg/kg and 10 mg/kg administered over four hours. Intravenous or oral quinine should be administered about every 12 hours and the total daily dose of quinine should rarely exceed 20 mg/kg. Intravenous fluid input should be controlled in falciparum malaria to prevent pulmonary oedema. Established renal failure is best treated by dialysis. The value of adrenocortical steroids for falciparum coma has not been established. Fresh blood transfusion may be helpful in small doses for severe anaemia and to replace clotting factors. Anticoagulants, such as heparin, should not be used in falciparum malaria.     

Possible involvement of GABAergic mechanism in protective effect of melatonin against sleep deprivation-induced behavior modification and oxidative damage in mice

Sleep deprivation for 72 h caused anxiety like behavior, weight loss, impaired locomotor activity and oxidative damage as indicated by increase in lipid peroxidation, nitrite level and depletion of reduced glutathione and catalase activity in sleep deprived mice brain. Treatment with melatonin (5 and 10 mg/kg, ip) significantly improved locomotor activity, weight loss and antianxiety effect as compared to control (sleep deprived). Biochemically, melatonin treatment significantly restored depleted reduced glutathione, catalase activity, attenuated lipid peroxidation and nitrite level as compared to control (72 h sleep-deprived) animals. A combination of flumazenil (0.5 mg/kg, ip) and picrotoxin (0.5 mg/kg, ip) with lower dose of melatonin (5 mg/kg, ip) significantly antagonized the protective effect of melatonin. However, combination of muscimol (0.05 mg/kg, ip) with melatonin (5 mg/kg, ip) potentiated protective effect of melatonin as compared to their effect per se. The results suggest that melatonin may produce its protective effect by involving GABAergic system against sleep deprivation-induced anxiety like behavior and related oxidative damage.     

Behavioural alterations in rats induced by single prenatal exposure of haloperidol

Haloperidol (50 mg/kg, i.p.) treatment was given once to two different groups of pregnant Charles Foster rats on gestational day 9 and 14, these being respectively the critical periods of neural morphogenesis and rapid neural cell proliferation in this species. Pregnant control rats were similarly treated with equal volume of vehicle. The pups born were subjected to open-field exploratory behaviour and elevated plus-maze behaviour tests of anxiety and learned helplessness test of depression at 9 weeks of age. The results indicate that prenatal haloperidol treatment on gestational day 14 induces a significant increase in open-field ambulation and faecal droppings whereas haloperidol treatment on gestational day 9 caused significantly decreased rearing and unaltered ambulation in rat offsprings. Rat offsprings treated with haloperidol on gestational day 9 and 14 also displayed significant anxiogenic behaviour pattern on elevated plus-maze. Significantly increased number of escape failures were observed in learned helplessness tests indicating presence of depression in haloperidol treated rat offsprings. These behavioural alterations were found to be more marked in rat offsprings treated with haloperidol on gestational day 14. The results suggest that prenatal single exposure of high dose of haloperidol during critical period of neural cell proliferation leaves a lasting imprint on offsprings resulting in abnormal emotional state.     

Neurons in the amygdala with response-selectivity for anxiety in two ethologically based tests

The amygdala is a key area in the brain for detecting potential threats or dangers, and further mediating anxiety. However, the neuronal mechanisms of anxiety in the amygdala have not been well characterized. Here we report that in freely-behaving mice, a group of neurons in the basolateral amygdala (BLA) fires tonically under anxiety conditions in both open-field and elevated plus-maze tests. The firing patterns of these neurons displayed a characteristic slow onset and progressively increased firing rates. Specifically, these firing patterns were correlated to a gradual development of anxiety-like behaviors in the open-field test. Moreover, these neurons could be activated by any impoverished environment similar to an open-field; and introduction of both comfortable and uncomfortable stimuli temporarily suppressed the activity of these BLA neurons. Importantly, the excitability of these BLA neurons correlated well with levels of anxiety. These results demonstrate that this type of BLA neuron is likely to represent anxiety and/or emotional values of anxiety elicited by anxiogenic environmental stressors.     

Asparagus racemosus Attenuates Anxiety-Like Behavior in Experimental Animal Models

Asparagus racemosus Linn. (AR) is used worldwide as a medicinal plant. In the present study, the anxiolytic activity of standardized methanolic extract of root of AR (MAR) was evaluated in open-field test (OFT), hole-board, and elevated plus maze (EPM) tests. Rats received oral pretreatment of MAR in the doses of 50, 100, and 200 mg/kg daily for 7 days and then were evaluated for the anxiolytic activity in different animal models. Both MAR (100 and 200 mg/kg) and diazepam (1 mg/kg, p.o.) increased the grooming behavior, number of central squares crossed, and time spent in the central area during OFT. Further, MAR (100 and 200 mg/kg) increased the head-dip and head-dip/sniffing behavior, and decreased sniffing activity in hole-board test. Furthermore, MAR (100 and 200 mg/kg) increased the percentage entries and time spent to open arm in EPM test paradigm. The anxiolytic activity in the experimental models was similar to that of diazepam. MAR (100 and 200 mg/kg) enhanced the level of amygdalar serotonin and norepinephrine. It also increased the expression of 5-HT_2A receptors in the amygdala. In another set of experiment, flumazenil attenuated the anxiolytic effect of minimum effective dose of MAR (100 mg/kg) in OFT, hole-board, and EPM tests, indicating GABA_A-mediated mechanism. Moreover, the anxiolytic dose of MAR did not show sedative-like effect in OFT and EPM tests compared to diazepam (6 mg/kg, p.o.). Thus, the anxiolytic response of MAR may involve GABA and serotonergic mechanisms. These preclinical data show that AR can be a potential agent for treatment of anxiety disorders.     

Corticotropin-releasing factor has an anxiogenic action in the social interaction test

The effects of intracerebroventricular (icv) injections of corticotropin-releasing factor (CRF, 100 and 300 ng) were investigated in the social interaction test of anxiety in rats. Both doses of CRF significantly decreased active social interaction without a concomitant decrease in locomotor activity. CRF also significantly increased self-grooming, an effect that was independent of the decrease in social interaction. These results indicate an anxiogenic action for CRF. Chlordiazepoxide (CDP, 5 mg/kg ip) pretreatment reversed the anxiogenic effects of icv CRF (100 ng), but CRF did not prevent the sedative effects of CDP. There were no statistically significant changes due to CRF in locomotor activity or rears or head dipping in the holeboard test. Both doses of CRF significantly increased plasma concentrations of corticosterone. The possible mechanisms of the behavioral effects of CRF are discussed.     

Anti-inflammatory and analgesic activity of Indian Hypericum perforatum L

A standardised 50% aqueous ethanolic extract of the Indian variety of Hypericum perforatum (IHp) was examined for its putative anti-inflammatory and analgesic activity at the doses of 100 and 200 mg/kg, po. The experimental paradigms used were carrageenan induced pedal edema and cotton pellet induced granuloma for anti-inflammatory activity, whereas the tail flick, hot plate and acetic acid induced writhing methods were used to asses analgesic activity. Indomethacin (20 mg/kg, ip) was used as the standard anti-inflammatory drug. Pentazocine (10 mg/kg, ip) and aspirin (25 mg/kg, ip), both clinically used analgesics, were used as standard analgesics for comparison. IHp extract showed significant anti-inflammatory and analgesic activity at both dose levels, in all the paradigms used. Additionally, IHp potentiated the anti-inflammatory activity of indomethacin and analgesic activities of pentazocine and aspirin.     

Mediation of isoproterenol-induced thirst in rats by beta2-adrenergic receptors.

Isoproterenol-induced thirst in rats has been attributed to the activation of beta-adrenergic receptors. Since these receptors can be further differentiated pharmacologically into beta1 and beta2 types, experiments were performed using several beta-adrenergic agonists and antagonists to determine the receptor type initiating the isoproterenol-induced thirst. The beta1- and beta2-adrenergic antagonist, d,l-propranolol (1 mg/kg, ip), blocked the increase in water intake usually accompanying acute subcutaneous administration of isoproterenol (25 microgram/kg) to female rats. Since l-propranolol is known to stabilize membranes and to possess anesthetic-like properties, d-propranolol was also used. This isomer has little beta-adrenergic-blocking activity but possesses anesthetic-like activity. Administration of d-propranolol (1 mg/kg, ip) failed to affect the drinking response to acute administration of isoproterenol (25 microgram/kg). Practolol (125 mg/kg), a beta1-adrenergic antagonist with little anesthetic properties, also had no effect on water intake of isoproterenol-treated rats. Butoxamine, a selective beta2-adrenergic antagonist, attenuated the drinking response to isoproterenol. Salbutamol (150 microgram/kg), a beta2-adrenergic agonist, mimicked the effect of isoproterenol on water intake. These results are consistent with the suggestion that beta2-adrenergic receptors mediate the isoproterenol-induced thirst in rats.     

Yohimbine induced anxiety and increased noradrenergic function in humans: effects of diazepam and clonidine

Yohimbine (30 mg) produced significant increases in subjective anxiety, autonomic symptoms, blood pressure, and plasma 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG) in ten healthy subjects. The effects of pretreatment with diazepam (10 mg) or clonidine (5 micrograms/kg) on these yohimbine induced changes was examined. Both diazepam and clonidine significantly antagonized yohimbine-induced anxiety, but only clonidine significantly attenuated the yohimbine induced increases in plasma MHPG, blood pressure, and autonomic symptoms. When given alone, clonidine significantly decreased plasma MHPG and blood pressure, whereas diazepam did not. These findings indicate that: (1) noradrenergic hyperactivity may be a factor in the production of some anxiety states; (2) the anti-anxiety effects of clonidine appear to result from its actions on receptors which decrease noradrenergic activity; (3) diazepam reverses yohimbine-induced anxiety without effects on several physiological or biochemical indicators of noradrenergic activity in humans.     

Effect of phenobarbitone administration to pregnant rats on anxiety in offsprings

Adults Charles-Foster rats were prenatally treated to phenobarbitone (10 mg/kg, i.p.) from day 13 to 21 of gestation, this being the critical period of neural development. Pregnant control rats were similarly treated with equal volume of vehicle. Adult rat offsprings at 8-9 weeks of age were subjected to open-field exploratory behaviour, elevated plus-maze and elevated zero-maze tests. The rat offsprings displayed significantly increased ambulation and rearings in an open-field arena when compared to control offsprings whereas self-grooming and faecal droppings remain unchanged. On elevated plus-maze test these prenatally treated rat offsprings spent significantly less time on open arms and more time and more number of entries in enclosed arms as compared to controls. Prenatally exposed rats also showed significant less time on open arms, less number of head dips and stretched attend postures on elevated zero-maze test indicating increased anxiogenic behavioural pattern in these animals. The results suggest that prenatal exposure to phenobarbitone leaves a lasting effect on the anxiety state of the offsprings.     

Central nervous activity of elenoside.

Elenoside is a cytotoxic arylnapthalene lignan (NSC 644013-W/1) derived from Justicia hyssopifolia (Family: Acanthaceae). The neuropharmacological activity of this lignan, a beta-D-glucoside was studied. The LD50 (24 h) of elenoside in mice is 305 +/- 7 mg/kg by i.p. route. In the present study elenoside was given to rats at doses of 25 and 50 mg/kg, and its effects on locomotor activity (Varimex test), muscular relaxant activity, open-field test and with chlorpromazine, 10 mg/kg was compared. On Varimex test, spontaneous activity was reduced. Elenoside produced a reduction in the permanence time on muscular relaxant activity (traction test). On open-field test, ambulation and rearing were reduced compared with the control group and an increase in boluses of dose-dependent rate was obtained. Thus it can be concluded that elenoside has central sedative effects and possible application in anxiety conditions.     

Effect of amino acid derivatives of beta-carboline-3-carboxylate on rat behavior

It was shown, that administration of methyl ether N-(beta-carboline-3-carbonyl)-glycine (GA) at dose level of 1-10 mg/kg markedly reduced exploratory behavior and motor activity in the open field test and facilitated manifestation of different rats defend reaction types. Methyl ether N-(beta-carboline-3-carbonyl)-leucine (LA) at the same doses was less effective. Besides GA (10 mg/kg) like earlier described anxiogenic compound FG 7142 suppressed isolation induced muricide behavior of rats. The results obtained combined with literary data allow us to conclude, that GA possesses expressed anxiogenic activity.     

Inhibition of anticonvulsant action of carbamazepine by aminophylline and caffeine in rats

Interaction of two well known methyl xanthines, aminophylline--an antiasthmatic agent--and caffeine--commonly present in beverages, on the seizure protective ability of carbamazepine (CBZ) against electrically and chemically induced seizures in rats was investigated. Aminophylline (75 mg/kg, ip) did not alter the activity of CBZ (10 mg/kg, ip; ED100) on maximal electroshock seizures while dose dependent antagonism of CBZ efficacy was seen at 100 and 150 mg/kg, ip. Similar effects were observed with caffeine (200 and 250 mg/kg, ip). At the highest tolerated doses, aminophylline (150 mg/kg, ip) and caffeine (250 mg/kg, ip) produced antagonism of CBZ protection against pentylenetetrazole seizures. These observations support the possibility that the antagonism due to the interaction of these drugs could be related to their action at adenosine receptor sites in the brain.     

Antinociceptive activity of methanolic extract of leaves of Achyranthes aspera Linn. (Amaranthaceae) in animal models of nociception

Antinociceptive activity of methanolic extract of leaves of A. aspera was studied by peripheral/non-narcotic model of nociception like acetic acid induced writhing syndrome test and central/narcotic models like hot plate and tail flick tests. The methanolic extract of the plant, administered orally (@ 300, 600 and 900 mg/kg, body weight) and the standard drug (piroxicam; 10 mg/kg body weight, po) produced significant analgesic activity in acetic acid induced writhing syndrome as compared to the vehicle treated control group. In the hot plate analgesic test, in A. aspera at the above doses and the standard drug treated group (morphine sulphate @ 1.5 mg/kg, ip), the duration of reaction time (sec) increased dose dependently and significantly compared to the control group. In the tail flick test, the plant extract produced dose dependant increase in reaction time which was significantly higher in the test and standard group compared to the control group. The plant possesses significant antinociceptive property as evidenced in all the animal models of nociception. It might possibly exert its effect through diverse mechanism that may involve both central and peripheral pathways. The preliminary phytochemical investigation revealed the presence of steroids, alkaloids and triterpene in the methanolic extract of leaves of A. aspera which may be responsible for its antinociceptive activity.     

Stereotypy and dyskinesias provoked in cats differentiate directly and indirectly-acting psychomotor stimulants

Cats were observed after treatment with different doses of d-amphetamine, apomorphine, piribedil, nomifensine and L-DOPA + benserazide. Nomifensine (30 mg/kg, ip), d-amphetamine (3, 5 and 7.5 mg/kg, ip) and L-DOPA (100 mg/kg, ip) induced stereotyped behaviors without a significant increase in dyskinetic movements. Piribedil (80 and 150 mg/kg, ip) induced dyskinetic movements without stereotypies. Apomorphine (3 and 10 mg/kg, ip) induced a high frequency of dyskinetic movements with stereotypies occurring only at the highest dose level (10 mg/kg). The dissociation between the stereotyped behaviors and dyskinesias induced by psychomotor stimulants parallels the distinction between indirect and direct receptor stimulation.