Diabetogenic effects of chronic oral cadmium adminstration to neonatal rats.

1 Chronic exposure of neonatal rats to oral cadmium (Cd) (0.1 and 1.0 micrograms/g daily for 45 days) disturbed glucose homeostasis, as reflected by hyperglycaemia, reduced liver glycogen and enhanced gluconeogenic potential of hepatic tissue. 2 This Cd-exposure regimen also increased hepatic cyclic adenosine 3',5'-monophosphate (cyclic AMP) which was accompanied by enhancement of basal, adrenaline and glucagon-stimulated form(s) of adenylate cyclase. 3 In order to assess the responsiveness of pancreatic beta cells to glucose, islets isolated from control as well as Cd-exposed animals were incubated in vitro and their rate of insulin secretion determined. In the presence of glucose 0.5 mg/ml, there was no significant difference in the rate of insulin release. However, at higher glucose concentrations (1.5 and 3.0 mg/ml), the islets from Cd-exposed rats released significantly less insulin than those of control animals. 4 The results are discussed in relation to the possible mechanism of the diabetogenic effect of Cd.     

Behavioural effects of deltorphins in rats.

When given i.c.v. in rats deltorphins induced a syndrome of behavioural stimulation consisting of increased locomotion rearing and sniffing. The increased locomotor activity and rearing were dose-related over the range of 0.13 to 3.8 nmol/rat for [D-Ala2]deltorphin II (DADELT II) and 1.04 to 20.8 nmol/rat for deltorphin. The delta-selective antagonist, naltrindole (10 mg/kg i.p.), completely abolished the behavioural stimulation induced by 1.3 nmol/rat of DADELT II and shifted the dose-response curve to the right, without decreasing the maximum effect. The mu-preferring antagonist, naloxone, was able to antagonize the DADELT II-induced locomotor activity but only at very high doses (10 and 20 mg/kg i.p.). The i.v. administration of a large dose (10 mg/kg) of the mu 1-selective antagonist, naloxonazine, did not affect the DADELT II response. At doses up to 38 nmol/rat, the i.c.v. injection of DADELT II never induced analgesia. At doses over 20.8 nmol/rat, deltorphin always induced spontaneous controlateral barrel rotations and circling, responses which were not blocked by prior administration of naloxone or haloperidol. In studies performed on the social behaviour of rats, i.c.v. administration of 0.38 nmol/rat of DADELT II was ineffective, while 1.3 nmol/rat increased the number of social contacts. Regression analysis showed that the increase in social contacts was a primary effect of the peptide, not correlated with the increased locomotor activity.     

L-carnitine ameliorates oxidative damage due to chronic renal failure in rats

Chronic renal failure (CRF) is associated with oxidative stress that promotes production of reactive oxygen species. L-Carnitine is a cofactor required for transport of long-chain fatty acids into the mitochondrial matrix. Recent research has shown that some clinical conditions (i.e., anorexia, chronic fatigue, coronary heart disease, diphtheria, hypoglycemia, and male infertility) benefit from exogenous supplementation of L-carnitine. The aim of this study was to examine the role of L-carnitine in protecting the aorta, heart, corpus cavernosum, and kidney tissues against oxidative damage in a rat model of CRF. Male Wistar albino rats were randomly assigned to either the CRF group or the sham-operated control group, which had received saline or L-carnitine (500 mg/kg, i.p.) for 4 weeks. CRF was evaluated by BUN and serum creatinine measurements. Aorta and corporeal tissues were used for contractility studies or stored along with heart and kidney tissues for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels. Plasma MDA, GSH levels and erythrocyte superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were also studied. In the CRF group, the contraction and the relaxation of aorta and corpus cavernosum samples decreased significantly compared with controls and were partially reversed by L-carnitine treatment. In the CRF group, there were significant increases in tissue MDA with marked reductions in GSH levels in all tissues and plasma compared with controls. In the plasma SOD, CAT and GSH-Px activities were also reduced. All these effects were reversed by L-carnitine as well. The increase in MDA level and the concomitant decrease in GSH level of tissues and plasma and also suppression of the antioxidant enzyme activities in plasma demonstrate that oxidative mechanisms are involved in CRF-induced tissue damage. L-carnitine, possibly via its free radical scavenging and antioxidant properties, ameliorates oxidative organ injury and CRF-induced dysfunction of the aorta and corpus cavernosum. These results suggest that L-carnitine supplementation may have some benefit in CRF patients.     

Effect of alcohol intake on some disturbances induced by chronic exposure to carbon disulphide in rats. I. Behavioural alterations

Female white Wistar rats were exposed to CS2 vapour (0.8 mg CS2/1 air) 11 months and to 10% ethanol as the only drinking liquid for the last 3 months of exposure. Spontaneous exploratory motor activity (SEMA), open-field behaviour, passive avoidance performance and the avoidance acquisition were tested. Ethanol did not change the exploratory motor activity and behaviour of CS2-exposed rats in the open-field and passive avoidance tests but it affected their performance in the conditioned avoidance test. The analysis of data suggests that ethanol may adversely affect memory and learning ability in CS2-exposed rats.     

Cannabinoids: neurochemical aspects after oral chronic administration to rats

Male and female Fischer rats were treated orally with Δ⁹-THC doses between 50 and 500 mg/kg or with crude marihuana extract between 50 and 1500 mg/kg, for 28 or 91 consecutive days. At necropsy, brains were weighed and kept frozen until 10% homogenates in 0.32 m sucrose could be made and analyzed. Homogenate samples were assayed for total protein, RNA, lipids, and acetylcholinesterase, succinic dehydrogenase and monoamine oxidase activities. Significant decreases were obtained for protein, RNA and acetylcholinesterase activity at 28 days and monoamine oxidase at 91 days. No changes in total lipids, glycolipids or cholesterol concentrations were observed. The neurochemical alterations coincided with behavioral symptoms of hyperactivity and convulsive activity. Both neurotoxicity and neurochemical changes were partially reversed after the longer interval of treatment.     

Decreased systemic clearance of caffeine due to cimetidine.

1 Five normal subjects received pre-treatment with cimetidine 200 mg three times daily and 400 mg at night for 6 days, or matching placebo. 2 Caffeine (300 mg) was given orally before any treatment and at the beginning of the last day of each treatment course. Treatments were randomly allocated and separated by at least one week. 3 A significant reduction occurred in the systemic clearance of caffeine and the half-life was prolonged as determined from measurement of caffeine in plasma and saliva. No change occurred in the apparent volume of distribution. 4 The oral bioavailability of caffeine was found to be complete in the one subject studied. 5 It is suggested that cimetidine inhibits the microsomal metabolism of caffeine. Although the steady state plasma caffeine would increase by approximately 70%, it is unlikely that this would produce adverse clinical effects.     

Behavioural and neurochemical adaptations to nicotine in rats: influence of NMDA antagonists.

1. The repeated co-administration of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (0.1 and 0.3 mg kg-1, i.p.) with nicotine (0.4 mg kg-1, s.c.) attenuated the development of tolerance to the locomotor depressant effect of the nicotine in rats. 2. The repeated co-administration of the competitive NMDA antagonist D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid, 2 and 8 mg kg-1, i.p.) also attenuated tolerance to the locomotor depressant effect of nicotine. 3. Dizocilpine (0.3 mg kg-1, i.p.) pretreatment attenuated sensitization to the locomotor stimulant effect of nicotine (0.4 mg kg-1, s.c.) and prevented sensitization of nicotine-induced dopamine release in the nucleus accumbens. However, pretreatment with dizocilpine alone caused a modest enhancement of the behavioural response to a subsequent acute dose of nicotine. 4. D-CPPene (2.0 mg kg-1, i.p.) pretreatment prevented sensitization to the nicotine-induced dopamine release in the nucleus accumbens. There was no enhanced locomotor response that could be attributed to nicotine pretreatment when D-CPPene was co-administered with nicotine. However, pretreatment with D-CPPene alone enhanced the locomotor response to an acute dose of nicotine. 5. The results suggest the involvement of NMDA receptors in adaptations of the behavioural and neurochemical effects of nicotine that occur as a result of repeated administration of the drug.     

Behavioural observations in gunn rats

The Gunn rat is a hooded mutant of albino rat with various biochemical defects, including a low UDP-glucuronosyl-transferase activity. As a consequence, about half of their offspring are jaundiced from birth, due to high free bilirubin levels, and develop widespread brain damage. The behaviour of both jaundiced and nonjaundiced Gunn rats was studied in four different tests in a shuttle-box and in a stepthrough passive avoidance situation, and compared with that of normal hooded rats. No differences among groups were found in performance of shuttle responses to a tone in a pseudoconditioning paradigm in which tones and shocks were given at random. However, rats from the two Gunn groups made less shuttlings to the tone in two tests that involved an avoidance contingency (each response cancelled one shock). In addition, nonicteric Gunn rats also performed poorly in a classical conditioning test in the shuttle-box (tones and shocks paired on every trial regardless of responses). This last deficiency of non-icteric Gunn rats may be explained by their higher tendency to freeze in situations involving stimulus-stimulus interactions. They also showed a higher latency than that of the two other groups to enter the dark side of the step-through apparatus on their first exposure to it. All animals seemed to learn the passive-avoidance task to the same extent, however, as shown in a retest carried out 48 h later. Both Gunn groups were hypersensitive to the stereotyped-behaviour-inducing action of apomorphine (0.125–1.0 mg/kg, i.p.), but all groups were about equally sensitive to that of d-amphetamine sulfate (0.5–4.0 mg/kg). Since apomorphine is disposed of by glucuronidation, this might be explained by the low UDP-glucuronosyl-transferase activity known to exist in the Gunn animals. The present results show that additional genetic defects have developed by in-breeding in the Gunn population, which are unrelated to brain damage caused by bilirubin, and which can be well characterized from a behavioural standpoint.     

Formaldehyde-protein conjugate-specific antibodies in rats exposed to formaldehyde

A large human population is exposed to formaldehyde (FA) environmentally and occupationally, leading to a variety of respiratory and dermatological disturbances. FA covalently binds with proteins to form FA-protein conjugates, which might lead to the formation of FA-specific antibodies. The focus of this investigation was to study the formation of antibodies against FA-protein conjugates in rats for their possible use as biological markers of FA exposure. Male Sprague-Dawley rats were fed FA via drinking water (1.6 mg/ml) for up to 6 mo. Blood was collected at 3 and 6 mo following FA exposure, and formation of anti-FA-albumin adduct (anti-FAA) antibodies measured in the serum samples (1:100 dilution) by an enzyme-linked immunosorbent assay (ELISA) using synthesized rat albumin conjugates of FA as the solid-phase antigen. Sera from FA-treated rats showed induction of antibodies to FAA in 50% of the animals at both 3 and 6 mo, and the antibody titer was higher at 6 mo, suggesting a greater antibody response with exposure period. These antibodies were highly specific for FAA as they did not cross-react with malondialdehyde-, 4-hydroxynonenal-, 4-hydroxyhexenal-, and acrolein-albumin adducts. The specificity of anti-FAA antibodies was further evaluated by inhibition studies that showed a dose-dependent decrease in binding when the serum was preincubated with increasing concentrations of FAA, and by Western blot analysis that showed immunoreactivity of the antibody with FAA but not with rat albumin. Furthermore, the anti-FAA antibodies (rat serum) also recognized FA-human albumin (FAHA) conjugates, but had only approximately one-third of the binding affinity in comparison to FAA. Induction of anti-FA-protein conjugate antibodies could be further evaluated to serve as a biomarker of FA exposure.     

Behavioural despair in rats: a new model sensitive to antidepressant treatments.

Rats when forced to swim in a cylinder from which they cannot escape will, after an initial period of vigorous activity, adopt a characteristic immobile posture which can be readily identified. Immobility was reduced by various clinically effective antidepressant drugs at doses which otherwise decreased spontaneous motor activity in an open field. Antidepressants could thus be distinguished from psychostimulants which decreased immobility at doses which increased general activity. Anxiolytic compounds did not affect immobility whereas major tranquilisers enhanced it. Immobility was also reduced by electroconvulsive shock, REM sleep deprivation and "enrichment" of the environment. It was concluded that immobility reflects a state of lowered mood in the rat which is selectively sensitive to antidepressant treatments. Positive findings with atypical antidepressant drugs such as iprindole and mianserin suggest that the method may be capable of discovering new antidepressants hitherto undetectable with classical pharmacological tests.     

Tolerance and sensitization to chronic and subchronic oral caffeine: effects on wheelrunning in rats

Twenty-four male Sprague-Dawley rats were tested for wheelrunning in conjunction with chronic (continuous) or subchronic (alternate day) oral caffeine administration. As expected, chronic administration led to complete tolerance to caffeine's locomotor stimulant effect, while subchronic administration produced sensitization. Results confirm earlier reports of enhanced stimulation with spaced administration of caffeine and tolerance with chronic administration.     

Behavioural effects of neonatal metallic mercury exposure in rats.

The effect of neonatal exposure of rats to mercury vapour (Hg0), at the concentration 0.05 mg/m3, 1 h (low dose) or 4 h (high dose), on the behaviour in adulthood were studied. Exposure occurred on days 11-17 (the period of rapid brain growth). Tests for spontaneous motor activity were performed at the ages of 2 and 4 months. Rats exposed to the high dose Hg0 showed a marked increase in variables locomotion and total activity but a decrease for rearing when tested at 2 months of age. At 4 months of age these rats showed a marked hypoactivity with respect to all three variables. Rats exposed to the low dose showed no significant differences at 2 months compared to controls. However, at the age of 4 months the same pattern (increase in variables locomotion and total activity but a decrease for rearing) already noticed in the high dose group at 2 months was observed. In the spatial learning tasks applied, the radial arm maze and circular swim maze, neonatally exposed pups showed a retarded acquisition to the former, while there was no difference compared to controls in the latter. These data indicate that neonatal exposure to mercury vapour results in similar behaviour changes as reported from offspring prenatally exposed to mercury vapour or methylmercury. Furthermore, exposure for 1 week to concentrations around Swedish threshold values (TLV) for 1 or 4 h resulted in dose and age-related behavioural changes.     

Behavioural effects of etiracetam in rats

The effects of etiracetam, a structural analogue of piracetam, were investigated in rats on Y-maze discrimination acquisition, on open field behaviour, on one-trial passive avoidance learning and on shuttlebox acquisition and extinction. The results indicate that this drug significantly enhances acquisition and may improve retention without having any detectable effects on spontaneous behaviour, not even in very high doses (500 mg/kg IP). Sensitivity to footshock, measured as “flinch” thresholds, was not altered by etiracetam in doses of 25 or 100 mg/kg IP. For a shuttlebox task the effective dose-range lies between 20–30 mg/kg IP, provided pretreatment during 4 days is given. Without pretreatment, i.e. when the drug is only administered during the relatively fast acquisition in the shuttlebox, it was found that acquisition was not enhanced, but extinction of the acquired behaviour was significantly inhibited. The effects of etiracetam can be found at lower dose-levels than with piracetam and also in tests (passive avoidance, shuttlebox) in which piracetam has no or only marginal effects.     

Evaluation of the oral toxicity of acetaldehyde and formaldehyde in a 4-week drinking-water study in rats

A subacute oral toxicity study of acetaldehyde and formaldehyde was carried out in rats. Groups of ten male and ten female 5-wk-old rats received one of the aldehydes in the drinking-water for a period of 4 wk, acetaldehyde being given at dose levels of 25, 125 and 675 mg/kg body weight/day and formaldehyde at dose levels of 5, 25 and 125 mg/kg body weight/day. A group of 20 males and 20 females served as controls and received unsupplemented drinking-water ad lib. An additional group of ten males and ten females was given unsupplemented drinking-water in an amount equal to the amount of liquid consumed by the group given the top dose of formaldehyde. Food and liquid intake were decreased in the groups on the top dose of both acetaldehyde and formaldehyde. Hyperkeratosis of the forestomach, observed only in the top-dose rats, was the only adverse effect of acetaldehyde detected. Effects of formaldehyde, also observed only in the top-dose group, were yellow discoloration of the fur, decreased protein and albumin levels in the blood plasma, thickening of the limiting ridge and hyperkeratosis in the forestomach, and focal gastritis in the glandular stomach. It was concluded that in this study the no-observed-adverse-effect levels of acetaldehyde and formaldehyde were 125 and 25 mg/kg body weight/day, respectively.     

Behavioural consequences of maternal exposure to natural cannabinoids in rats

Cannabis sativa preparations (hashish, marijuana) are the most widely used illicit drugs during pregnancy in Western countries. The possible long-term consequences for the child of in utero exposure to cannabis derivatives are still poorly understood. Animal models of perinatal cannabinoid exposure provide a useful tool for examining the developmental effects of cannabinoids. Behavioral consequences of maternal exposure to either cannabis preparations or to its main psychoactive component, ⁹-tetrahydrocannabinol (THC) in rat models are reviewed in this paper. Maternal exposure to cannabinoids resulted in alteration in the pattern of ontogeny of spontaneous locomotor and exploratory behavior in the offspring. Adult animals exposed during gestational and lactational periods exhibited persistent alterations in the behavioral response to novelty, social interactions, sexual orientation and sexual behavior. They also showed a lack of habituation and reactivity to different illumination conditions. Adult offspring of both sexes also displayed a characteristic increase in spontaneous and water-induced grooming behavior. Some of the effects were dependent on the sex of the animals being studied, and the dose of cannabinoid administered to the mother during gestational and lactational periods. Maternal exposure to low doses of THC sensitized the adult offspring of both sexes to the reinforcing effects of morphine, as measured in a conditioned place preference paradigm. The existence of sexual dimorphisms on the developmental effects of cannabinoids, the role of sex steroids, glucocorticoids, and pituitary hormones, the possible participation of cortical projecting monoaminergic systems, and the mediation of the recently described cannabinoid receptors are also analyzed. The information obtained in animal studies is compared to the few data available on the long-term behavioral and cognitive effects on in utero exposure to cannabis in humans.     

Behavioural and neurochemical effects of repeated administration of cocaine in rats.

The effects of repeated administration of cocaine (15 mg/kg, i.p. twice daily at 8-hr intervals) were investigated on the spontaneous motor activity (SMA) and stereotypy (ST) as well as on the various neurotransmitters (e.g. norepinephrine, NE; dopamine, DA; serotonin, 5-HT; acetylcholine, ACh) in different brain areas (e.g. diencephalon-midbrain, DM; pons-medulla, PM; caudate nucleus, CN) in rats.Following repeated injections of cocaine, both SMA and ST gradually increased, reaching a peak in each case on about the 9th day, then gradually decreased up to the 18th or 20th day, after which the activities were maintained at minimum level which was slightly higher than normal levels. Concomitantly, the DA level in the CN and DM increased and 5-HT in the DM and PM decreased reaching their maximum or minimum levels following cocaine injections on the 9th day; these changes were gradually minimized by the 18th day and remained so up to the 30th day. There were also slight changes in NE and ACh levels. It thus appears that, following repeated cocaine administrations, the changes in the drug-induced behavioural effects can be correlated roughly with the changes in the DA level in the CN and the 5-HT levels in the DM and PM.     

Behavioural and neuroendocrine responses to D-fenfluramine in rats treated with neurotoxic amphetamines

The amphetamine derivatives p-chloroamphetamine (pCA), 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') and D-fenfluramine can, if given repeatedly in high doses to rats, produce a degeneration of serotonergic nerve terminals which we have previously shown to result in a reduction in D-fenfluramine-evoked release of 5-HT in vivo. It is therefore possible that fenfluramine-evoked responses may have value as a probe of 5-HT neurodegeneration in man. The present study examined the effect of pre-treatment with these three agents (pCA 12 mg/kg×2; MDMA 20 mg/kg×8; D-fenfluramine 12.5 mg/kg×8, 14 days prior to testing) on behavioural (5-HT syndrome) and neuroendocrine [prolactin and adrenocorticotrophin (ACTH)] responses in rats to acute administration of D-fenfluramine and other serotonergic agonists. All three pre-treatments attenuated the D-fenfluramine-evoked behavioural syndrome, but did not affect the prolactin or ACTH responses to acute challenge with D-fenfluramine (apart from a small effect of pre-treatment with pCA on the ACTH response to D-fenfluramine). For comparison, the effect of pCA pre-treatment on the behavioural responses to acute administration of pCA and the 5-HT(1A) and 5-HT(2) receptor agonists 8-hydroxy-2-(di- n- propylamino)tetralin (8-OH-DPAT) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), respectively, were also examined. pCA pre-treatment attenuated all components of the behavioural response to pCA but had little or no effect on the behavioural responses to 8-OH-DPAT or DOI, suggesting that there was no alteration in post-synaptic 5-HT(1A) or 5-HT(2) receptor function. While the loss of behavioural effect of D-fenfluramine on rats pre-treated with neurotoxic amphetamines can be understood in terms of the loss of D-fenfluramine's 5-HT-releasing action following 5-HT neurodegeneration, the lack of change in the neuroendocrine responses to D-fenfluramine is not easily explicable in this way. These results emphasise the need for further research into the actions of D-fenfluramine before carrying it forward as a probe of neurodegeneration in man.     

Impact on behavioral changes due to chronic use of sertraline in Wistar albino rats

Aim:

Despite having better tolerability and a wide range of clinical applications over other antidepressants, selective serotonin reuptake inhibitors (SSRIs) are also known to be associated with serious adverse effects like suicidal ideation on chronic use. The present study had explored the impact of the chronic use of sertraline, an SSRI, on the behavioral changes in Wistar albino rats.

Materials and Methods:

The study was conducted on 30 Wistar albino rats of either sex; divided into five groups. Four groups were subjected to chronic mild stress induced by using various stressors randomly scheduled in a week and continued for a period of 3 weeks. The stressed rodents were subjected to sertraline treatment for 9 weeks in different human therapeutic doses extrapolated to animal doses. Behavioral changes were monitored, assessed, and evaluated throughout the treatment phase with the help of tests such as locomotor activity test, forced swim test, tail suspension test, antianxiety test, and sucrose preference test (SPT).

Results:

All tests except SPT, demonstrated significant (P < 0.05) reduction in depressive-like activity in the stressed rodents by the mid-treatment phase, followed by an abrupt onset of the depressive state by the end of the treatment phase. SPT showed a significant (P < 0.05) increase in sucrose consumption throughout the treatment phase.

Conclusion:

Behavioral changes following chronic sertraline administration conferred gradual remission of depression state on initial treatment phase, followed by a reversal of effect on chronic use.KEY WORDS: Behavioral changes, chronic mild stress, selective serotonin reuptake inhibitors, sertraline     

Analysis of hepatic gene expression during fatty liver change due to chronic ethanol administration in mice

Chronic consumption of ethanol can cause cumulative liver damage that can ultimately lead to cirrhosis. To explore the mechanisms of alcoholic steatosis, we investigated the global intrahepatic gene expression profiles of livers from mice administered alcohol. Ethanol was administered by feeding the standard Lieber-DeCarli diet, of which 36% (high dose) and 3.6% (low dose) of the total calories were supplied from ethanol for 1, 2, or 4 weeks. Histopathological evaluation of the liver samples revealed fatty changes and punctate necrosis in the high-dose group and ballooning degeneration in the low-dose group. In total, 292 genes were identified as ethanol responsive, and several of these differed significantly in expression compared to those of control mice (two-way ANOVA; p < 0.05). Specifically, the expression levels of genes involved in hepatic lipid transport and metabolism were examined. An overall net increase in gene expression was observed for genes involved in (i) glucose transport and glycolysis, (ii) fatty acid influx and de novo synthesis, (iii) fatty acid esterification to triglycerides, and (iv) cholesterol transport, de novo cholesterol synthesis, and bile acid synthesis. Collectively, these data provide useful information concerning the global gene expression changes that occur due to alcohol intake and provide important insights into the comprehensive mechanisms of chronic alcoholic steatosis.