Effects of repeated methylphenidate treatment in the young rat: sensitization of both locomotor activity and stereotyped sniffing.

The behavioral effects of repeated methylphenidate (MPH) treatment were assessed in young rats. In 4 experiments, rats (starting at Postnatal Day 10 or 16) were pretreated on 5 consecutive days with saline or MPH (2.5-20.0 mg/kg i.p.). Sensitization was assessed after 1 or 7 abstinence days, with rats receiving a test day challenge injection of either a low dose of MPH (2.5 mg/kg) or the same dose of MPH as given during pretreatment. Results show that a test day injection of 2.5 mg/kg MPH produced a sensitized locomotor response in rats pretreated with 2.5-20.0 mg/kg MPH. This MPH-induced locomotor sensitization was evident only after 1 abstinence day. Various pretreatment doses of MPH (5, 10, 15, or 20 mg/kg) were capable of sensitizing the stereotyped sniffing of young rats, but only rats pretreated and tested with the highest dose (20 mg/kg) of MPH showed an augmented stereotyped sniffing response that was still robust after 7 abstinence days. Results indicate that young rats are capable of exhibiting sensitization after an extended abstinence period, which contrasts with previous research suggesting that psychostimulant treatment does not produce long-term sensitization in young rats.     

Hepatotoxicity induced by the herbicide atrazine in the rat

The hepatotoxicity of atrazine was investigated by studying clinical parameters related to hepatic function and by electron microscopy. Three groups to male albino rats (Wistar strain) received 100, 200 and 400 mg of atrazine/per kg of body weight/per day, for 14 days. One group received 600 mg atrazine/per kg of body weight/per day, for 7 days. At termination of dosing, the animals were sacrificed and blood was drawn for the determination of serum total lipids, glucose, alanine aminotransferase (ALT) and alkaline phosphatase (SAP). A dose dependent decrease in serum glucose concentration was observed in all the groups. In contrast, a dose relate increase in total serum lipids, was apparent at all dose levels studied. Activity of serum ALT and SAP increased approximately 60% and 200% respectively in rats given 600 mg atrazine/kg bw for 7 days. The liver was examined grossly and microscopically. Electron microscopy disclosed no changes in the hepatocytes of rats treated with the low dose (100 mg/kg bw). At high doses, electron microscopy revealed hepatocytic proliferation and degeneration of smooth endoplasmic reticulum, lipid accumulation and alteration of bile canaliculi proportional to dose and duration of treatment.     

Comparison of the effects of vitamin E and/or quercetin in attenuating chronic cyclosporine A-induced nephrotoxicity in male rats

1. The aim of the present study was to investigate the effects of vitamin E and/or quercetin (Q) on renal function, oxygen radical concentrations in the kidney and some anti-oxidant enzyme activities in rats treated with cyclosporine A (CsA). 2. Groups of rats (270 +/- 15 g), on standard rat chow and water, received all their treatments by gavage for either 4 or 8 weeks. Control groups received either olive oil (0.5 mL) or 25% ethanol (0.5 mL) + olive oil (0.5 mL) per day as vehicle. All experimental groups received 25 mg CsA/kg per day in 0.5 mL olive oil. The vitamin E group received 100 mg vitamin E/kg per day in olive oil in addition to CsA treatment. The quercetin group received 15 mg of Q/kg per day in 0.5 mL of 25% ethanol in addition to CsA treatment. The vitamin E + quercetin group received the two anti-oxidants at the concentrations given in addition to CsA treatment. 3. Quercetin, at a concentration less than one-quarter of vitamin E, was more efficient in lowering blood urea nitrogen, serum creatinine and kidney malondialdehyde in CsA-treated rats. However, neither of the two anti-oxidants was able to normalize these analytes to control values after either 4 or 8 weeks treatment. 4. Quercetin (50 micromol/kg per day) elevated all renal anti-oxidant enzyme activities to values observed in the negative controls. However, vitamin E (232 micromol/kg per day) only normalized glutathione peroxidase activity at the end of either 4 or 8 weeks treatment. Combination treatment with the two anti-oxidants abolished all the ill-effects of CsA. 5. Combination treatment with the two anti-oxidants of renal transplant patients receiving CsA may be beneficial in ameliorating the chronic nephrotoxic effects of the important immunosuppressive drug CsA.     

Blockade of sensitization to methylphenidate by MK-801: partial dissociation from motor effects

The role of MK-801's locomotor effect in blocking the development of sensitization to methylphenidate was investigated utilizing a computerized locomotor activity monitoring system. After 7 days of acclimation to a 12:12 light-dark cycle (lights on at 07:00), male Sprague-Dawley rats (n=62) were housed in test cages and motor activity was recorded continuously for 16 days. The first 2 days of recording served as a baseline for each rat, and on day 3 each rat received a saline injection. On days 4 to 9 rats were randomly divided into seven groups: Rats received either six daily s.c. injections of methylphenidate (2.5 mg/kg; Group 1), or six daily i.p. injections of 0.30 mg/kg, 0.05 mg/kg MK-801 (Groups 2 and 3, respectively); two MK-801 pre-treatment groups received a single i.p. injection of 0.05, or 0.30 mg/kg MK-801 one hour prior to 2.5 mg/kg methylphenidate (n=8 each) on day 4 followed by five daily injections of 2.5 mg/kg methylphenidate; and finally, two cotreatment groups received a challenge dose of 2.5 mg/kg methylphenidate on day 4 followed by either 0.05 or 0.30 mg/kg MK-801 i.p. one hour prior to 2.5 mg/kg methylphenidate from days 5 to 9. All groups were allowed five days of no treatment before being re-challenged on day 15 with the same treatment they received on day 4. Methylphenidate and 0.30 mg/kg MK-801 sensitized to their own locomotor effects, but 0.05 mg/kg MK-801, which had no acute motor effects, did not. The administration of MK-801 (0.30 mg/kg) prior to methylphenidate either singly on day 4, or coadministered throughout the repeated methylphenidate treatment phase, blocked the development of sensitization to methylphenidate. However, MK-801 at 0.05 mg/kg delayed the development of sensitization when co-administered on days 5 to 9, but a single injection 1 h prior to methylphenidate on day 4 did not prevent sensitization to subsequent methylphenidate administration. In conclusion, MK-801 prevents sensitization to methylphenidate; motor stimulation by MK-801 is not necessary for short-term prevention or delay of sensitization to methylphenidate but may be necessary for a persistent blockade of sensitization.     

Isomerically pure bromobiphenyl congeners and hepatic mono-oxygenase activities in the rat: influence of position and degree of bromination.

Isomerically pure di-, tri-, tetra-, penta-, hexa-, and octabromobiphenyls were injected ip into weanling rats at a dosage of 0.2 mmol/kg/day for 3 consecutive days and the animals were killed 96 hr after the last injection. The influence of position and degree of bromination of the biphenyl nucleus on hepatic function was assessed by measuring changes in activities of hepatic p-nitroanisole O-demethylase (OD) and aniline hydroxylase (AH), by examining morphological changes by electron microscopy, and by comparing the results with those of animals treated with equivalent doses of Firemaster BP6. Bromobiphenyl residues were extracted from liver and analyzed by gas-liquid chromatography. Hepatic O-demethylase activities were increased proportionally as the degree of bromination increased, observations which correlated well with the increased tissue residues and changes in morphology. Marked increases in aniline hydroxylase were observed following treatment with certain di- and tribromobiphenyl congeners but, as the degree of bromination increased above four atoms per molecule, aniline hydroxylase activity was reduced to levels equal to or below those of control, vehicle-treated animals. In contrast, increases in both mono-oxygenases were observed following treatment with Firemaster BP6, fivefold increases for OD and twofold for AH. In vitro experiments with highly brominated congeners suggested that these influenced the AH assay by interacting with microsomal cytochrome P-450.     

Distribution of endosulfan in plasma and brain after repeated oral administration to rats

Rats were fed endosulfan (5 or 10 mg/kg) containing alpha- and beta-isomers in the ratio of 2:1, daily for 15 days. The distribution pattern of endosulfan, its isomers and metabolite, endosulfan sulfate, was estimated in the plasma and brain of the rats. On day 16, the alpha-isomer in rats receiving 5 mg/kg was highest in the cerebrum (3.76 microgram/g) followed by the remaining part of the brain (2.66 microgram/g), and the cerebellum (2.04 microgram/g). The concentration of the beta-isomer was 0.06 microgram/g in the cerebrum and 0.02 microgram/g in the cerebellum; no beta-isomer was detected in the remaining part of the brain. The plasma concentration of alpha- and beta-isomers was 2.26 and 0.46 microgram/ml, respectively. No metabolite other than endosulfan sulfate was detected in plasma. No significant changes in brain tissue were observed in any of the groups under treatment. On day 30 (15 days after the last treatment), the concentration in plasma declined more rapidly than that in the brain tissue. At a higher dose (10 mg/kg), the distribution pattern of isomers and its metabolite, endosulfan sulfate, followed almost the same trend except that the concentration was higher than in rats receiving lower doses.     

Decreased reactivity to anxiolytics caused by early protein malnutrition in rats

In order to investigate whether early malnutrition causes lasting changes in the reactivity to anxiolytic drugs, rat dams during lactation (21 days) and pups after weaning until the 49th day of life were fed on 8% casein diet (M rats), while their well-nourished controls received 25% casein (W rats). From day 50 on all animals ate the same balanced diet. Experiments started on the 91st day. Rats deprived for 22 hours drank water containing either 1.8% or 2.7% sodium chloride for 30 min in a test chamber, total intake being measured. Dose-effect curves for diazepam (0.5-5.0 mg/kg, IP), as well as for the nonbenzodiazepine anxiolytics ipsapirone (0.5-5.0 mg/kg), ritanserin (0.05-1.0 mg/kg) and isamoltane (2.5-20.0 mg/kg) were determined in M as well as in W rats. Diazepam and ipsapirone dose-dependently released drinking suppressed by either salt concentration in W rats, but caused little or no effect in M rats. Ritanserin and isamoltane were ineffective in both groups. These and previously reported results show that early protein malnutrition markedly reduces anticonflict effects of anxiolytics, indicating long-lasting impairment of neuronal systems underlying emotional behavior.     

Subacute toxicity in rats of orally administered fenitrothion alone and in a selected formulation

Young adult male and female Sprague-Dawley rats received 1.0, 5.0, 10.0, or 20.0 mg/kg body wt of technical fenitrothion (O,O-dimethyl O-(4-nitro-m-tolyl)phosphorothioate) in ethanol:propylene glycol (25:75) in the absence or presence of 1.5% ($\text{v}\text{v}$) of each of Atlox 3409F (emulsifier) and Dowanol TPM (cosolvent) by daily gavage for 30 consecutive days. At 7, 14, 21, and 30 days of treatment, five randomly selected rats from each treatment group were killed; tissues (liver, kidney, brain, spinal cord, and distal sciatic nerve) were preserved for morphological examination. The effects of treatment were assessed by measuring changes in blood plasma pseudocholinesterase (ψChE), erythrocytic and brain acetylcholinesterase (AChE), and hepatic and renal nonspecific carboxylesterase (CE) as well as routine hematology and serum biochemistry. At 8, 30, 60, and 90 days after treatment, five animals of each group were killed to assess the reversibility of any observed biochemical, physiological, or histopathological effects. No changes in the routine hematological and serum biochemical parameters or in tissue morphology were observed which could be related either to the vehicle, emulsifier(s)-cosolvent, or to a dose-dependent effect of fenitrothion. A dose-dependent inhibition of the tissue esterases was observed at doses above 1.0 mg fenitrothion/kg body wt. Recovery of esteratic activity from the treatment was rapid except for those rats receiving the largest dose; however, within 2 months after treatment, the activities of all treated rats were comparable to control activities. The emulsifier (Atlox 3409F) and the cosolvent (Dowanol TPM), at concentrations routinely employed in aerial spraying formulations, did not substantially enhance or reduce the toxicity of fenitrothion.     

15-Deoxyspergualin Prolongs Pancreatic Islet Allo- and Xenograft Survival in Mice

The new immunosuppressant 15-deoxyspergualin was evaluated in allogeneic and xenogeneic pancreatic islet transplantation. In the allograft study 500 collagenase-isolated C57BL/6 mouse islets were transplanted under the renal capsule of alloxan-diabetic C57BL/Ks mice that were either 15-deoxyspergualin-treated (n = 15) or given saline only (n = 8). When 15-deoxyspergualin was given (5 mg/kg b.wt. intraperitoneally) until day 28 after transplantation in a special dosage schedule, 10 out of 15 animals were normoglycaemic one week after transplantation and 6 were still normoglycaemic after ten weeks. All 8 control animals were hyperglycaemic after 18 days. Light microscopy showed graft rejection in hyperglycaemic mice, but only mild infiltration of lymphocytes in the grafts of normoglycaemic animals. In the xenograft study C57BL/Ks mice were transplanted under the renal capsule with 500-750 foetal porcine islet-like cell clusters. The grafts were examined for evidence of rejection with light microscopy at different time points after implantation. In the control animals given saline only (n = 37) there was progressive evidence of rejection starting on day seven. In 15-deoxyspergualin treated animals (2.5 mg/kg intraperitoneally; n = 27) there was significantly less infiltration at days 7, 14 and 21. After 32 days there was, however, no difference between controls and 15-deoxyspergualin treated mice. A doubling of the 15-deoxyspergualin dose (5.0 mg/kg intraperitoneally; n = 5) did not further improve the survival of the xenografted islet-like cell clusters. There was no synergistic effect when cyclosporine A (12.5 mg/kg intraperitoneally) was added to the 15-deoxyspergualin therapy (n = 34). Cyclosporine A in itself was inefficient (n = 5) in protecting the xenograft from rejection. Thus, 15-deoxyspergualin treatment induced marked prolongation of graft survival in an allogeneic adult islet transplant model (mouse to mouse) and delayed rejection in a foetal xenogeneic (pig to mouse) islet transplant model.     

Cardioprotective effect of ascorbic acid on doxorubicin-induced myocardial toxicity in rats

Objective:

To investigate the preventive and curative role of ascorbic acid on doxorubicin (dox)-induced myocardial toxicity in rats.

Materials and Methods:

Animals were divided into five groups of six animals each. Group I served as normal control and received saline 5 ml/kg/day intraperitoneal (i.p.) for a period of 15 days. Group II animals received ascorbic acid 20 mg/kg per oral (p.o.) for 15 days as a pretreatment control (PR). Group III animals received dox 2.5 mg/kg body weight (b.w.), i.p., in six equal injections for two weeks for a total cumulative dose of 15 mg/kg b.w. Group IV animals received ascorbic acid 20 mg/kg p.o. for 15 days as a pretreatment followed by dox 2.5 mg/kg b.w., i.p., in six equal injections for two weeks for a total cumulative dose of 15 mg/kg body weight. Group V animals received dox 2.5 mg/kg b.w., i.p., in six equal injections for two weeks for a total cumulative dose of 15 mg/kg b.w. followed by ascorbic acid 20 mg/kg p.o for 15 days as post-treatment control (CR). The biochemical parameters such as tissue glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD), and enzyme biomarkers such as creatine phosphokinase (CPK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were monitored.

Results:

Pretreatment with ascorbic acid (20 mg/kg p.o.) significantly protected the myocardium from the toxic effect of dox (PR), by increasing the levels of antioxidant enzymes such as GSH, SOD, and CAT toward normal and decreased the levels of MDA, CPK, LDH, AST, and ALT as compared with dox-treated rats. Post-treatment with ascorbic acid to dox-treated group (CR) significantly increased the levels of tissue GSH, SOD, CAT and significantly decreased the level of MDA as compared with dox-treated group. It also reduced the severity of cellular damage of the myocardium as confirmed by histopathology. The restoration of the endogenous antioxidant system clearly depicts that ascorbic acid produced its protective effect by scavenging the reactive oxygen species.

Conclusion:

The results obtained in this study provide evidence for the usefulness of the ascorbic acid as a cardioprotective agent.     

Limited hepatotoxic potential of acrylonitrile in rats

The possible hepatotoxicity of acrylonitrile (ACN) was investigated based on reports of decreased hepatic glutathione in rats and liver abnormalities in man after exposure to ACN. Male and female rats pretreated po daily for 3 days with sodium phenobarbital (400 μmol/kg) or with Aroclor 1254 (300 μmol/kg) were given ACN (50, 75, 100, or 150 mg/kg) po for 1, 2, or 3 days, or 100 or 500 ppm ACN in drinking water for 21 days. Rats were killed 30 min or 24 hr after one dose of ACN or on Day 22 in the subacute study. Hepatic nonprotein sulfhydryl (NP-SH) concentration and the activities in serum of sorbitol dehydrogenase (SDH) and transminase (GPT) were measured. The liver was examined grossly and microscopically. Hepatic NP-SH decreased significantly (39, 60, 74, and 81%) at 30 min after 50, 75, 100, or 150 mg ACN, respectively. In some experiments serum SDH was significantly elevated (approximately fourfold) 24 hr after 150/mg/kg ACN. Pretreatment with phenobarbital and Aroclor 1254 resulted in only a slight enhancement of the ACN-induced elevation in serum SDH or GPT activities. Serum SDH increased 60% in rats given 500 ppm ACN in drinking water. Focal superficial necrosis of the liver associated (p < 0.001) with hemorrhagic gastritis of a distended forestomach was found in rats necropsied 24 hr after administration of 150 mg/kg ACN. Other than this superficial necrosis, light microscopy revealed only minor changes in liver tissue. Electron microscopy disclosed no changes in the organelles of hepatocytes of rats treated for 21 days with ACN.     

Induction of hepatic microsomal drug-metabolizing enzymes by inhibitors of 5-lipoxygenase (5-LO): studies in rats and 5-LO knockout mice.

The effect of 5-lipoxygenase (5-LO) inhibitors on the hepatic microsomal mixed-function oxidase (MFO) system of rodents was investigated. After establishing the relative in vitro and in vivo potencies of the 3 test compounds, male Crl:CD (SD) BR rats received CJ-11,802 (0, 10, 50, or 200 mg/kg/day), zileuton (0, 10, 60, or 300 mg/kg/day) or ZD2138 (0 or 200 mg/kg/day) once daily by oral gavage for 14 (zileuton and ZD2138) or 30 (CJ-11,802) consecutive days. Controls were given an equivalent volume of 0.5% methylcellulose vehicle. At necropsy, all livers were weighed, and sections from representative animals (control and highest dose for each compound) were utilized to prepare hepatic microsomal fractions, which were assayed for cytochrome P-450 (CYP) content and the activities of cytochrome c reductase (CRed), para-nitroanisole O-demethylase (p-NOD), ethoxyresorufin O-deethylase (EROD), and pentoxyresorufin O-dealkylase (PROD). A dose-related increase in liver weight occurred in rats given CJ-11,802 and zileuton, while animals administered ZD2138 were unaffected. Rats given CJ-11,802 (200 mg/kg/day) and zileuton (300 mg/kg/day) had increases in CYP, EROD, PROD, CRed and p-NOD compared to corresponding controls, while only the latter two activities were elevated in animals administered ZD2138. To determine if induction of the hepatic microsomal MFO system was related to 5-LO inhibition, male DBA wild-type and 5-LO knockout mice were administered either CJ-11,802 (200 mg/kg/day) or vehicle by oral gavage for 14 consecutive days. At necropsy, liver weight, CYP content, and CRed activity were measured and all were increased similarly in the treated wild-type and knockout mice compared to corresponding controls, indicating that induction was not related to inhibiting 5-LO.     

Halogen substituents at the 4- and 4'-positions of biphenyl: influence on hepatic function in the rat

Isomerically pure biphenyl substituted at the 4- and 4′-positions by fluorine, chlorine, bromine, or iodine were administered ip (0.2 mmol/kg) to weanling rats for 3 consecutive days and the animals were killed 4 days after the last injection. The influence of the halogen on hepatic function was assessed by measuring hepatic p-nitroanisole O-demethylase and aniline hydroxylase activities in the 12,000g, 20-min supernatant of 20% (w/v) liver homogenate, by examining the tissue by light and electron microscopy following fixation, and by quantitating the hepatic residues of halogenated biphenyls by gas-liquid chromatography. No effect was observed with 4,4′-difluorobiphenyl, whereas 4,4′-dichloro- and 4,4′-dibromobiphenyl caused marked induction of hepatic mono-oxygenases and proliferation of the hepatic smooth endoplasmic reticulum, the effect being more pronounced with the latter compound. In contrast to expectation, no morphological or biochemical alterations were observed following treatment with 4,4′-diiodobiphenyl despite the high hepatic residues detected. Biological influence does not appear to be related to the pathway of biotransformation or to the size of the halogen in the 4- and 4′-positions.     

Time course of the tri-o-cresyl phosphate-induced testicular lesion in F-344 rats: enzymatic, hormonal, and sperm parameter studies

Tri-o-cresyl phosphate (TOCP), a known neurotoxic compound, causes testicular toxicity in both leghorn roosters and Fischer 344 rats. The present study was initiated to follow the onset of the testicular lesion through possible changes in sperm numbers and production, serum hormones, and various enzyme activities. Rats were administered TOCP daily (150 mg/kg) for periods of 3, 7, 10, 14, or 21 days. Vehicle-treated animals served as controls. Sperm motility and sperm number per milligram cauda epididymis were both lower in treated animals by Day 10. Testicular weight to body weight ratio was significantly decreased only in the longest treatment duration animals (21 days). Testicular neurotoxic esterase and nonspecific esterase activities were also inhibited, while beta-glucuronidase activity was not affected. Luteinizing and follicle-stimulating hormone levels were normal, as were both serum and interstitial fluid testosterone concentrations. Sertoli cell fluid secretion, as measured by testis weight increase after efferent duct ligation, showed no significant changes. Other organs (spleen, liver, kidney, pancreas, small intestine, adrenal and pituitary glands) had no overt signs of pathology as observed by light microscopy in animals treated for 21 days. A separate group of animals was treated for 21 days and subsequently examined after 98 days of observation (two cycles of the rat seminiferous epithelium). No recovery of spermatogenesis was seen, indicating that the toxicity was irreversible at the dose used. The effects noted in these studies further define the testicular lesion produced by TOCP and show that 150 mg/kg/day for 21 days produced irreversible testicular toxicity.     

5-HT(1A) receptor activation improves anti-cataleptic effects of levodopa in 6-hydroxydopamine-lesioned rats

Background and the purpose of the study

In Parkinson›s disease (PD) prolong use of L-DOPA causes some motor disorders such as wearing-off and L-DOPA induced dyskinesia (LID). In this investigation the effect of 8-OHDAPT, as a 5-HT_1A agonist on anti-cataleptic effect of L-DOPA in 6-hydroxydopamine (6-OHDA) lesioned male Wistar rats was investigated.

Methods

Catalepsy was induced by unilateral injection of 6-OHDA (8 µg/2µl/rat) into the central region of the SNc. After 3 weeks as a recovery period, animals received intraperitoneally (i.p.) L-DOPA (15 mg/kg) twice daily for 20 days, and anti-cataleptic effect of L-DOPA was assessed by bar-test at days of 5, 10, 15 and 20.

Results and major conclusion

The results showed that L-DOPA had anti-cataleptic effect only until the day of 15, and its effect was decreased on the day of 20. On the day of 21, rats were co-injected with three different doses of 8-OHDAPT (0.1, 0.5 and 2.5 mg/kg, i.p.) and L-DOPA (15 mg/kg, ip). 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OHDAPT) improved anti-cataleptic effect of L-DOPA at the dose of 0.5 mg/kg. Moreover the effect of 8-OHDAPT on anti-cataleptic effect of L-DOPA (15 mg/kg, ip) was abolished by 1-(2-methyoxyphenyl)-4-[4-(2-phthalamido) butyl] piperazine hydrobromide (NAN-190; 0.5 mg/kg, i.p.) as a 5-HT_1A receptor antagonist. According to the obtained results, it may be concluded that activation of 5-HT_1A receptors by 8-OHDAPT may improve anti-cataleptic effect of L-DOPA in a 6-OHDA- induced rat model of PD. Further studies are required to clarify the exact mechanism of interaction between 5-HT_1A and dopaminergic neurons.     

The effects of triethyltin and trimethyltin in rats responding under a DRL schedule of reinforcement

Rats were trained to respond under a schedule of reinforcement in which only those responses separated by a 10-to 14-sec period of no responding produced a feed pellet (DRL 10 to 14 sec). Each rat received a single dose of trimethyltin (TMT) (5.6, 7.5, or 10 mg/kg) or triethyltin (TET) 1, 3, 4.25, or 5.6 mg/kg). The lowest dose of TMT (5.6 mg/kg) and the lowest dose of TET (1 mg/kg) were without significant effect. At 7.5 mg/kg and 10 mg/kg TMT, the percentage of the total responses spaced 10 to 14 sec apart decreased over the first 8 to 12 days after TMT. Those rats receiving 7.5 mg/kg TMT gradually returned to control values over the next 2 to 3 weeks while those rats receiving 10 mg/kg never recovered. Rats receiving 3, 4.25, and 5.6 mg/kg TET showed a decrease in the percentage of reinforced responses immediately after receiving TET. The behavior of those rats receiving 3 mg/kg returned to control values in 24 hr. Following 4.25 mg/kg TET, the health of the rats deteriorated rapidly. They were kept alive through heroic measures, but then were killed after testing on the 12th day following TET due to their failing health. At 5.6 mg/kg, the rats were killed on the 4th day due to failing health. These results indicate that TMT and TET differ with respect to potency and time course. The behavioral deficits produced by TET parallel the time course of general toxicity while the behavioral effects of acute TMT administration can persist in time long after the general appearance of the rats has returned to normal.     

Repeated administration of N-methyl-4-phenyl 1,2,5,6-tetrahydropyridine to rats is not toxic to striatal dopamine neurones

N-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine ( MPTP ) (10 mg/kg/day i.p.) was administered to rats for 16 days, which were then observed for a further 9-11 days. MPTP administration did not alter spontaneous locomotor activity or amphetamine (2.5 mg/kg ip)-induced locomotion. Apomorphine (0.25 mg/kg sc) did not alter locomotion in control rats but increased activity in MPTP treated animals. The stereotyped response to apomorphine (0.25 mg/kg sc) and amphetamine (2.5 and 5.0 mg/kg ip) was unaltered by MPTP administration. The striatal content of dopamine, HVA and DOPAC was unaltered by MPTP intake. The uptake of [3H]dopamine and [3H] 5HT in striatal synpatosomes was not changed by MPTP . The results suggest that MPTP , in the dose used, is not toxic to nigro-striatal dopamine neurones in the rat. This contrasts with its neurotoxic actions in monkeys and man.     

Maternal hepatic and embryonic effects of 1,2,3,4-tetrachlorobenzene in the rat

To assess possible maternal hepatic and reproductive effects of this uncharged, low molecular weight, lipophilic chlorinated benzene 0, 100, 300 and 1000 mg/kg/day of 1,2,3,4-tetrachlorobenzene (TCB) was orally administered to pregnant rats on days 9-13 of gestation and the animals were killed on day 14 of pregnancy. Phenobarbital and beta-naphthoflavone were administered to other pregnant rats as positive hepatic controls. Maternal mortality (7/19 rats) was increased and body weight gain was greatly decreased in the 1000 mg/kg/day TCB group. Liver to body weight ratio and hepatic microsomal protein content were unaffected by any TCB treatment. On day 14 maternal NADPH-cytochrome c reductase activity was increased at 1000 mg/kg/day, while the maternal hepatic microsomal cytochrome P-450 content was significantly induced by both 300 and 1000 mg/kg/day of TCB. Microsomal N-demethylation of aminopyrine was increased from 2.6 to 4.0 and 4.5 nmol/mg protein/min at doses of 300 and 1000 mg/kg TCB, respectively. However, maternal hepatic microsomal ethoxyresorufin O-deethylase activity was not consistently increased by TCB. Hepatic glutathione S-transferase activity towards 1,2-dichloro-4-nitrobenzene was increased only by the 1000 mg/kg/day TCB treatment. The rate of microsomal p-nitrophenol and phenolphthalein glucuronidation was increased by TCB administration. Embryonic growth was adversely affected by TCB treatment. Yolk sac diameter, embryonic crown-rump length, and head length were all decreased by treatment with 300 mg/kg/day TCB. This TCB treatment did not significantly elevate the number of dead or abnormal embryos.     

Reproduction and teratological studies with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in the rat and rabbit.

1-(2-Chloroethyl)-3-Cyclohexyl-1-Nitrosourea (CCNU), one of a group of nitrosoureas used for the treatment of cancer, was evaluated for its effects on various parameters of reproduction and postnatal development in the rat and on embryonal and fetal development in the rat and rabbit. Weekly ip treatment of male rats for 9 weeks with 2.5, 5, or 10 mg/kg/week had no effect on copulatory activity, but untreated females bred to males receiving 5 or 10 mg/kg/week had a significant decrease in numbers of implantations, and the resorption rate was increased at all levels of treatment. Treatment of female rats ip with 0.75, 1.5, or 3.0 mg/kg/day for 14 days prior to breeding and through Day 20 of gestation resulted in a high incidence of intrauterine, perinatal, and postnatal mortality. Doses of 2, 4, or 8 mg/kg/day given ip during different 4-day intervals of organogenesis or 6 mg/kg/day given throughout organogenesis (Days 6–15) were teratogenic in the rat. Major abnormalities such as omphalocele, ectopia cordis, hydrocephalus, syndactyly, anophthalmia, and aortic arch anomalies occurred most frequently in groups given 4 or 8 mg/kg on Days 6–9, or 6 mg/kg on Days 6–15 of gestation. Treatment of female rats ip with doses of 0.75, 1.5, or 3.0 mg/kg/day during the last third of gestation and throughout 21 days of lactation had no effect on prenatal, perinatal, or postnatal survival, but pup weights on Day 21 were reduced at all levels of treatment. Doses of 1.5, 2.25, or 3.0 mg/kg administered iv or ip to rabbits on Days 6–18 of gestation resulted in a high incidence of abortion at 3 mg/kg but no drug-related fetal anomalies were detected.     

The effects of 5-HT1A receptor agonists, 5-HT1A receptor antagonists and their interaction on the fear-potentiated startle response

The effects of physical and psychological stress on circulating nicotine levels and conversion of nicotine to cotinine were examined in the rat. Animals received one of three dosages of nicotine (0, 6, and 12 mg/kg) via miniosmotic pumps. On day 14 of drug infusion, animals from each drug condition were randomly assigned to one of three stress conditions (noise, rubber ligature, or no stress). After 2.5h of stress exposure, animals were killed and plasma nicotine and cotinine were measured in vivo and hepatic conversion of nicotine to cotinine was determined in vitro. Stress lowered blood nicotine levels. However, this difference was statistically significant only among animals receiving 12 mg/kg per day nicotine. In contrast, stress had no consistent effect on either measure of conversion of nicotine to cotinine in rats. Taken together, these results suggest that stress lowers circulating nicotine levels. However, the mechanism by which this occurs remains unclear. Received: 17 September 1997/Final version: 14 November 1997