Role of tricyclic antidepressants in the central regulation of hyperalgesia and stress analgesia

The effect of hypophysectomy (HE) on pain thresholds was studied in female noninbred rats. Hyperalgesia was observed after HE since the first till the sixth day of the observation period. Droperidol (1 mg/kg i.p.) and amitryptyline (5 mg/kg i.p.) produced hyperalgesia in sham-operated rats, which was potentiated in hypophysectomized animals. In rats taken into the experiment 3 days after operation, no increase in the pain threshold was recordable during the 30-minute painful stress, and poststress autoanalgesia did not develop subsequently. The opposing data were obtained in sham-operated animals. On intraperitoneal administration of phentanyl (25 micrograms/kg) after the 30-minute painful stress hypophysectomized rats did not manifest any potentiation of its analgesic effect in contradistinction to sham-operated animals. Simultaneous administration of phentanyl at the same dose and melipramine (5 mg/kg i.p.) produced considerable potentiation of analgesia if administered after stress. In hypophysectomized rats, that effect was somewhat reduced.     

Effect of acute melipramine administration on motor activity and defensive conditioned reflexes of passive and active avoidance in rats

The administration of threecyclic antidepressant melipramine to Wistar rats (15 mg/kg, intraperitonaly, 2 h before of experiments) increases time of an "open field" centre leaving. Thus melipramine does not influence horizontal and vertical activity, and also the number of bolus. At the development of a passive avoidance conditioned reflex melipramine significantly slows down realization of a unconditional mink reflex by untrained rats, increasing the latency of call in a dark compartment of the chamber. After training significant deterioration of a reflex reproduction is observed. At research of a defensive conditioned reflex of active avoidance melipramine worsens both development and reproduction of a reflex. The comparative analysis of the literary data of imipramine action on uptake of serotonine and noradrenaline and the analysis of the literary data on a role of these systems in the processes of learning and memory allows to suggest, that the effect of melipramine is connected mainly to amplification activity of serotoninergic system of a brain. It is supposed, that acute administration of melipramine creates emotionally negative state, worsens processes of learning and memory, strengthening mainly activity of a brain serotoninergic system. It specifies that serotoninergic system of a brain is system of punishment. Its activation interferes with formation and consolidation of connections between conditional and unconditional irritation.     

Modification of the State of Adrenergic Systems: Effects on Experimental Tumor Growth and Antitumor Activity of Chlofiden

We studied the effects of treatments with adrenaline hydrochloride, obsidan (a -adrenoblocker), melipramine (an inhibitor of monoamine uptake by neurons), and reserpine (a sympatholytic drug) on tumor growth (Pliss' lymphosarcoma in rats) and on the antitumor activity of a novel cytostatic drug, chlofiden. We found that adrenaline and reserpine enhanced the antitumor effect of chlofiden. Isolated applications of adrenaline and melipramine exerted slight antitumor effects, while after reserpine treatment there was a trend toward stimulation of tumor growth. Under the conditions of the model used, obsidan demonstrated no noticeable antitumor activity and did not modify the antitumor effect of chlofiden. Possible mechanisms of the observed effects are discussed.     

Behavioral effects of acute and chronic triazolam treatments in albino rats

Previous behavioral studies on triazolam (TZ), which are small in number, could only speculate about tolerance to the anxiolytic effect of TZ, as the experiments did not cover sufficient time (of 4 to 7 days) for tolerance to develop. Therefore longer time for chronic TZ administration is used. We investigated the effects of TZ on motor activity and exploratory behavior using plus maze and open field. Three experiments were conducted. In the first, five groups of rats were acutely treated with different doses of TZ (0.25 mg/kg-4.0 mg/kg). In the second set of experiments, rats were treated chronically with a single daily dose of TZ (started with 0.25 mg/kg and increased by time to 1.0 mg/kg) for 5 weeks (representing clinical use). In the third, rats were treated chronically with three daily doses of TZ (started with 0.25 mg/kg and increased by time to 0.5 mg/kg) for 20 days (mimicking drug abuse). Acute TZ administration produced dose dependent anxiolytic effects and a decrease in motor activity with higher doses. Chronically treated rats, either once daily or three times daily doses, showed tolerance to both anxiolytic and sedative effects of TZ. It may be concluded that tolerance to the anxiolytic and sedative effects of TZ would develop after chronic administration either with clinical use or its abuse.     

Effects of multiple, chronic and early hashish exposure on mating behavior, nest-building and gestation in mice

1. The effects of hashish extract on social behavior were investigated in pairs of mice living together from mating to parturition. The drug was administered orally to both animals at a dose of 20 mg delta 9-tetrahydrocannabinol/kg three times a week, either (I) during the 3 weeks from mating to parturition, (II) during the 12 weeks from weaning to mating and parturition, or (III) only during the 3 weeks after weaning. 2. In the mating tests, an acute administration (I) caused a general sedation. Chronically treated animals (II) showed decreased sexual behavior and lower social investigations despite significantly more non-social activities. Early drug treatment (III) had no effect on mating behavior. In all three series of experiments the females had conceived by the next morning. 3. The nest-building behavior during pregnancy was suppressed after multiple (I) and chronic (II) drug administration. In early drug-treated animals (III) the transport of nesting material was only slowed down. Non-social activities were normal or increased in all three series. 4. Parturition was significantly delayed by one day after multiple (I) and chronic (II) drug administration. The birth weight was not affected, but the litter size was decreased after chronic drug treatment. Early drug administration (III) had no effects on these parameters. 5. In conclusion, whereas tolerance to the sedative effects of hashish developed very rapidly, the drug influences on social behavior were stable. Therefore, discussions on legalization of cannabis should pay attention to the drug effects on social behavior.     

Cardiopulmonary effects of nalbuphine hydrochloride and butorphanol tartrate in sheep

The cardiopulmonary, sedative and analgesic effects of butorphanol tartrate and nalbuphine hydrochloride were evaluated in six adult crossbred Dorset sheep (Ovis aries). The animals were divided randomly into two groups of three. The first group received butorphanol tartrate (0.5mg/Kg s.c.) followed in 3 days by nalbuphine hydrochloride (1 mg/Kg, s.c.). The second group received nalbuphine followed in 3 days by butorphanol. Cardiopulmonary parameters were evaluated at baseline (once the animal had accommodated to restraint); immediately following analgesic administration; and at 15, 30, 60, 90 and 120 minutes after analgesic administration. No significant changes (alpha greater than .05) from baseline were seen in any of the measured cardiopulmonary parameters from either the butorphanol or nalbuphine groups. Butorphanol produced the most dramatic analgesic and sedative effects with onset of both within 15 minutes of administration and peak effects occurring 30 minutes post injection. The degree of analgesia was diminished at 120 minutes while the sedative effect returned to near baseline by 90 minutes. The nalbuphine group also showed an onset of analgesia 15 minutes post injection reaching a peak effect after 30 minutes. However, onset of sedation occurred 30 minutes post injection achieving a peak effect at 60 minutes which was markedly less than that of butorphanol. As in the butorphanol group, analgesia was diminished at 120 minutes.     

Chronic vs acute carbamate administration in exercising rats

Physostigmine (PH), alone, and pyridostigmine (PY), in combination with atropine and 2-PAM, have been shown to protect animals against organophosphate poisoning. While acute administration of either of these carbamates increased heating rates and decreased endurance of exercising rats, chronically administered PY did not induce these decrements, and we hypothesized that chronic administration of PH could also result in similar attenuation of these effects. Thus, PH was administered acutely (iv) or chronically (osmotic mini-pump) in the following 4 groups (510-530g, male, N = 10/group): C (control, saline iv), AC-200 (acute, 200 ug/kg, 58% whole blood cholinesterase (ChE) inhibition), CH-7 (chronic, 125 ug/hr, 7 days, 60% inhib.), and CH-14 (chronic, 125 ug/hr, 14 days, 56% inhib.). Rats were run (11 m/min, 26 degrees C) to exhaustion. The run times and heating rates (% of control) were: AC-200 - 47, 213%; CH-7 - 60, 157%; CH-14 - 92, 109%. Additionally, ultrastructural changes noted in diaphragms of acutely treated animals were less evident in chronically treated animals. Thus, the decremental effects of acute PH administration on endurance, thermoregulation, and ultrastructure were attenuated with chronic administration at similar levels of ChE inhibition.     

Potential role of regucalcin as a specific biochemical marker of chronic liver injury with carbon tetrachloride administration in rats

The potential sensitivity of liver specific protein regucalcin as a biochemical marker of chronic liver injury with carbon tetrachloride (CCl₄) administration in rats was investigated. CCl₄ (10%; 1.0 ml/100 g body wt) was orally given 5 times at 3-day intervals to rats, and the animals were killed by bleeding at 3, 6, 18, and 30 days after the first administration of CCl₄. The body weight of rats was significantly lowered 3 and 6 days after CCl₄ administration as compared with that of control rats administered with corn oil, and then the weight was restored at 18 and 30 days. Serum glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) activities were significantly increased 3 days after the administration, while a significant increase in serum -glutamyltranspeptidase (-GTP) activity was seen at 3 and 6 days after the administration. Serum GOT, GPT, and -GTP activities were restored to control levels at 18 and 30 days after CCl₄ administration. Serum albumin, -fetoprotein, and ammonium levels were not changed by CCl₄ administration. Meanwhile, serum regucalcin concentration was markedly increased 3 and 6 days after CCl₄ administration, and a significant increase in serum regucalcin concentration was observed 18 and 30 days after the administration. Liver regucalcin mRNA and liver cytosolic regucalcin levels were significantly decreased 18 and 30 days after CCl₄ administration. Liver content of calcium, which intracellular calcium homeostasis is maintained, was significantly increased between 3 and 30 days after CCl₄ administration. Hepatic mitochondrial succinate dehydrogenase activity was significantly increased 30 days after the administration. The present study demonstrates that serum regucalcin has a potential sensitivity as a specific biochemical marker of chronic liver injury with CCl₄ administration in rats.     

Dosing time-dependent nephrotoxicity of cyclosporin A during 21-day administration to Wistar rats

The incidence of cyclosporine A (CsA) nephrotoxicity with reference to the temporal stage of administration was studied during a chronic 21-day treatment in male Wistar rats. Oral administration (20 mg/kg/day) was given at four different times: 1, 7, 13, or 19 hours after light onset (HALO). Plasma creatinine and blood urea nitrogen (BUN) levels were determined at regular intervals over the 24 h: before treatment (day 0); 7, 14, and 21 days after the beginning of treatment (days 7, 14, and 21); and 7 and 14 days after CsA withdrawal (days 28 and 35). At the same times, creatinine clearance and g-glutamyl transferase urinary excretion were determined in the groups of animals treated at 7 and 19 HALO. Residual concentrations of CsA in the renal tissue were measured at the end of the treatment period (day 21) in all groups. Nephrotoxicity of CsA was dependent on the temporal stage of administration. The renal vasoconstriction showed by the increase in plasma creatinine and BUN levels and the decrease in creatinine clearance was maximal when the CsA was given at 7 and 19 HALO and was correlated to the tissue concentrations of CsA. Tubular injury seems to occur earlier and the return to normal function less rapidly in animals treated at 19 HALO compared with animals treated at 7 HALO.     

The effect of acute and chronic administration of timolol on cardiac sympathetic neural discharge, arrhythmia, and beta adrenergic receptor density associated with coronary occlusion in the cat

The effect of timolol (5 mg/kg, p.o., b.i.d. 7 or 14 days) on cardiac beta adrenergic receptor density, the times to arrhythmia (AR) and death (D), heart rate, mean arterial blood pressure, and postganglionic cardiac sympathetic neural discharge after acute coronary occlusion in cats was examined. In the control animals, receptor densities in the left and right atria did not differ, but were lower than the right ventricle. Left ventricle and septum receptor densities were higher, with the left ventricle the highest. The importance of the gradation of beta receptors with increasing density from base to apex appears to be its relation to cardiac contractile function. Occlusion in cats not treated with timolol did not alter the cardiac beta receptor densities. After timolol for 7 or 14 days, no occlusion, receptor density increased in left ventricle and septum although the increase was only significant after 14 days. A comparison of the beta adrenergic receptor densities in cats pretreated with timolol for 7 or 14 days with or without occlusion revealed that, in general, a decrease (p greater than 0.05) occurred for the occlusion group. Timolol decreased heart rate and blood pressure prior to occlusion. The mean times to AR and D were not significantly increased by either dosing regimen of timolol, although the trend was for an increase in the time to D after 7 days of timolol and an increase in the time to AR and D after 14 days of timolol. When compared with data obtained in saline cats, chronic timolol produced minimal changes in postganglionic cardiac sympathetic neural discharge. Timolol given chronically (p.o.) or acutely (5 mg/kg, i.v. given 15 min prior to occlusion) also did not prevent the cardiac sympathetic discharge associated with the development of AR. The time to AR and D in the acutely treated cats was increased but not significantly. Since cardiac sympathetic neural discharge increased as blood pressure fell in the control period but did not increase after occlusion in the timolol treated animals, the combination of timolol and occlusion may have modified neural discharge via an action on the baroreceptor mechanism. That chronic administration of timolol produces an effect not present in cats in which only occlusion was done is supported by the observation that chronic treatment produced an occlusion-induced decrease in beta adrenergic receptor density.(ABSTRACT TRUNCATED AT 400 WORDS)     

Investigations on the effects of long-term administration of a methionine-enkephalin analogue on the adrenal zona fasciculata of rats treated with dexamethasone or dexamethasone and ACTH

Prolonged (7 days) methionine-enkephalin (DALA) treatment provoked a dose-dependent increase in the volume of zona fasciculata cells of dexamethasone-administered rats, along with a notable rise in the plasma concentration of corticosterone and the activity of 11 beta-hydroxylase. Comparable dose-dependent effects were observed after chronic administration of ACTH to dexamethasone-suppressed rats. The chronic administration of the maximum dose of DALA (500 micrograms/kg/day) was found to significantly further the trophic action of ACTH on the zona fasciculata of dexamethasone-treated animals. It is suggested that enkephalins act independently of and synergistically with ACTH in stimulating the growth and steroidogenic capacity of the rat adrenal zona fasciculata.     

l-Tyrosine Induces DNA Damage in Brain and Blood of Rats

Mutations in the tyrosine aminotransferase gene have been identified to cause tyrosinemia type II which is inherited in an autosomal recessive manner. Studies have demonstrated that an excessive production of ROS can lead to reactions with macromolecules, such as DNA, lipids, and proteins. Considering that the l-tyrosine may promote oxidative stress, the main objective of this study was to investigate the in vivo effects of l-tyrosine on DNA damage determined by the alkaline comet assay, in brain and blood of rats. In our acute protocol, Wistar rats (30 days old) were killed 1 h after a single intraperitoneal l-tyrosine injection (500 mg/kg) or saline. For chronic administration, the animals received two subcutaneous injections of l-tyrosine (500 mg/kg, 12-h intervals) or saline administered for 24 days starting at postnatal day (PD) 7 (last injection at PD 31), 12 h after the last injection, the animals were killed by decapitation. We observed that acute administration of l-tyrosine increased DNA damage frequency and damage index in cerebral cortex and blood when compared to control group. Moreover, we observed that chronic administration of l-tyrosine increased DNA damage frequency and damage index in hippocampus, striatum, cerebral cortex and blood when compared to control group. In conclusion, the present work demonstrated that DNA damage can be encountered in brain from animal models of hypertyrosinemia, DNA alterations may represent a further means to explain neurological dysfunction in this inherited metabolic disorder and to reinforce the role of oxidative stress in the pathophysiology of tyrosinemia type II.     

Effects of Neonatal Treatments on Pain and Audiogenic Sensitivity and Brain Content of Monoamines in Adult Rats

In adult Wistar, KM, and Wag/Rij rats, the threshold of pain sensitivity (tail-flick test) and audiogenic sensitivity were estimated after neonatal administration of Semax (analog of ACTG_4–10 fragment) or after placebo (administration of saline for the control of the effect of neonatal pain stimulation). These neonatal treatments did no affect the rates of sensomotor development at an early age (Fox tests), i.e., did not affect directly the physiological activity of rat pups at the age of up to 21 days. In all control rats injected with saline (pain stimulation), the latencies of audiogenic fits increased reliably, while their degree decreased. Administration of Semax raised these parameters to the level of those in intact animals, i.e., increased the sensitivity to sound. Neonatal administration (per os) of caffeine to KM rats increased reliably the latency of audiogenic fits. The thresholds of pain sensitivity in the rats of all strains were significantly lower saline injected animals than in the intact control, just as the level of dopamine in the hippocampus of KM rats. These data are interpreted as an evidence of changes in the development of some brain systems in response to neonatal treatments.     

Effect of withdrawal of diazepam or morphine treatment on gastric motility (charcoal meal test) in mice: possible role of different central and peripheral receptors

Increased gastrointestinal motility in mice as one of the withdrawal symptoms of commonly abused drugs like diazepam or morphine and its possible mechanism of action was studied. Male Laka mice (20-25 g) were made addict to either diazepam (20 mg/kg, ip for 7 days) or morphine (10 mg/kg, sc for 9 days). Withdrawal symptoms were noted 24 hr after the last injection of diazepam or morphine. The animals were injected with Ro 15-1788 (flumazenil) (1 mg/kg, ip) or naloxone (2 mg/kg, ip) in the respective group to precipitate the withdrawal symptoms. Gastrointestinal motility was assessed by charcoal-meal test. Animals developed tolerance to acute sedative effect of diazepam, and similarly to the acute nociceptive action of morphine. On abrupt cessation of these drugs after chronic treatment the animals showed hyperlocomotion and hyperreactivity in diazepam withdrawal group and hyperalgesia on hot plate in morphine withdrawal groups, respectively. Increase in gastrointestinal motility was observed in all the drug withdrawal groups. Treatment with respective antagonists, Ro 15-1788 (flumazenil) and naloxone precipitated the withdrawal symptoms. The results suggest the involvement of both central and peripheral receptors of benzodiazepines and opioid (mu) receptors in the withdrawal symptoms of the benzodiazepines and morphine, respectively.     

Divergent regulation of gonadotropin subunit mRNA levels by androgens in the female rat.

To examine the effects of gonadal steroids on the pretranslational regulation of the gonadotropin subunits in the female, adult female rats, beginning 7 or 28 days after ovariectomy, received daily injections of testosterone propionate (T), dihydrotestosterone propionate (D), or estradiol benzoate (E) for 7 days. Intact cycling females and ovariectomized rats that received vehicle served as controls. Serum was obtained for LH and FSH levels to assess changes in gonadotropin secretion. Total RNA from individual rats was recovered and analyzed by blot hybridization with specific radiolabeled cDNA probes for the alpha, LH beta, and FSH beta subunits. Autoradiographic bands were quantitated and standardized to mRNA levels in the intact animals. Ovariectomy resulted in a rise in serum gonadotropin levels and all three gonadotropin subunit mRNA levels. Estrogen replacement resulted in suppression of alpha, LH beta, and FSH beta mRNAs whether given at 7 or 28 days after ovariectomy. In contrast, whereas androgen replacement decreased alpha and LH beta mRNAs, D or T did not consistently suppress FSH beta mRNAs. We conclude that chronic estrogen administration to the castrated female rat uniformly suppresses all three gonadotropin subunit mRNA levels. In female rats, as in male rats, chronic androgen administration fails to negatively regulate FSH beta mRNAs.     

Effect of short-term administration of vasopressin on arterial pressure and norepinephrine turnover in Long-Evans rats

Vasopressin (AVP) in acute experiments has been shown to influence cardiovascular reflexes, but the effect of a more prolonged administration of AVP on the sympathetic nervous system has not been investigated. Long-Evans rats were treated for 7 days with AVP (Pitressin tannate in oil, with single daily doses of 100 or 500 mU.100 g-1, s.c.) to determine whether AVP alters norepinephrine (NE) turnover in kidney, intestine, or skeletal muscle. Control rats were given equal doses of peanut oil daily. NE turnover was determined by measuring the decline in tissue levels of NE for 8 h after inhibition of tyrosine hydroxylase with alpha-methyl-p-tyrosine (300 mg.kg-1, i.p. every 4 h). Measurements of water intake, urine output, and urine osmolality showed that chronic administration of the high dose, but not the low dose, of AVP produced maintained increases in urine osmolality and decreases in water intake and urine output. Body weight, plasma osmolality, plasma electrolytes, and hematocrit were not significantly altered by AVP treatment, but mean arterial pressure was elevated significantly (control, 105 +/- 3 mmHg versus AVP, 119 +/- 4 mmHg, p less than 0.05) (1 mmHg = 133.3 Pa) in the high dose group. Plasma renin activity was decreased slightly, but significantly in rats treated with the high dose of AVP. Compared with results in control animals, there were no statistically significant changes in NE turnover after chronic administration of either the low or the high dose of AVP. The results indicate that administration of AVP for 7 days to rats in normal fluid balance does not result in a decrease in NE turnover in peripheral organs.     

Concentration of sialic acid in alloxan diabetic rat islets of Langerhans.

A microanalytical procedure for the determination of total and surface sialic acid concentrations was employed to establish their changes in relation to the length of alloxan diabetes in rat islets of Langerhans. 14 and 60 days after alloxan administration (65 mg/kg), the number of Langerhans islets was significantly decreased (p < 0.001) compared to the control. According to their size, the distribution of islets displayed no significant difference in diabetic and control animals 14 days after alloxan administration, while after 60 days no large islets (dia > or = 128 microns) were found in diabetic animals. The surface sialic acid was significantly increased in the small islets (p < 0.001), whereas no change was found in the large islets 14 days after alloxan administration. After 60 days, the surface sialic acid of both small and large islets was significantly decreased (p < 0.001). These results demonstrate that chronic beta-cell destruction induces a decrease in the sialic acid content in the pancreatic islet cells, suggesting that sialic acid might play a role in insulin secretory regulation regarding chronic effects of alloxan beta-cytotoxicity.     

Lithium: Short-term and chronic effects on plasma testosterone and luteinizing hormone concentrations in mice

The effects of short-term and chronic lithium administration on the concentrations of plasma testosterone (T) and luteinizing hormone (LH) were evaluated in C57BL/6 mice, maintained on a fixed photo-period of LD 14:10 (white lights on at 06:00 h, CST). Lithium chloride was injected intraperitoneally twice daily (at 09:00 and 16:00 h) in groups of adult male mice at a dosage of 2.5 meq/kg for 7 days, and 1.25 meq/kg for 21 days. Circulating levels of T and LH were measured by standard radioimmunoassay (RIA) methods. Plasma T levels showed a significant increase in mice treated with lithium for 7 days as compared to those in saline-injected control animals. However, there was no significant difference in the concentrations of plasma T between chronic (21 days) lithium-treated mice and the matched control. Plasma LH levels remained unchanged following both short-term and chronic lithium treatment.     

High levels of methionine and methionine sulfoxide: Impact on adenine nucleotide hydrolysis and redox status in platelets and serum of young rats

We investigated acute and chronic effects administration of methionine (Met) and/or methionine sulfoxide (MetO) on ectonucleotidases and oxidative stress in platelets and serum of young rats. Wistar rats were divided into four groups: control, Met, MetO, and Met + MetO. In acute treatment, the animals received a single subcutaneous injection of amino acid(s) and were euthanized after 1 and 3 hours. In chronic protocol, Met and/or MetO were administered twice a day with an 8-hour interval from the 6th to the 28th day of life. Nucleoside triphosphate phosphohydrolase and 5′-nucleotidase activities were reduced in platelets and serum by Met, MetO, and Met + MetO after 3 hours and 21 days. Adenosine deaminase activity reduced in platelets at 3 hours after MetO and Met + MetO administration and increased after 21 days in animals treated with Met + MetO. Superoxide dismutase and catalase activities decreased in platelets in MetO and Met + MetO groups after 3 hours, while reactive oxygen species (ROS) levels increased in same groups. Catalase activity in platelets decreased in all experimental groups after chronic treatment. Met, MetO, and Met + MetO administration increased plasmatic ROS levels in acute and chronic protocols; glutathione S-transferase activity increased by MetO and Met + MetO administration at 3 hours, and ascorbic acid decreased in all experimental groups in acute and chronic protocols. Thiobarbituric acid reactive substances increased, superoxide dismutase and catalase activities reduced in the Met and/or MetO groups at 3 hours and in chronic treatment. Our data demonstrated that Met and/or MetO induced changes in adenine nucleotide hydrolysis and redox status of platelets and serum, which can be associated with platelet dysfunction in hypermethioninemia.     

Hypermethioninemia Increases Cerebral Acetylcholinesterase Activity and Impairs Memory in Rats

In the present study we investigated the effect of chronic hypermethioninemia on rat performance in the Morris water maze task, as well as on acetylcholinesterase (AChE) activity in rat cerebral cortex. For chronic treatment, rats received subcutaneous injections of methionine (1.34–2.68 μmol/g of body weight), twice a day, from the 6th to the 28th day of age; control rats received the same volume of saline solution. Groups of rats were killed 3 h, 12 h or 30 days after the last injection of methionine to AChE assay and another group was left to recover until the 60th day of life to assess the effect of early methionine administration on reference and working spatial memory of rats. AChE activity was also determined after behavioral task. Results showed that chronic treatment with methionine did not alter reference memory when compared to saline-treated animals. In the working memory task, we observed a significant days effect with significant differences between control and methionine-treated animals. Chronic hypermethioninemia significantly increased AChE activity at 3 h, 12 h or 30 days after the last injection of methionine, as well as before or after behavioral test. The effect of acute hypermethioninemia on AChE was also evaluated. For acute treatment, 29-day-old rats received one single injection of methionine (2.68 μmol/g of body weight) or saline and were killed 1, 3 or 12 h later. Results showed that acute administration of methionine did not alter cerebral cortex AChE activity. Our findings suggest that chronic experimental hypermethioninemia caused cognitive dysfunction and an increase of AChE activity that might be related, at least in part, to the neurological problems presented by hypermethioninemic patients.