Impaired spatial memory after ketamine administration in chronic low doses

Ketamine is a noncompetitive antagonist of the NMDA-receptors, used as a dissociative anesthetic, presently included in the category of the psychoactive substances known as "club drugs". Ketamine administration was associated with impaired working memory and increased psychopathological symptoms, but there is a lack of information regarding the effects of chronic sub-anesthetic doses. Adult Wistar rats were administered ketamine, 5 and 10 mg/kg twice daily, subcutaneously for 14 days. One week later, rats were tested in an object recognition/object location task and in the open field arena. There was altered performance in both the object recognition/location and in the open field tests by the group chronically exposed to the lower dose of ketamine. These animals displayed a decreased discrimination index (p<0.05) in the object recognition task, were unable to recognize the displacement of a familiar object and displayed decreased activity across open filed sessions. Importantly, these alterations were not observed in animals administered a higher dose of ketamine. Collectively, these results consistently show that chronic administration of ketamine in sub-anesthetic doses may lead to decreased habituation and inability to update spatial representations.     

Tolerance and dependence after chronic administration of clonidine to the rat

Acute administration of clonidine (10-70 microgram/kg, IP) disrupted operant behavior maintained by a fixed ratio schedule of reinforcement [1]. When chronically administered (100 microgram/kg, IP and 3 microgram/ml in drinking water) tolerance to the behavioral depressant effect developed within a few days and was complete by 14 days. Abrupt termination of drug treatment in tolerant rats resulted in an abstinence reaction which was characterized by suppression of operant performance for as long as one week. These results demonstrated the development of tolerance to and dependence on clonidine in rats. These behavioral observations in rats may be related to rebound hypertension and irritability of patients given this alpha-adrenergic agonist for treatment of hypertension.     

Alteration of the rat exocrine pancreas after chronic scopolamine administration

N-Methyl scopolamine (NMS) 25 mg kg-1 was given to rats for 14 days as a single daily intraperitoneal injection or by constant infusion through osmotic minipumps placed in the abdominal cavity. The anticholinergic drug reduced significantly body and pancreatic weights, and total pancreatic DNA contents, an indication of tissue growth inhibition. Total enzyme and protein contents were however significantly increased with the drug infusion more efficiently than by the daily injection. It is suggested that pancreatic hypertrophy observed after NMS treatment can be ascribed partially to inhibition of enzyme release elicited by blocking the enteropancreatic reflex causing over a long period enzyme accumulation in the gland. In conclusion, chronic anticholinergic treatment resulted in pancreatic aplasia and hypertrophy and could serve as a good model to study muscarinic receptor modulation in the pancreas.     

Effects of diphenylhydantoin and trimethadione on seizure activity during cobalt experimental epilepsy in the rat

Rats rendered chronically epileptic by the application of cobalt to the right parietal cortex were simultaneously prepared with permanent cortical and temporalis muscle electrodes for longitudinal recording of the electroencephalogram and electromyogram. Automatic injections of trimethadione (100 mg/kg per 6 hr and 100 mg/kg per 3 hr) or diphenylhydantoin (5 mg/kg per 6 hr and 10 mg/kg per 6 hr) were administered through indwelling intraperitoneal cannulae from days 7–13 after cobalt placement. At this time, spontaneous seizure activity in saline treated cobalt epileptic rats was maximal. Although neither anticonvulsant completely suppressed seizures, the higher dose of diphenylhydantoin and the lower dose of trimethadione caused a significant reduction in the incidence of completely generalized grand mal convulsions. While neither dose of diphenylhydantoin had any influence on the frequency of occurrence of incompletely generalized seizures, the incidence of this type of seizure activity after the lower dose of trimethadione was actually increased. Upon termination of chronic diphenylhydantoin administration at either dosage level, a significant enhancement of incompletely generalized seizure activity occurred. Scizure activity in cobalt-epileptic rats after termination of treatment with either dose of trimethadione, on the other hand, remained similar to that of controls. These results suggest that the chronic model of epilepsy resulting from cerebral cobalt application in the rat may provide a suitable indicator of the effectiveness of anticonvulsants in chronic seizure disorders.     

Repeated REM sleep deprivation after chronic haloperidol administration in the rat

Repeated haloperidol administration produces up-regulation of dopamine (DA) receptors. REM sleep deprivation (REMSD) does also, but in addition, has been shown to produce REM sleep rebound. Should DA receptor up-regulation play a role in REM sleep rebound, haloperidol could conceivably have effects similar to those observed following REMSD. This is the central question investigated in this study. Male Wistar rats were prepared for sleep recordings. They were randomly assigned to the following groups: group 1, REMSD by small platforms (40 h REMSD + 8 h recording); group 2, was the large platform control group (40 h in large platforms + 8 h of recording); group 3, received 2-week daily administration of haloperidol (3 mg/kg, IP) plus REMSD (40 h REMSD + 8 h of recording); group 4, 2-week administration of haloperidol (3 mg/kg) without sleep manipulation and at the end 40 h were allowed to elapse, following which 8 h of sleep recordings was carried out. In each group the sleep manipulation and/or sleep recordings were repeated five consecutive times. Repeated REMSD produced increases of REM sleep time after each recovery in group 1. Large platforms did not produce increases of REM sleep during the recovery trials. The 2-week administration of haloperidol plus REMSD prevented REM sleep rebound (group 3). The 2-week administration of haloperidol without sleep manipulation (group 4) produced a REM sleep reduction. Dopamine modulation seems not to be important for REM sleep rebound. Hypersensitivity of DA receptors developed after REMSD may be an epiphenomenon associated with this sleep manipulation, but seems not to participate in REM sleep enhancement after REMSD. Received: 27 December 1995/Final version: 17 December 1996     

Pharmacokinetics and brain distribution of zolpidem in the rat after acute and chronic administration

Abstract— The pharmacokinetics of zolpidem were studied after single dose, administered for either 7 or 28 days to rats. Thirty minutes after the last dose, animals were killed and the brain removed. The highest concentrations in plasma, which were observed at the first sampling time (0·5 h) were 2341±540 (day 0), 1956 ± 325 (day 7) and 2908 ± 1369 ng mL^?1 (day 28). Corresponding AUC values of 1742 ± 488, 1583 ± 422 and 2683 ± 1249 ng mL^?1 h were found. MRT increased significantly from 0·46 ± 0·06 h on day 0 to 0·67 ± 0·02 h on day 28. The cerebral levels showed no significant change during the chronic administration (766 ± 285, 685 ± 171 and 887 ± 264 ng g^?1, respectively). No modification of the principal kinetic parameters was detected up to the 28th day of treatment.     

Effects of acute delta 9-THC administration on EEG and EEG power spectra in the rat

This study was designed to determine the acute effects of delta 9-THC on the cortical EEG with the spectral analysis technique. Adult female Sprague-Dawley rats were implanted with chronic cortical and temporalis muscle electrodes. Intraperitoneally administered delta 9-THC (5 and 10 mg/kg) produced a reduction in peak-to-peak voltage of the desynchronized cortical EEG during wakefulness. Associated spectral power was reduced to about 50% of control during the first hour after injection of delta 9-THC and gradually returned toward the control value over an 8-hr period. Occurrences of delta 9-THC-induced high-voltage EEG bursts, overriding the reduced EEG tracing, were associated with an EEG spectral peak at 6 Hz. The first few slow-wave sleep (SWS) episodes appearing after delta 9-THC administration were associated with more slow-frequency waveforms and more slow-frequency spectral power than with control slow-wave sleep episodes. During control rapid eye movement (REM) sleep episodes, an EEG theta wave pattern, with an associated spectral peak at about 8 Hz, was characteristic. Conversely, the first few REM sleep episodes emerging after delta 9-THC administration contained overriding high-voltage bursts, the related power spectra of which had two peaks at about 7 and 11 Hz.     

Sex differences in muscarinic receptor binding after chronic ethanol administration in the rat

Male and female rats were administered ethanol (5% v/v) in a liquid diet for 18 weeks. Pair-fed control animals were fed the same diet except that dextrose was substituted isocalorically for ethanol. Normal controls received a commercial laboratory chow for the same duration. Results showed that, in females, chronic ingestion of an ethanol liquid diet significantly increased the number of muscarinic receptor binding sites compared to both control groups. In contrast, for males, there was no significant difference in the mean number of binding sites among the treatment groups. Furthermore, the mean maximum number of binding sites for males and females varied across brain areas. Males had a significantly greater number of receptor binding sites than females in the striatum, while females had a greater number in the cortex. It was suggested that the geuder differences observed in the present study could be mediated by hormonal effects on central muscarinic functioning.     

Effects of chronic morphine administration and naloxone on EEG, EEG power spectra, and associated behavior in two inbred rat strains.

Utilizing behavioral and electroencephalographic (EEG) assessments, two inbred rat strains, Lewis (LEW) and Fischer 344 (F344), were exposed to morphine (IV) over a period of 7 days to discern differences in tolerance development. Following morphine injection, the LEW group demonstrated a greater mean total amount, as well as a greater rate of reduction, of stuporous behavior across the 7 days tested. Differences in patterns of latency to onset of slow-wave sleep between the two strains were also exposed. EEG analysis of spectral parameters utilizing an analysis of variance with repeated measures revealed that peak frequency, mean frequency, and edge frequency differed as a function of inbred rat strain. All spectral parameters differed as a function of duration of morphine injection; linear trends were indicated for both strains. Naloxone was administered (IV) following the 7 days of morphine to delineate dependence differences. LEW animals reflected a greater amount of behavioral responses, for example, wet-dog shakes, diarrhea, body stretch, and sluggish behavior. However, F344 rats demonstrated a greater alteration in two spectral parameters assessed: peak frequency and total power. Genetic variability appears to play a major role in both morphine tolerance and dependence as indicated by differences in EEG and behavioral responses.     

Sex differences in locomotor activity after acute and chronic cocaine administration.

Adult, intact and gonadectomized male and female Wistar rats (n = 9) were exposed to an automated open field to assess the behavioral effects of acute cocaine administration (saline, 1.0 and 10.0 mg/kg subcutaneous). The subjects were exposed to the open field for 10 min, removed to be injected and returned to the open field for another 30 min. Three saline and two drug sessions were run in counterbalanced order. Locomotor activity in intact and castrated male rats and ovariectomized female rats decreased following injection, irrespective of the dose of cocaine. The locomotor activity of intact female rats was higher than that of any other group of subjects. It decreased during the session after saline and 1.0 mg/kg cocaine, but increased towards the end of the 30 min session after 10.0 mg/kg. Rearing measures paralleled the observations on locomotor activity. To determine the effects of chronic, home-cage, cocaine administration, five of the subjects in each group were injected with 10.0 mg/kg cocaine for 9 consecutive days. The remaining four subjects received saline injections. On day 10, all subjects were re-exposed to the open-field for 10 min, removed, injected with 10.0 mg/kg cocaine and returned to the open field for another 30 min. Chronic home cage cocaine administration produced an increase in cocaine's effects on locomotor activity and rearing in intact female rats only. However, behavioral sensitization was also observed in intact female rats who had been treated with saline for 9 consecutive days, suggesting that behavioral sensitization to cocaine in intact female rats may develop very rapidly and independent of environmental context.     

Temporally distinct cognitive effects following acute administration of ketamine and phencyclidine in the rat

Non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonists such as phencyclidine (PCP) and ketamine are commonly and interchangeably used to model aspects of schizophrenia in animals. We compared here the effects of acute administration of these compounds over a range of pre-treatment times in tests of instrumental responding (VI 30 s response schedule), simple reaction time (SRT) and cognitive flexibility (reversal learning and attentional set shifting digging task) in rats. At standard pre-treatment times (15–30 min), both ketamine and PCP produced overall response suppression in VI 30 and increased reaction times in SRT suggesting that any concomitant cognitive performance deficits are likely to be confounded by motor and/or motivational changes. However, the use of extended pre-treatment times produced deficits in cognitive flexibility measured up to 4 h after drug administration in the absence of motor/motivational impairment. Generally, PCP increased impulsive responding in the SRT indicating a possible loss of inhibitory response control that may have contributed to deficits observed in reversal learning and attentional set-shifting. In contrast to PCP, ketamine did not have the same effect on impulsive responding, and possibly as a consequence produced more subtle cognitive deficits in attentional set-shifting. In summary, acute treatment with NMDAR antagonists can produce cognitive deficits in rodents that are relevant to schizophrenia, provided that motor and/or motivational effects are allowed to dissipate. The use of longer pre-treatment times than commonly employed might be advantageous. Also, ketamine, which is more frequently used in clinical settings, did not produce as extensive cognitive deficits as PCP.     

癫痫发作及电针时大鼠脑内c-fos蛋白的表达

本实验在海马青霉素致痫模型上观察了致痫及致痫加电针后脑内c-fos蛋白的变化,结果表明致痫时海马CA_1区、齿状回、梨状皮层、背测内嗅皮层、杏仁核见到较多的c-fos表达,电针后c-fos在CA_1区明显减少,在CA_3区及上述余各区则显著增加,提示:致痫能引起与癫痫发作有关的某些核团c-fos表达,电针抗痫作用可能和调节上述部位c-fos表达有关。     

Distribution of neostigmine and its metabolites in rat tissues after acute and chronic administration

The rate and pattern of neostigmine metabolism in different tissues of rat were studied after acute and chronic subcutaneous administration of the ¹⁴C-labelled drug. Radioactivity in plasma, liver, kidney and muscle was determined and the analysis of different metabolites and neostigmine was carried out by paper chromatography. The $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ of parent drug and its metabolites is on the average 10 min in plasma, 33 min in liver, and 1.5 hr in muscle. Neostigmine is metabolised in the liver at a rate of 2.24 × 10^?2μmol/min/g (wet weight) and 3-hydroxyphenyltri-methylammonium (3-HPTMA) is metabolized at a rate of 2.89 × 10^?2μmol/min/g. Metabolic degradation of neostigmine proceeds in muscle at a rate of 2.1 × 10^?2μmol/g. During chronic administration, the concentration of neostigmine and its metabolites rose in liver between day one to eight from 0.63 to 5.89 μmolg of tissue and in muscle from 0.085 to 0.39 μmol/g of tissue. Liver contained the highest concentration of glucuronide of 3-HPTMA (G-3-HPTMA) followed by neostigmine and 3-HPTMA. G-3-HPTMA concentration was 0.321 μmol on day 1 and increased to 2.89 μmol/g liver on day 8. The neostigmine concentration increased from 0.14 to 1.62 μmol/g of liver during the same period. Similar increases in the concentration of neostigmine and its metabolites were also obseved in muscle under the same conditions. 3-Hydroxyphenyldimethyl amine (3-HPDMA) and an unknown metabolite also consistently increased in liver and muscle.     

Inhibition of dapsone-induced methaemoglobinaemia by cimetidine in the rat during chronic dapsone administration.

Dapsone undergoes N-acetylation to monoacetyl dapsone as well as N-hydroxylation to a hydroxylamine which is responsible for the haemotoxicity (i.e. methaemoglobinaemia; Met Hb) of the drug. Since dapsone is always given chronically, we have investigated the ability of cimetidine to inhibit Met Hb formation caused by repeated dapsone administration. The drug was given (i.p.) to four groups (n = 6 per group) of male Wistar rats, 300-360 g. Group I received 10 mg kg-1 at 1, 24, 48 and 72 h. Group II received 10 mg kg-1 at 1, 8, 24, 32, 48, 56, 72 and 80 h. Groups III and IV received the drug as for groups I and II, respectively, as well as cimetidine (50 mg kg-1) 1 h before each dose of dapsone. Twice daily dapsone administration (Group II) resulted in a significantly greater (P less than 0.05) Met Hb AUC (757 +/- 135 vs 584 +/- 115% Met Hb h), dapsone AUC (140 +/- 17.5 vs 113 +/- 13.0 micrograms h mL-1) and monoacetyl dapsone AUC (48.2 +/- 18.3 vs 10.8 +/- 4.6 micrograms h mL-1) compared with a single daily dapsone dose (group I). The administration of cimetidine before the once daily dose of dapsone (group III) resulted in a significant (P less than 0.05) fall in Met Hb (302 +/- 179 vs 584 +/- 115% Met Hb h) and an increase in both the dapsone (151 +/- 22.2 vs 113 +/- 13.0 micrograms h mL-1) and monoacetyl dapsone AUC values (33.6 +/- 5.8 vs 10.8 +/- 4.0 micrograms h mL-1) compared with a single daily dose of dapsone (group I).(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in liver tyrosine aminotransferase after acute and chronic administration of morphine in the rat.

Acute administration of Morphine (20 mg/kg/s.c.) in the rat results in a rise of liver tyrosine aminotransferase (TAT) expressed as mumoles of p-hydroxyphenylpyruvate/100 mg/h. With chronic administration, a tolerance develops to this enzymatic effect. TAT induction is not evident in pregnant rats, given the narcotic, in which enzyme levels are already initially high. After delivery TAT returns to normal levels and it is possible to show both induction and tolerance developing to morphine. Enzyme activity in fetal livers is much lower than that of adult animals: after maternal administration of morphine only a modest TAT increase is seen which is not, however, statistically significant. TAT activity is fully evident in livers of offspring, with much higher mean levels in newborn rats from morphine-treated animals, as a possible consequence of morphine deprivation. In this latter group of newborn rats narcotic administration causes TAT activity to return to levels as high as those of naive animals. On the other hand, morphine administration to the prole of naive rats results in an induction of liver TAT.     

Behavioral stimulation without alteration of β and 5-HT receptors and adenylate cyclase activity in rat brain after chronic sertraline administration

Effects of chronic treatment with selective 5-HT reuptake inhibitors (SSRIs) on the monoaminergic functions have not been much investigated in compared with tricyclic antidepressants. Therefore, we compared the effects of 3-week treatment with sertraline, a potent SSRI, to those of imipramine (10 mg/kg, IP, twice a day), on monoamine receptors and adenylate cyclase (AC) activity in rat brain. Two-week treatment with both sertraline and imipramine reduced immobility in the water wheel test to the comparable extent. Sertraline treatment did not affect K_d and B_max of [³H]CGP12177 and [³H]ketanserin bindings or cAMP accumulation by norepinephrine, isoproterenol, 5’-guanylylimidodiphosphate [Gpp(NH)p] and forskolin in the cortical membrane compared with vehicle-treated rats. On the other hand, imipramine treatment decreased B_max of both bindings and norepinephrine- or isoproterenol-stimulated cAMP accumulation. Treatment with either antidepressant induced no apparent changes in [³H]8-OH-DPAT [2-(N, N-dipropylamino)-8-hydroxy-1,2,3,4-tetrahydronaphthalene] binding in the hippocampal membrane. These results suggested that chronic treatment of sertraline induced little effect on monoamine receptors and AC activity in the brain and that the alteration of these functions may not be primarily involved in antidepressive effects of antidepressants, at least of SSRIs. Received: 19 April 1996 /Final version: 29 October 1996     

Changes in hypothalamic paraventricular nucleus catecholaminergic activity after acute and chronic morphine administration

The participation of hypothalamic noradrenaline in the expression of neuroendocrine signs of morphine withdrawal has been proposed. The present study in rats examined: (1) the relationships between corticosterone secretion and the possible modifications in noradrenaline and dopamine content and turnover in the hypothalamic paraventricular nucleus after acute and chronic morphine administration; (2) the changes in cyclic adenosine monophosphate (cAMP) levels in the paraventricular nucleus after the same treatments. The results showed that acute morphine injection in control rats increased corticosterone release, 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) production, and noradrenaline turnover. Dopamine turnover in the paraventricular nucleus was decreased and the cAMP levels remained unchanged. In chronic morphine-treated rats, there was no elevation in noradrenaline turnover or in corticosterone secretion, indicating that tolerance developed to the acute effects of the opioid. Correspondingly, no alterations in dopamine turnover were observed when chronic morphine-treated rats were compared with control rats acutely injected with morphine. cAMP levels in the paraventricular nucleus were unchanged during the tolerant state. The results raise the possibility that noradrenergic afferents play a significant role in the alterations of paraventricular nucleus function and pituitary-adrenal axis activity in response to acute and chronic morphine and suggest that these modifications are not mediated through adenylate cyclase activation. The present data provide further support for the idea of adaptive changes in noradrenergic neurons projecting to the paraventricular nucleus during chronic morphine exposure.