Inhibitory effect of cyclooxygenase inhibitors on the step-through passive avoidance performance in mice treated with NC-1900, an arginine-vasopressin fragment analog.

To examine the participation of endogenous cyclooxygenase (COX) in the mnemonic effect of NC-1900, an arginine-vasopressin fragment analog, the latencies of mice in the step-through passive avoidance (PA) task were determined following the administration of COX inhibitors and/or NC-1900 (1 ng/kg). When administered immediately after the acquisition trial (Acq) in the PA task, indomethacin (20 mg/kg), a nonspecific COX inhibitor, and NS-398 (10 and 20 mg/kg), a specific COX-2 inhibitor, but not piroxicam (10 and 20 mg/kg), a specific COX-1 inhibitor, decreased the latency on the retention trial (Ret). The mnemonic effect of 1 ng/kg NC-1900 on the Ret in the PA task was also inhibited by the administration of either indomethacin (20 mg/kg) or NS-398 (20 mg/kg) but not by piroxicam. However, when 20 mg/kg indomethacin and NS-398 were administered 3 h after the Acq, the increase in Ret latency induced by NC-1900 was not inhibited. These results suggested that the action of NC-1900 on the early stage of memory formation in the PA task may be modulated by endogenous COX-2 but not by COX-1.

Roles of glutamate receptor subtypes in the development of vestibular compensation after unilateral labyrinthectomy in the guinea pig.

We investigated the roles of ionotropic glutamate receptor subtypes in the development and recovery of spontaneous nystagmus (SN) after unilateral labyrinthectomy (UL) in guinea pigs. When administered at 3 h after UL, N-methyl-D-aspartate (NMDA) and kainate (KA), which are NMDA and non-NMDA receptor agonists, respectively, increased the frequency of SN. The effect of KA was more potent than that of NMDA. In contrast to these agonists, MK-801 and CNQX decreased the frequency of SN. Although the administration of KA at 48 h after UL increased the frequency of SN, it did not exhibit any effects at 72 h after UL. MK-801 caused a recurrence of SN following administration at 48 and 72 h after UL. Neither NMDA nor CNQX exhibited any effects after administration at 48 or 72 h after UL. A newly synthesized compound, NC-1200, which has inhibitory action on the glutamate response, decreased the frequency of SN in a dose-dependent manner following administration at 3 h after UL, but did not exhibit any effects when administered at 48 and 72 h after UL. From these results, it was found that NMDA and non-NMDA receptors play important roles in the development of SN after UL, and that the NMDA receptor contributes to the development of ocular motor compensation.

Permanent bilateral common carotid arterial ligation impairs visual but not auditory conditioned avoidance behavior in rats.

The effect of permanent bilateral common carotid arteries ligation (BCCAL) on visual function was investigated using conditioned avoidance task in Wistar rats. Behavioral experiments began 1 month after ligation. When light was used as a conditioned stimulus, the number of avoidance failures of BCCAL rats was higher than that of sham-operated control animals. However, the performance of the same avoidance task using a buzzer instead of light stimulus was not impaired by BCCAL. BCCAL impaired performance in the Morris water maze learning task and the rhythm of diurnal and nocturnal spontaneous motor activities. These results indicate that BCCAL treatment induces dysfunction of the visual system in rats, and consequently results in apparent deficits in conditioned avoidance behavior. BCCAL-induced deficits in performance in the water maze and rhythm of the motor activities are at least partially attributable to optical dysfunction.

[The ameliorating effects of a novel NC-1900 on impairments of learning/memory caused by glutamic acid].

The effects of a novel vasopressin fragment analog NC-1900 (pGlu-Asn-Ser-Pro-Arg-Gly-NH2 acetate) were studied on learning and/or memory impairment in passive avoidance task and on cell damage of cultured cerebro-cortical neurocytes induced by glutamic acid. A small dose of NC-1900 (1 ng/kg, s.c.) ameliorated impairments of learning and/or memory induced by intracisternal injection of 467.6 micrograms of 10 microliters glutamic acid. NC-1900 also ameliorated the impairments induced by intracisternal NMDA, AMPA-antagonist CNQX and by metabotropic receptor (mGluR1) agonist 3,5-dihydroxyphenylglycine but not by kainate agonist domoic acid nor MK-801 in mice. NC-1900 (100 pM, 1nM) ameliorated the cell damage of cultured rat cerebro-cortical neurocytes induced by 100 and 1000 microM of glutamic acid. These results suggest that NC-1900 may serve as a remedies in various patients with certain brain disorders induced by excess glutamic acid.

NC-1900, a [pGlu4,Cyt6]AVP(4-9) analogue, facilitates the learning performance of rats on delayed nonmatching to sample task in Y-water maze.

The effect of a novel peptide, NC-1900 (pGlu-Asn-Ser-Pro-Arg-Gly-NH2) on learning behavior in normal animals was studied in delayed nonmatching to sample tasks in rats using a Y-water maze. In the acquisition tests, a nonmatching to sample task, a delayed nonmatching to sample task with a delay time of 10 min (10-min DNMTS task), and a 20-min DNMTS task were performed for 15 sessions. NC-1900 was administered subcutaneously 1 h prior to the start of the acquisition test once a day. In the retention tests, the 10-min DNMTS task (on days 3, 10 and 17) and 20-min DNMTS task (on days 4, 11, 19 and 26) were conducted over time in the absence of administration of NC-1900 following completion of the acquisition test of the 10-min DNMTS task. In the acquisition of the 10- and 20-min DNMTS tasks, the NC-1900 100 pg/kg group exhibited significantly higher correct choice percentages or percentages of rats that achieved the criteria (mean correct choice percentage for 3 days of 90% or higher) in comparison with the control group. In the retention tests, in contrast to the correct choice percentages on each test day for the 20-min DNMTS task of the control group being approximately 50%, rats administered NC-1900 demonstrated high correct choice percentages at all dose levels, although there were some variations on each test day. These results demonstrate that NC-1900 clearly facilitated acquisition and retention of DNMTS tasks in rats using a Y-water maze.

No. 302, a newly synthesized [pGlu4,Cyt6]AVP(4-9) analogue, prevents the disruption of avoidance behavior.

We investigated the effects of [pGlu4,Cyt6]AVP(4-9) fragments and its analogues on cycloheximide (CHX)-induced learning impairment in rats using the step-through-type passive avoidance test in rats. CHX (2.8 mg/kg, s.c.) significantly shortened the step-through latency in the retention trial. pGlu-Asn-Cys(Cys)-Pro-Arg-Gly-NH2 ([pGlu4, Cyt6]AVP(4-9); 10 ng/kg, s.c.), a major metabolite of arginine vasopressin, improved the CHX-induced learning impairment. Asn-Cys-Pro-Arg-OH ([Cys6]AVP(5-8); 1 ng/kg) corrected avoidance learning in the CHX-treated group, whereas neither Cys(Cys)-Pro-Arg-OH nor pGlu-Asn-Cys(Cys)-Pro-OH had any effect (1, 10 and 100 ng/kg, s.c.). pGlu-Asn-Ser-Pro-Arg-Gly-NH2 (No. 302), a newly synthesized [pGlu4,Cyt6]AVP(4-9) analogue, significantly prolonged the latency shortened by CHX at doses of 0.1, 1 and 10 ng/kg (s.c.). Asn-Ser-Pro-Arg-OH also improved the learning disruption induced by CHX, although the effective dose was 100 times higher than that of No. 302. The half-life of No. 302 in rat blood was about 5.5, 22 and 25 times longer than that of [pGlu4,Cyt6]AVP(4-9), [Cys6]AVP(5-8) and Asn-Ser-Pro-Arg-OH, respectively. These results suggest that [Cys6]AVP(5-8) is the minimal effective amino acid sequence in [pGlu4,Cyt6]AVP(4-9), and show that No. 302 is a potent, pharmacologically active peptide with high stability in the blood.

Characteristics of the ambulation-increasing effect of GBR-12909, a selective dopamine uptake inhibitor, in mice.

Behavioral effects of a dopamine uptake inhibitor, GBR-12909 (GBR), were evaluated by ambulatory activity in mice. The single administration of over 10 mg/kg of GBR, i.p. and p.o., significantly increased the ambulatory activity. The repeated administration of GBR, at only 10 mg/kg, produced a reverse tolerance to its ambulation-increasing effect. However, a cross-reverse tolerance was induced between GBR (10 and 20 mg/kg) and methamphetamine (2 mg/kg) in both directions. Furthermore, 5 mg/kg of GBR significantly enhanced the effects of methamphetamine, cocaine, imipramine, morphine, scopolamine and caffeine. R-THBP, a coenzyme of tyrosine hydroxylase, also enhanced the effect of GBR. In contrast, the ambulation-increasing effect of 10 mg/kg of GBR was markedly reduced by haloperidol, chlorpromazine, tetrabenazine, oxypertine, reserpine and alpha-methyl-p-tyrosine. On the other hand, the effect of GBR was only slightly and/or scarcely modified by apomorphine, caerulein, physostigmine, pilocarpine, N6-(L-2-phenylisopropyl)-adenosine and naloxone. The neurochemical experiment in rats, not in mice, revealed that GBR possessed more dominant action on dopaminergic systems than noradrenergic or serotonergic systems. However, the behavioral characteristics of GBR are similar to those of methamphetamine and cocaine, which possess less selective action than GBR on dopaminergic and noradrenergic systems.

Breeder differences within Wistar strain rats in step-through type passive avoidance response.

Characteristics of acquisition and retention of the one-training and repeated-training passive avoidance responses of the step-through type were investigated in 3 lines of so-called Wistar strain rats: HLA:Wistar, JLA:Wistar and Std:Wistar and in F344/Du Crj rats. In the adaptation and the first acquisition trials in the repeated-training task, Std:Wistar rats took comparatively longer latency times to enter the dark chamber from an illuminated runway than the other lines and strain of rats. In contrast, JLA:Wistar rats took a number of trials to stay for 300 sec or longer in the runway. HLA:Wistar, Std:Wistar and F344/Du Crj rats showed similar response latencies in the first retention trial. JLA:Wistar rats showed the shortest latencies among 3 lines of Wistar and F334/Du Crj rats, exhibiting much poorer acquisition and retention abilities than the other rats. The response latencies in the retention trials were longer in the order of HLA:Wistar greater than or equal to F344/Du Crj greater than Std:Wistar greater than JAL:Wistat rats. These results suggest that there are marked breeder differences in their passive avoidance response even in the rats that have the same strain name.

A brief brain ischemia produces morphological damage of hippocampal CA1 pyramidal cells without affecting the sensitivities of psychoactive drugs in two types of discrete avoidance tasks in Mongolian gerbils.

Effects of subcutaneous administration of psychoactive drugs: methamphetamine (0.13-1 mg/kg), chlorpromazine (0.5-2 mg/kg), physostigmine (0.05-0.2 mg/kg), scopolamine (0.031-0.5 mg/kg), pentobarbital (5-20 mg/kg), diazepam (0.5-2 mg/kg) and morphine (1.3-5 mg/kg) on discrete lever-press and shuttle avoidance responses were investigated in Mongolian gerbils that had received a brief (5 min) bilateral brain ischemic operation. Although some of the ischemic animals tended to show a retardation of acquisition of the avoidance responses, the established baselines were almost identical between the sham-operated and ischemic groups. In the lever-press task, morphine increased the response rate, whereas chlorpromazine, physostigmine, pentobarbital and diazepam decreased both the response and avoidance rates in a dose-dependent manner. In the shuttle avoidance task, both the response and avoidance rates were dose-dependently increased by methamphetamine, scopolamine and morphine, but chlorpromazine, physostigmine, pentobarbital and diazepam dose-dependently decreased them. These drug effects were almost the same between the sham-operated and ischemic groups. However, the ischemic-operation produced a significant loss of pyramidal cells in the CA1 sector of the hippocampus, the remaining level being less than 10% that of the sham-operated control animals.

Breeder differences within Wistar strain rats in acquisition of discrete shuttle avoidance response and in sensitivity to chlorpromazine.

Characteristics of acquisition processes of discrete shuttle avoidance response were investigated in 3 lines of Wistar strain rats: HLA:Wistar, JLA:Wistar, Std:Wistar and in F344/Du Crj rats. Std:Wistar and F344/Du Crj rats rapidly acquired the avoidance response, showing an avoidance rate of higher than 90% until the middle stage of the 1st training session in which 120 trials were carried out, and they also maintained a high level of avoidance response in the latter sessions. HLA:Wistar and JLA:Wistar rats, however, exhibited a poorer acquisition of the avoidance response than Std:Wistar and F344/Du Crj rats. These two lines of Wistar rats finally achieved average avoidance rates of around 80% after 5 sessions of training and showed a long-lasting warm-up period in each session. Std:Wistar and F344/Du Crj rats had more resistance than the other two lines to extinction of the acquired avoidance response. Chlorpromazine (2-8 mg/kg, i.p.) suppressed the avoidance response in a dose-dependent manner. The sensitivities to chlorpromazine were higher in the order of JLA:Wistar greater than HLA:Wistar greater than Std:Wistar not equal to F344/Du Crj rats. These results suggest that there are major breeder differences even in the same strain of rats in their behavioral and physiological characteristics. The present results also suggest that Std:Wistar rats show extremely close characteristics with those of F344/Du Crj rats.

Modification of drug-induced tremor by systemic administration of kainic acid and quisqualic acid in mice.

The effects of excitatory amino acids, kainic acid and quisqualic acid, on the tremorine- and harmaline-induced tremor were quantitatively examined in mice using the power spectral analyzing method. The severity of the tremor was determined quantitatively in terms of the cumulative sum of the mean square value of the data. Kainic acid enhanced the tremor induced by tremorine but depressed the tremor induced by harmaline. Quisqualic acid depressed the tremor induced by both tremorine and harmaline in a dose-dependent manner. Kainic acid shifted the frequency of each component of the tremor induced by tremorine to the high frequency side, but quisqualic acid did not affect the frequency of tremor of the tremor induced by tremorine. The frequency of tremor of the tremor induced by harmaline was shifted by both excitatory amino acids to the low frequency side, and another component of tremor in the power spectral densities developed, of which the mean square values were very small. The present results suggest that, at least in part, the glutamatergic system can take a role on the modification of drug-induced tremor.

Depression of drug-induced tremor by a new isoxazol derivative in mice.

The effects of a newly synthesized compound, MLV-208, on drug-induced tremor were investigated in mice. The study involved a power spectral analysis of the random current induced by movement of a magnet attached to the mouse on a wire coil. To induce tremor, tremorine and harmaline were subcutaneously injected. The power spectral density function defined the frequency composition of the tremor, and its severity was determined quantitatively in terms of the mean square value of the data in any frequency range of concern. MLV-208 depressed the power spectral density of both the tremorine- and harmaline-induced tremors, but reduced more effectively the former than the latter. The peak frequency of the tremorine-induced tremor did not change in the presence of MLV-208, while MLV-208 sometimes developed a new peak of the power spectral densities of the harmaline-induced tremor in the low frequency side, in addition to the original tremor component.

Further studies on quantification of drug-induced tremor in mice: effects of antitremorgenic agents on tremor frequency.

The effects of diazepam, dantrolene and atropine on drug-induced tremors were investigated in mice from the point of view of the tremor frequency. The study involved a power spectral analysis of the random current induced by movement of a magnet (attached to the mouse) on a wire coil. To induce tremor, tremorine and harmaline were subcutaneously injected. The power spectral density function defined the frequency composition of the tremor and its severity was determined quantitatively in terms of the mean square value of the data in any frequency range of concern. Diazepam markedly depressed the power spectral density of the tremorine- and harmaline-induced tremor and reduced the tremor frequency. With higher doses of diazepam, the peak frequency of the tremorine-induced tremor shifted to the lower frequency side as if the tremor components were taken into the component of the spontaneous motor activity. Dantrolene and atropine suppressed the power spectral density without affecting tremor frequency. The relationship between the change of tremor frequency and the site of action of antitremorgenic agents are discussed.

[A quantitative analyzing method for drug-induced tremor].

A method for analyzing drug-induced tremor in mice was developed using a power spectral analysis of the random current induced by the movement of a magnet attached to a mouse on a wire coil. The power spectral density function defined the frequency composition of the drug-induced tremor, and the mean square value of the data in any frequency range of concern was determined.