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We investigated the disruption of spatial cognition due to transient forebrain ischemia using an 8-arm radial arm maze task in rats. Five or 10 min of ischemia did not affect the task acquisition. When rats established spatial cognition by daily training of the task, 10 min of ischemia significantly decreased the number of correct choices and increased the errors in the task when performed 24 h after reperfusion. These changes, however, returned to the normal level after about 4 days of daily training. Glutamic acid (Glu) and acetylcholine (ACh) release from the dorsal hippocampus (DH) was observed to transiently increase during ischemia. However, neither the content of noradrenaline (NA) nor the release of NA in the DH changed during ischemia. The NA and ACh release from the DH, however, gradually decreased during reperfusion, and the decrease became significant at 24 h after reperfusion. The NA content of the frontal cortex (FC) and the DH increased 7 days after reperfusion. These results suggest that the disruption of spatial cognition induced by 10 min of ischemia may be attributed to a greater degree to the dysfunction of the hippocampal ACh and NA, and cortical NA systems, rather than to the development of neuronal cell death in these areas.

Behavioral changes in the chronic phase of permanent occlusion of the right middle cerebral artery (MCA) in rats were investigated. One month after MCA occlusion, 23 rats were unable and 7 rats were able to solve a radial 8-arm maze task during a 1-month period. Three months after occlusion, 19 MCA-occluded rats failed to solve the task successfully again during at least a 1-month period (the cognitively impaired rats), and 11 MCA-occluded rats were able to solve it (the cognitively unimpaired rats). When a delay of 60 min was imposed for this task, five cognitively unimpaired rats failed to solve it. The locomotor activity of the cognitively impaired rats increased significantly 2 months after occlusion, and this increase showed good correlation with spatial cognitive deficit. However, the mean time a rat spent at each arm remained unchanged among the cognitively impaired, unimpaired, and sham-operated rats. There was no significant difference in the ratio between the cognitively impaired and unimpaired rats for disturbed motor coordination. These results suggest that MCA occlusion is capable of producing long-term spatial cognitive disturbance in rats. In addition, this spatial cognitive deficit does not seem to be primarily due to hypermotility or a disturbance in motor coordination.

The effects of nomifensine (NOM) and methamphetamine (MA) on ambulation and rearing of rats in the open-field test were investigated. NOM and MA were injected i.p. into intact rats and nucleus accumbens (ACC)- and caudate-putamen (CP)-lesioned rats and infused into the ACC and CP. NOM (1-10 mg/kg, i.p.) and MA (1-5 mg/kg, i.p.) produced hyperactivity. However, NOM at 20 mg/kg, i.p. decreased the activity and induced repetitive head bobbing and squatting. Lesions of the ACC and CP increased open-field activity. However, lesion of the CP increased rearing more than lesion of the ACC. The increase in ambulation induced by NOM was inhibited by lesion of the ACC, whereas that induced by MA was inhibited by lesion of the CP. Although NOM (1-10 micrograms/2 microliters) and MA (0.5-10 micrograms/2 microliters) injections into the ACC and CP induced hyperactivity, the effect of NOM was greater after injection into the ACC, whereas the effect of MA was greater following injection into the CP. These results suggest that the ACC has a greater role in ambulation, while CP has a greater one in rearing. The present results, while they verified the significance of the ACC and CP in NOM- and MA-hyperactivity, also revealed a differential role of the ACC in NOM-hyperactivity and the CP in MA-hyperactivity.

2-a13 Presynaptic but not postsynaptic silent synapses re expressed with advanced aging of astrocyte in vitro iroyuki Kawano1 , Shutaro Katsurabayashi1, Kaori Kubota1, otaro Takasaki1,2, Kenichi Mishima1,2, Katsunori Iwasaki1,2, ichihiro Fujiwara1 Dept. of Neuropharmacol., Faculty of Pharmaceutical Science, Fukuoka niv., Fukuoka, Japan 2 A.I.G. Institute for Aging & Brain Science, Fukuoka niv., Fukuoka, Japan

The plasma levels of free and sulfoconjugated forms of 3-methoxy-4-hydroxyphenylglycol (MHPG) were examined before and after treatment in 16 patients with unipolar major depressive disorders without melancholia. The patients were treated with intravenous administration of clomipramine for 4 weeks. Seven depressive disorder patients who showed marked improvement (the improvement group) revealed significant reduction in their plasma sulfoconjugated MHPG levels. In 6 depressive disorder patients who showed no improvement (the no-improvement group), the plasma sulfoconjugated MHPG levels showed no significant change after treatment. The remaining 3 patients, who showed ambiguous change after treatment, were excluded from the analysis. Levels of plasma-free MHPG showed significant change after treatment in neither the improvement group nor in the no-improvement group. It is suggested that levels of plasma sulfoconjugated MHPG may serve as an indicator of brain noradrenergic activity.

The aim of this study was to determine whether or not angiotensin-converting enzyme inhibitor, enalapril, could ameliorate the chronic tubulo-interstitial nephropathy (TIN) in uninephrectomized (UNx) rats. Chronic TIN(M) was induced by 2-bromoethylamine hydrobromide. Rats were assigned to five groups; control, UNx-control (UNxC), UNx treated with enalapril (UNxE), UNxMC and UNxME. Enalapril was given for 12 months as drinking water (50 mg/l). At 6 months, albuminuria in UNxE decreased significantly compared with UNxC, but without change in UNxM rats. By 12 months, although all rats in control, UNxC and UNxE remained alive, 1 and 4 rats died in UNxME and UNxMC, respectively. Albuminuria in UNxC was reduced significantly by enalapril but not in UNxM rats. Both urine volume and urine osmolality became equal to control by enalapril in UNx rats, but not in UNxM rats. Serum cholesterol levels were normalized by enalapril in UNx rats, but not in UNxM rats. Levels of serum creatinine and blood urea nitrogen were invariably higher in UNxM than in UNx rats, irrespective of enalapril. Glomerular sclerosis was statistically decreased by enalapril in both UNx and UNxM rats. Enalapril reduced the overall tubulo-interstitial lesions in UNx rats, but not in UNxM group. However, in UNxM rats tubular changes in medullary portion were significantly ameliorated by enalapril. These data suggest that enalapril has a beneficial effect on chronic TIN in this model.

The effects of delta 9-tetrahydrocannabinol (delta 9-THC) on the rise in intracellular Ca2+ concentrations ([Ca2+]i) after stimulation with 15 mM or 29 mM K+ in rat whole brain synaptosomes were examined. A fluorescent chelating agent, Rhod-2, was employed to monitor any alterations of K(+)-evoked [Ca2+]i. Pretreatment with 10(-10) M delta 9-THC for 3 min enhanced K(+)-evoked [Ca2+]i significantly, while 10(-9), 10(-8) or 5 x 10(-8) M delta 9-THC significantly inhibited the K(+)-evoked [Ca2+]i. These results suggest that delta 9-THC had a biphasic effect on the K(+)-evoked Ca2+ response in rat brain synaptosomes.

Background: The proteolytic activity of human ADAMTS13 regulates the size of von Willebrand factor (VWF) multimers, controlling excessive platelet aggregation and preventing microvascular thrombus formation. Deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura (TTP) and patients with TTP often have neurological deficits such as stupor or coma. Therefore, ADAMTS13 appears necessary for vascular homeostasis in the brain and may also influence the response to brain injury during ischemic stroke. Method and Result: We investigated the role of ADAMTS13 in a mouse middle cerebral arterial occlusion (MCAO) model of ischemia-reperfusion injury in the brain. We compared 24 wild type mice (WT) and 24 ADAMTS13 gene deleted mice (KO), which are healthy and fertile. All mice were males 6–8 weeks of age. Investigators were blinded to the genotype until all analyses were finished. We applied MCAO for 30 minutes followed by 23.5 hours of reperfusion. The cerebral blood flow (CBF) around the cortex of the ischemic region was measured by laser Doppler flowmetry for 60 minutes after MCAO. In both WT and KO mice, the CBF decreased to less than 20% of baseline during MCAO and returned to normal immediately after reperfusion. However, during the subsequent 30 min the CBF decreased to 34.6±5.8% of baseline for KO mice compared to 83.2±6.8% of baseline for WT mice (P < 0.01) and remained significantly decreased at 24 hours, suggesting that ADAMTS13 deficiency promotes thrombosis after reperfusion injury. The infarction volumes of the brain were determined from the area not stained by 2,3,5,-triphenyltetrazolium chloride (TTC) 24 hours after MCAO. KO mice had significantly increased volume of brain infarction compared with WT (31.0±6.5mm3 vs 11.4±1.9 mm3, P < 0.01). The degree of post-ischemic inflammation was estimated by Western blotting of plasma HMGB1 (high-mobility group box1) 24 hours after MCAO. Plasma HMGB1 was increased to 34.4 ± 5.3 ng/ml in KO mice, compared to 19.6 ± 3.5 ng/ml in WT mice (P < 0.05). The KO and WT mice did not differ during the MCAO procedure in body temperature, survival (80% vs 85%) at 24 hours, prothrombin time, arterial pH, pO2 or pCO2. Conclusion: ADAMTS13 deficiency aggravates the extent of persistent brain ischemia, infarct volume and inflammatory response after brief MCAO. Therefore, ADAMTS13 plays a neuroprotective role against ischemia-reperfusion injury.

The characteristics of the release of endogenous dopamine and noradrenaline from rat brain synaptosomes were studied using HPLC with an electrochemical detector. The spontaneous release of dopamine and noradrenaline was inhibited by approximately 50-60% in a Ca2(+)-free medium or a 100 microM La3(+)-containing medium. Also, the high-K+ (30 mM)-evoked release of dopamine and noradrenaline was inhibited by approximately 50-60% in a Ca2(+)-free medium or a 100 microM La3(+)-containing medium. From these results, the ratio of the Ca2(+)-dependent component to the total release of noradrenaline seemed to be similar to that of dopamine. On the other hand, 20 microM La3+ or 1 microM diltiazem inhibited both the spontaneous and 30 mM K(+)-evoked release of dopamine by approximately 50-60% but inhibited neither the spontaneous nor the 30 mM K(+)-evoked release of noradrenaline. The K(+)-evoked rise in intrasynaptosomal Ca2+ concentration was mostly blocked in Ca2(+)-free medium or 100 microM La3(+)-containing medium but was only partially blocked by 20 microM La3+ or 1 microM diltiazem. These data indicate alternative possibilities in that the Ca2(+)-dependent release of noradrenaline might be less sensitive to a change of intracellular Ca2+ concentration than that of dopamine and that the calcium channels directly involved in the noradrenaline release may be more resistant to diltiazem and La3+ than those involved in the dopamine release.

For the purpose of elucidating the pathophysiology of memory disturbance in hydrocephalus, the authors studied behavioral change in experimentally induced hydrocephalic rats by using a radial eight-arm maze which is known to be a useful experimental tool for assessing spatial memory in animals.

The characteristics of hydrolysis of sulfoconjugated noradrenaline (NA) and dopamine (DA) in plasma using sulfatase were investigated. Ascorbic acid has been used as an antioxidant during the hydrolysis of conjugated NA or DA. Hydrolysis of NA sulfates was considerably inhibited by adding ascorbic acid (0.5–10 m m ), and slightly inhibited by adding dithiothreitol (1–10 m m ). In contrast, the hydrolysis of DA sulfates was not affected after either ascorbic acid or DTT treatment. On the basis of these findings, the levels of NA sulfates previously reported are found to be markedly lower than the actual levels of NA sulfates in human plasma.

Behavioral effects of amantadine, especially on abnormal behavior in mice and rats, were reevaluated, in comparison with those of tricyclic antidepressants, methamphetamine and L-DOPA. 1) Amantadine at 10 approximately 50 mg/kg, i.p., tended to decrease ambulation and rearing in rats and mice. The drug at 50 mg/kg, i.p., caused piloerection and hyperirritability and at doses over 80 mg/kg, i.p., it impaired coordinated motor activity in rats. 2) Amantadine inhibited methamphetamine-induced hyperactivity, but apomorphine-induced stereotyped behavior was unaffected in rats. 3) Amantadine was equipotent to imipramine in suppressing haloperidol-induced catalepsy in rats, but L-DOPA was without effect. On the other hand, amantadine was 40 and 400 times as potent as imipramine and L-DOPA, respectively, in suppressing delta 9-tetrahydrocannabinol (THC)-induced catalepsy in rats. 4) Amantadine was as potent as imipramine in suppressing the muricide of olfactory bulbectomized rats, but was 3.5, 8.8 and 225.5 times as potent as methamphetamine, imipramine and L-DOPA, respectively, in inhibiting THC-induced reversible muricide in rats. 5) Amantadine at 50 mg/kg did not elicit circling behavior in the rat with unilateral nigral lesion induced by 6-hydroxydopamine. 6) Amantadine at high doses caused irritable aggression characterized by squealing in rats pretreated with intraventricular 6-hydroxydopamine. The most important characteristic of amantadine is its prominent effect suppressing the THC-induced catalepsy and muricide. This may be a reflection of the feature of amantadine activating the dopaminergic as well as the serotonergic systems.

Changes in brain catecholamine content after lesioning the nucleus accumbens (ACC) and the effects of antidepressants were investigated using HPLC-ECD. ACC lesion reduced dopamine (DA) in the rostral caudate-putamen (r-CP), lateral hypothalamus (LH) and central amygdala (ACE). Imipramine (IMP) and nomifensine (NOM) increased DA in r-CP, caudal (c)-CP and basolateral amygdala. Mianserin (MIAN) and zimelidine (ZIM) increased DA only in c-CP. ACC lesion did not change DOPAC. Only IMP (in c-CP) and NOM (in r-CP and c-CP) increased DOPAC. Noradrenaline (NA) was decreased in c-CP and ACE after ACC lesion. IMP and ZIM displayed no effect on NA, while NOM increased NA in LH and frontal cortex (FC) and MIAN only in FC. These results suggest an important role for DA but not NA in the exhibition of muricide after ACC lesion, and in the antimuricide effect of antidepressants.

The present study was designed to examine the influence of Δ 9 -tetrahydrocannabinol (THC) on the central dopaminergic system using circling behavior. THC 5 mg/kg i.p. produced ipsilateral circling in rats with unilateral nigral lesion by 6-hydroxydopamine. THC-induced ispilateral circling was completely antagonized by 0.2 mg/kg of haloperidol. These findings suggest that THC may cause a presynaptic stimulation of nigrostriatal dopaminergic neurons.

Harmine, a hallucinogen with potent monoamine oxidase inhibitory properties, induced abnormal behavior, including tremor, scratching, head twitch and cage biting, in the mouse. A dose-dependent tremor was produced by all routes of administration of harmine. Although oxotremorine tremor was markedly suppressed by atropine, harmine tremor was unaffected by cholinergic drugs, remarkably inhibited by dopaminergic drugs, antidepressants and diazepam, mildly diminished by p-chlorophenylalanine, markedly augmented by 5-hydroxytryptophan and mildly increased by alpha-methyl-p-tyrosine. These findings suggest that a catecholaminergic (particularly dopaminergic) and serotonergic system imbalance plays an important role in the manifestation of harmine tremor. In view of these characteristics, harmine tremor may be useful as an effective experimental model for the evaluation of antiparkinsonism drugs, along with oxotremorine tremor because of the different mechanism of occurrence. In addition, harmine tremor appears to be useful in characterizing the properties of antidepressant drugs.

Rats receiving intraventricular injection of 6-hydroxydopamine (6-OHDA) were housed in isolation for one month and placed in the same cage as an untreated rat while being subjected to continuous tail pinching. 6-OHDA-treated rats violently attacked the untreated rat and stabilized fighting between the two animals persisted for over 1 hr. The 6-OHDA-treated rats consistently played the dominant role in the dominant-subordinate relationship established between the rats. By allowing this fighting to continue for 1 hr, gastric erosion associated with severe hemorrhage occurred with a high incidence in the untreated rats. These erosions were comparable in rats examined immediately after fighting and in those examined after 1 hr and 3 hr. Poststress rest was not required for erosion to occur. The presence of bite wounds incurred during fighting was unrelated to the incidence of gastric erosion. In addition, it was unnecessary to fast the untreated rats beforehand. Based on these findings, the present model apparently does not rely on physical stimulation. These factors and the ease of its execution make the present new experimental model of stress ulcers very useful.

Clonidine (2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride, St155, Catapres), after administration of a single large dose, was found to induce automutilation in mice housed individually in the absence of objects to bite. This abnormal behavior was not significantly altered with chronic administration of the drug, and showed no sex difference. The mechanism underlying this automutilation seems to be different from that of the aggressive behavior induced by the same drug in mice caged in group.s

Triazolam was 4 to 5 times as potent as diazepam in reducing hyperemotionality of either septal-lesioned or olfactory bulbectomized rats (O.B. rats), and in suppressing muricide in O.B. rats. This agent was equipotent with diazepam in inhibiting fighting behavior of long-term isolated mice, but was longer in duration of action. Triazolam was approximately 4 times more potent than diazepam in preventing pentetrazol convulsion, but was 10 times less potent in inhibiting maximal electroshock convulsion in mice. The muscle relaxant effect of triazolam as assessed by the inclined screen test was 34 times, and the effect on rotarod performance was 17 times more potent than that of diazepam in mice. Triazolam (0.2 approximately 0.5 mg/kg i.v.) changed the EEG to a drowsy pattern in unanesthetized rabbits with a chronic electrode implant, and suppressed the EEG arousal response to auditory stimulation and electrical stimulation given to either the mesencephalic reticular formation or posterior hypothalamus. The limbic afterdischarges induced by either hippocampal or amygdaloid stimulation were also markedly inhibited by triazolam. These EEG effects of triazolam were qualitatively similar to, but were 4 to 5 times more potent than those of diazepam. These results indicate that triazolam is a potent tranquilizer with a longer duration of action, and the muscle relaxant effect is considerable as compared with diazepam.