Hironaka Aihara

Serotonin-2 receptor-mediated regulation of release of acetylcholine by minaprine in cholinergic nerve terminal of hippocampus of rat

5-Hydroxytryptamine (5-HT) inhibited the K+-induced release of [3H]acetylcholine [( 3H]ACh) from slices of the hippocampus of the rat, dose-dependently. Minaprine (3-(2-morpholinoethylamino)-4-methyl-6-phenylpyridazine, Fig. 1) had no effect on the release of [3H]ACh. However, it inhibited the (formula; see text) Fig. 1. Chemical structure of minaprine dihydrochloride. attenuation of the release of [3H]ACh by 5-HT dose-dependently. The 5-HT2 receptor antagonists, mianserine, methysergide and spiperone, prevented the inhibitory effect of the 5-HT, as well as did minaprine. The attenuating effect of 5-HT was not mimicked by the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and was not prevented by a 5-HT1A and 5-HT1B mixed receptor antagonist, propranolol, or by the 5-HT3 receptor antagonists, cocaine and metoclopramide. Minaprine inhibited the bindings of [3H]5-HT, [3H]8-OH-DPAT and [3H]ketanserin in the hippocampus. The inhibitory effect of minaprine on the binding of [3H]ketanserin was more marked than on the binding of [3H]5-HT and [3H]8-OH-DPAT, and was non-competitive. The Ki value of minaprine for the binding of [3H]ketanserin was 2.9 microM. The inhibitory effect of 5-HT on the release of [3H]ACh was observed in the presence of tetrodotoxin. By electrolytic lesioning of the medial septum, the K+-induced release of [3H]ACh from the slices of hippocampus was significantly reduced and the release was no longer inhibited by 5-HT. The lesioning significantly decreased the binding of [3H]ketanserin in the hippocampus, with hardly any reduction in the binding of [3H]5-HT and [3H]8-OH-DPAT.(ABSTRACT TRUNCATED AT 250 WORDS)

5-HT2 antagonists and minaprine block the 5-HT-induced inhibition of dopamine release from rat brain striatal slices

5-Hydroxytryptamine (5-HT) inhibited the K+-induced [3H]dopamine [( 3H]DA) release from slices of rat striatum. Minaprine (3-(2-morpholinoethylamino)-4-methyl-6-phenylpyridazine) attenuated the inhibitory effect of 5-HT in a dose-dependent manner. 5-HT2 receptor antagonists, ketanserin and mianserin, prevented the effect of 5-HT as well as minaprine did. The inhibitory effect of 5-HT was not mimicked by a 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and was not prevented by a 5-HT1A and 5-HT1B mixed receptor antagonist, propranolol. Minaprine was a potent inhibitor of the binding of [3H]ketanserin to binding sites in the striatum over the concentration range 10(-6)-10(-4) M. Lesion of the medial forebrain bundle with 6-hydroxydopamine (6-OHDA) significantly reduced the K+-induced [3H]DA release from the striatum and release was no longer inhibited by 5-HT. Lesioning, however, did not change significantly the [3H]ketanserin binding in the striatum. These results suggest that minaprine suppresses the inhibitory effect of 5-HT on DA release in the striatum via the inhibition of 5-HT binding at the 5-HT2 receptor on the nerve terminal of the DA-ergic neuron and, further, that the proportion of the 5-HT2 receptor site which is located on the nerve terminal of the DA-ergic neuron is small in the striatum.

Behavioral, electroencephalographic and histopathological studies on mongolian gerbils with occluded common carotid arteries

The effect of brain ischemia on passive avoidance test was investigated in mongolian gerbils with ischemia induced by a 5 min bilateral occlusion of the carotid arteries. Severe impairment of memory was apparent when the training session of the passive avoidance test was carried out 2 or 14 days after the bilateral ischemia. Two days after the occlusion, the amplitude of hippocampal theta waves were slightly decreased and Nissls degradation was apparent in the CA1 neurons in the hippocampus. The changes in hippocampal neurons become progressively more severe. The amplitude of the hippocampal theta waves diminished considerably and the CA1 neurons in the hippocampus disappeared 14 days after the occlusion. We suggest that the hippocampal damage, especially abnormalities in the CA1 neurons, evidenced by histopathological and electroencephalographic results, may be related to deficits in memory following bilateral common carotid arteries occlusion.

Antiulcer and gastroprotective effects of solon, a synthetic flavonoid derivative of sophoradin. Role of endogenous prostaglandins

Abstract Solon is a synthetic isoprenyl flavonoid derived from sophoradin which is isolated from the root of an ancient Chinese plant. Solon was administered orally or intraperitoneally to rats. It inhibited dose dependently gastric ulcers produced by acidified aspirin, water immersion and restraint stress. Solon was also gastroprotective for the stomach as it reduced dose dependently the gastric necrotic lesions induced by absolute ethanol given orally. The degree of gastroprotection decreased with time, the optimal effects occurring 60–90 min after oral administration. Pretreatment with indomethacin partly prevented the gastroprotective effects of Solon. When given alone to fasted rats, Solon increased dose dependently the mucosal content of prostaglandins (PG), suggesting that the protective effects of this drug may be mediated at least in part by endogenous PG.

Copper complexes of non-steroidal antiinflammatory agents: Analgesic activity and possible opioid receptor activation

Cu(II)2(acetylsalicylate)4, Cu(II)(anthranilate)2, Cu(II)2[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetate]4, Cu(II)(3,5-diisopropylsalicylate)2, Cu(II)(salicylate)2, Cu(II)2{2-[3-(trifluoromethyl)-phenyl]aminonicotinate}4, Cu(II)(l-alaninate)2, Cu(II)(l-cystinate)2, and Cu(II)(glycinate)2 were generally found to be more effective analgesics than their parent ligands, Cu(II)(chloride)2, and Cu(II)2(acetate)4 in the Writhing Mouse and Adjuvant Arthritic Rat pain models following subcutaneous and oral administration. Comparison of the time course of analgesia for salicylic acid and Cu(II)(salicylate)2 in the adjuvant arthritis pain model revealed that this complex had more sustained activity in addition to being more potent than salicylic acid. Cu(II)2(indomethacin)4 was also found to be as effective as morphine in both pain models. These data and pertinent literature are discussed in support of the hypothesis that copper complexes activate copper-dependent opioid receptors.

Inhibition of gastric H+, K+-ATPase by chalcone derivatives, xanthoangelol and 4-hydroxyderricin, from Angelica keiskei Koidzumi

Abstract— Two chalcone derivatives, xanthoangelol (I) and 4‐hydroxyderricin (II) isolated from Angelica keiskei Koidzumi, inhibited pig gastric H+, K+ ‐ATPase with IC50 values of 1.8 and 3.3 μM, respectively. The inhibition by I or II was competitive with respect to ATP and was non‐competitive with respect to K+. I and II also inhibited K+, stimulated p‐nitrophenyl phosphatase, with IC50 values of 1.3 and 3.5 μM, respectively. Proton transport in‐vitro was inhibited by I or II, in a dose‐dependent manner. I at 100 mg kg−1, i.p. significantly inhibited acid secretion and the formation of stress‐induced gastric lesions. These results suggest that the antisecretory effect of I is due to the inhibition of gastric H+, K+‐ATPase.

Involvement of amygdaloid catecholaminergic mechanism in suppressive effects of desipramine and imipramine on duration of immobility in rats forced to swim

The suppressive effect of systemic injection of desipramine and imipramine on the duration of immobility in rats forced to swim was inhibited by 6-hydroxydopamine given into the medial amygdaloid nucleus as a pretreatment. Pretreatment with 5,7-dihydroxytryptamine given into the medial amygdaloid nucleus had no effect on the immobility-reducing effect of tricyclic antidepressants. The concentrations of catecholamines and serotonin in 6-hydroxydopamine- and 5,7-dihydroxytryptamine-pretreated rats, respectively, were significantly lower than those in the saline-injected rats. These results suggest that the suppressive effect of systemic injection of desipramine and imipramine on the duration of the immobility of rats forced to swim was mediated by the catecholaminergic but not the serotonergic mechanisms in the medial amygdaloid nucleus.

Action of nootropic drugs on transcallosal responses in rats

The effects of nootropic drugs and related compounds on transcallosal responses were examined in urethane-anesthetized rats. The transcallosal response was recorded from the surface of the anterior neocortex following electrical stimulation of the contralateral corpus callosum. The transcallosal response consisted of a biphasic positive-negative waveform. Hopantenate increased the amplitude of the positive- and negative-waves, without affecting the latency. Aniracetam, idebenone, bifemelane hydrochloride, TRH and meclofenoxate increased the amplitude of the negative-wave, without affecting the latencies. Vinpocetine and eburunamonine had no effect on the transcallosal response. Muscimol, amino-oxyacetic acid, diazepam and pentobarbital increased the amplitude of the positive-wave and decreased the amplitude of the negative-wave, without affecting the latencies. Bicuculline and picrotoxin increased the amplitude of the negative-wave, without affecting the latencies. Physostigmine decreased the amplitude of the negative-wave, without affecting the latency. Atropine was without effect. The pharmacological nature of the transcallosal response is discussed, based on findings with 16 different pharmacological agents.

Contralateral circling behavior induced by intranigral microinjections of taurine and GABA in rats.

Circling behavior induced by unilateral microinjections of taurine and gamma-aminobutyric acid (GABA) into the substantia nigra zona reticulata (SNR) was studied in rats. Both taurine (10-100 micrograms/rat) and GABA (30-300 micrograms/rat) induced the contralateral circling behavior in a dose-dependent manner when they were microinjected into the SNR. Neither compound induced ipsilateral circling. An ipsilateral injection of 6-hydroxydopamine (6-OHDA) into the nucleus caudatus putamen (CPU) caused a reduction of the dopamine (DA) content in the injected side and decreased the circling behavior induced by taurine but not GABA. Electrolesion of the ipsilateral nucleus ventromedialis thalami (VM) decreased both taurine- and GABA-induced circling. In contrast, only GABA-induced circling was reduced by the electrolesion of the ipsilateral nucleus parafascicularis thalami (PF). Electrolesion of the ipsilateral nucleus accumbens (ACB) did not modify the circling behavior induced by GABA, but did decrease the circling induced by taurine. Electrolesion of the ipsilateral globus pallidus (GP) or nucleus entopeduncularis (EP) did not attenuate the circling behavior induced by either taurine or GABA. These results suggest that taurine-induced circling behavior may be mediated by the nigrostriatal-nigrothalamic system, and the ACB. In contrast, the nigrothalamic system may play an important role in GABA-induced circling behavior.

Effects of restraint and water-immersion stress and insulin on gastric acid secretion in rats

Effects of restraint and water-immersion stress (RWIS) and of insulin injection on gastric acid secretion were investigated in relation to blood glucose levels and to brain glucose uptake in rats. Venous blood glucose levels (VBG) were significantly increased while arterial blood glucose level (ABG) was slightly increased by RWIS. In contrast, ABG and VBG were significantly decreased by administration of insulin; the decrease in ABG was greater than that in VBG. Glucose uptake into the brain, calculated from the ABG-VBG, was significantly decreased both by RWIS loading and by insulin administration. The uptake of [14C] 2-deoxy-D-glucose [( 14C]-2DG) into the brain was also significantly decreased in RWIS-loaded or insulin-treated rats. Gastric acid output was significantly increased both by RWIS loading and by insulin administration. The increased acid output paralleled the decrease of glucose uptake into the brain in RWIS-loaded and insulin-treated rats. Results suggest that RWIS-induced gastric acid secretion is regulated by brain glucose uptake and that this gastric acid secretion is a hypothalamic neuron-mediated event as is insulin-stimulated gastric acid secretion.