Changes in rat liver cyclo(His-Pro) binding sites upon castration and testosterone administration.

Histidyl-proline diketopiperazine [cyclo(His-Pro)] binding was compared in livers from male and female rats. Cyclo(His-Pro) binding of female rat liver was very much lower than that of male rat liver. Scatchard analysis showed that the sex difference in cyclo(His-Pro) binding was due to different binding capacity. Cyclo(His-Pro) binding of castrated male rat liver was significantly decreased. Testosterone replacement raised the binding to the control level, and an excess of testosterone increased the specific binding beyond the control level. The testosterone-induced changes in cyclo(His-Pro) binding were also due to variation in the binding capacity. These findings indicate that testosterone is an important factor in the regulation of cyclo(His-Pro) binding in the rat liver.

Comparison of the effects of bifemelane hydrochloride and indeloxazine hydrochloride on scopolamine hydrobromide-induced impairment in radial maze performance.

The antiamnesic effects of bifemelane hydrochloride (bifemelane) and indeloxazine hydrochloride (indeloxazine) on radial maze performance in rats were assessed. This performance was dependent on working memory and spatial memory, without aversive electric stimuli. When administered alone, neither bifemelane nor indeloxazine had an effect on the task performance of normal rats. However, impairment of the performance of rats induced by scopolamine hydrobromide (scopolamine) injection was dose-dependently reduced by oral treatment with bifemelane. On the other hand, indeloxazine, which was reported to enhance the learning behavior in a passive avoidance test, did not improve the radial maze task performance of scopolamine-treated rats. It has been shown that dysfunction of the cholinergic neuronal system plays an important role in memory loss and that bifemelane induces recovery of reduced cerebral cholinergic neuronal activity associated with brain ischemia or aging. In accordance with these previous findings, our results suggest that bifemelane is useful in the treatment of memory loss and cognitive dysfunction in patients with dementia and cerebrovascular disease.

Hypothalamic regulation of histidyl-proline diketopiperazine binding sites in the rat liver.

The effects of hypothalamic hormones and electrolytic lesioning of the ventromedial hypothalamic nuclei (VMH) on histidyl-proline diketopiperazine (cyclo(His-Pro] binding in the rat liver were studied. VMH-lesioning markedly decreased cyclo(His-Pro) binding in the liver. Scatchard analysis revealed that the loss of cyclo(His-Pro) binding induced by VMH lesioning was due to a decrease in the number and affinity of binding sites. Somatostatin (SS) administration decreased cyclo(His-Pro) binding. The SS-induced changes in cyclo(His-Pro) binding were due to changes in the binding affinity. On the other hand, the administration of TRH or LH-RH did not affect cyclo(His-Pro) binding in the liver, although cyclo(His-Pro) has been proposed to be a metabolite of TRH. These findings suggest that the hypothalamus may regulate the cyclo(His-Pro) binding sites in the liver probably by controlling pancreatic SS secretion, since a VMH-lesion is reported to cause hypersecretion of pancreatic SS.

Alterations of the muscarinic cholinergic (mACh) receptors in the striatum of the MPTP-induced parkinsonian model in mice: in vitro quantitative autoradiographical analysis.

The alteration of muscarinic cholinergic (mACh) receptors in the striatum of mice after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was examined using a [3H]quinuclidinyl benzilate [( 3H]QNB) in vitro labeling macro-autoradiographic technique and mACh receptor concentration was quantitatively analyzed using a computer analysis system. Two weeks after cessation of MPTP administration, the striatal mACh receptors were significantly increased. In the subchronic phase, at 6 weeks, the striatal mACh receptors were significantly decreased but recovered to the normal level by the treatment with L-dihydroxyphenylalanine (L-DOPA) for two weeks before sacrifice. These findings indicated that the striatal mACh receptors are strongly regulated by the nigrostriatal dopaminergic function.

Alterations of somatostatin and its modulation by levodopa in MPTP-treated mouse brain.

We examined the changes in the concentrations of neuropeptides in various regions of the mouse brain 1, 2 or 6 weeks after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment (30 mg/kg i.p. twice/day for 5 days) and further examined the effects of levodopa injections (200 mg/kg i.p.) for 14 days starting 4 weeks after MPTP treatment on regional somatostatin (SRIF) concentrations. Substance P, cholecystokinin-octapeptide and thyrotropin-releasing hormone did not show any significant changes up to 6 weeks after MPTP treatment, whereas the SRIF concentration increased 1 week after MPTP treatment but decreased thereafter, showing a marked decrease in the striatum and hippocampus after 6 weeks. In the striatum, the decreased concentration of SRIF recovered to the normal level with levodopa injections. This SRIF depletion could be a change secondary to dopamine depletion. On the other hand, in the cerebral cortex, while showing no change in the SRIF concentration after MPTP treatment, the concentration decreased significantly with levodopa injections. In the hippocampus, the decreased SRIF levels were still low after levodopa treatment. Since it has been reported that SRIF concentrations are significantly reduced in the frontal cortex and hippocampus of demented parkinsonians and patients with senile dementia of the Alzheimer type and that levodopa treatment induced various psychiatric side effects, the results of the present study suggest some relationship among levodopa treatment, SRIF depletion and the demented state.

Changes of neuropeptides and their receptors in experimental stroke gerbil brains.

Eight kinds of neuropeptides and four kinds of neuropeptide receptors were examined in the right and left hemispheres of mongolian gerbils after unilateral carotid ligation-induced stroke and in normal controls. Five hours after ligation of the right common carotid artery, beta-endorphin concentration in the right hemisphere (ischemic side) of the stroke group was significantly increased compared with that in the contralateral hemisphere (non-ischemic side), but there were no differences between sides in other neuropeptides either with or without stroke. Furthermore, although there were no differences in [3H]naloxone binding, [3H]thyrotropin-releasing hormone binding or 125I-vasoactive intestinal polypeptide binding in the brain in this model of stroke, [3H]enkephalin binding was significantly lower on the ischemic side than on the non-ischemic side in the stroke group. These results suggest that increased activity in the beta-endorphinergic system in the brain might be partly caused by ischemic brain failure.

Ultrastructural changes of the substantia nigra, ventral tegmental area and striatum in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice.

The substantia nigra pars compacta (SNc), ventral tegmental area (VTA) and striatum in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated young adult mice were examined for the occurrence of marked ultrastructural changes. In the median SNc dopaminergic neurons, the Golgi apparatus and rough endoplasmic reticulum were dilated and there was a decrease in the number of ribosomes in the rough endoplasmic reticulum (Nissl substance). The mitochondrial cristae were often disarranged. Characteristic electron dense deposits were often observed in the neuronal fibers, many of which were dilated. However, no clear evidence of nuclear degeneration was seen. On the other hand, ultrastructural abnormalities were not seen in the dopaminergic neurons in the VTA. In both the latero-dorsal and latero-ventral striatum, many dilated neuronal fibers, which contained only a few synaptic vesicles and sparse subcellular structures were observed, but no significant ultrastructural changes could be seen in the medial part of the striatum in MPTP-treated mice. Thus, the effect of MPTP treatment is inhomogenous within the mouse striatum, as would be expected from the appearance of ultrastructural changes in only some of the dopaminergic neurons in the SNc.

Amine fluorescence histochemical investigation of the striatum in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced parkinsonian mice.

Treatment of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) markedly decreased dopamine fluorescence in the lateral part of the striatum but not in the median part of the striatum. However, dopamine fluorescence in lateral part of the striatum recovered by treatment L-dihydroxyphenylalanine(L-DOPA).

Reduction of muscarinic cholinergic receptors in mouse striatum by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and its recovery by levodopa treatment.

The effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration on muscarinic chelinergic receptors (mACh-R) in the mouse striatum and their modulation with levopoda treatment were studied. Striatal mACh-R binding decreased significantly 6 weeks after MPTP treatment, but recovered to control levels 2 weeks after treatment with levodopa. The changes in the mACh-R were caused by changes in receptor binding capacity but not associated with receptor binding affinity. These results suggests that striatal mACh-R is dependent on dopaminergic activity in the striatum.