摘要:

AbstractThe neuropathologic changes that may underlie autonomic nervous system dysfunction in nondiabetic elderly human subjects or as a complication of diabetes have been systematically examined in sympathetic ganglia of a series of autopsied human subjects. As in animal models of aging and diabetes, enormously swollen terminal axons were found closely apposed to the perikarya of principal sympathetic neurons in prevertebral superior mesenteric sympathetic ganglia of aged and diabetic human subjects. Dystrophic axons consisted of two stereotyped forms: the first was composed of large numbers of misalligned aggregates of neurofilaments surrounded by variable numbers of small dense core vesicles; the second was characterized by large numbers of mitochondria, vacuoles, and dense and multivesicular bodies. The fine structural characteristics of neuroaxonal dystrophy, its predilection for prevertebral rather than paravertebral sympathetic ganglia, and the tendency for multiple dystrophic axons to cluster preferentially around selected neurons were identical in aged and diabetic human ganglia and were similar to changes seen in animal models of aging and diabetes. Neither diabetic nor aging ganglia demonstrated evidence of neuronal degeneration. Such structural changes may represent a degenerative influence of diabetes and aging on the normal remodeling of nerve terminals in autonomic ganglia, i. e., the continually ongoing process of turnover and replacement of axonal terminals. Similarity of lesions in human diabetes and aging suggests the possibility of pathogenetic mechanisms that are common to diabetes and the aging process. The substantial parallels between humans and animal models provide support for the validity of testing some proposed pathogenetic mechanisms directly in animal models. © 1992 Wiley‐Liss, I

ISSN:0887-4476    

DOI:10.1002/syn.890120102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractExperiments were conducted to elucidate the relationships among striatal dopamine receptor density, behavioral manifestations of D1/D2synergism (i. e., the requirement of concomitant stimulation of D1and D2receptors for the expression of stereotyped sniffing, licking and gnawing), and behavioral supersensitivity to dopamine agonists. The state of D1/D2synergism was found to be independent of striatal D1or D2receptor density in rats as: (1) increasing striatal D1and/or D2receptor density (as confirmed by quantitative receptor autoradiography) by chronic treatment with SCH 23390 (0.5 mg/kg/day for 21 days) and/or haloperidol (0.5 mg/kg/day for 21 days) did not alter the normal pattern of D1/D2synergism as determined by behavioral responsiveness to agonist stimulation of D1or D2receptors, and (2) 5 days of reserpine treatment (1 mg/kg/day), although not significantly changing striatal D1or D2receptor density, induced a breakdown in D1/D2synergism (i. e., behavior was elicited by independent stimulation of D1or D2receptors).In addition, the density of striatal D2binding sites was not indicative of behavioral sensitivity to D2agonists. Chronic haloperidol treatment increased behavioral sensitivity to the D2agonist quinpirole by a factor of 2. When tested 96 h after bilateral 6‐hydroxydopamine injections or after 5 daily reserpine injections, supersensitivity to quinpirole was at least double that following chronic haloperidol, without accompanying increases in striatal D2density. This enhanced sensitivity to quinpirole was no greater than that observed in neurologically intact rats treated concomitantly with a maximally stimulating dose of SKF 38393. Furthermore, rats with unilateral 6‐hydroxydopamine lesions that were treated chronically with eticlopride continued to rotate contralateral to the lesion in response to quinpirole despite having hemispheric symmetry of striatal D2receptor binding. By contrast, when rats with unilateral 6‐hydroxydopamine lesions were given 5 daily reserpine injections, rotation was abolished, having been replaced by intense stereotyped sniffing, indicative of bilateral supersensitivity.The results support the hypothesis that two distinct types of dopamine supersensitivity exist: A modest one associated with increased D2density, and a more profound one associated with a breakdown in D1/D2synergism and independent of D2de

ISSN:0887-4476    

DOI:10.1002/syn.890120103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractRTI‐55 (3β‐(4‐iodophenyl)tropan‐2β‐carboxylic acid methyl ester), one of the most potent inhibitors of dopamine uptake reported to date, was radioiodinated and tested as a probe for the cocaine receptor in Sprague‐Dawley rat brain. Saturation and kinetic studies in the striatum revealed that [125I]RTI‐55 bound to both a high‐ and low‐affinity site. The Kdfor the high‐affinity site was 0.2 nM, while the Kdfor the low‐affinity site was 5.8 nM. The corresponding number of binding sites in the striatum was 37 and 415 pmol/g protein. The pharmacological profile of specific [125I]RTI‐55 binding in the striatum was consistent with that of the dopamine transporter. Additionally, [125I]RTI‐55 was found to bind with high affinity to the cerebral cortex. Scatchard analysis revealed a single high‐affinity component of 0.2 nM with a density of 2.5 pmol/g protein. The pharmacological profile demonstrated by [125I]RTI‐55 in the cerebral cortex matched that of the serotonin transporter. Autoradiographic analysis of sagittal brain sections with [125I]RTI‐55 binding was consistent with these findings. Specific binding of [125I]RTI‐55 was blocked by dopamine uptake inhibitors in areas rich in dopaminergic nerve terminals. Conversely, serotonin uptake inhibitors blocked the binding of [125I]RTI‐55 in brain areas rich in serotonergic neurons. These results demonstrate that [125I]RTI‐55 may be a very useful ligand for the dopamine and serotonin trans

ISSN:0887-4476    

DOI:10.1002/syn.890120104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractPrevious studies have demonstrated that para‐substituted WIN 35,065‐2 analogs of cocaine show high binding affinity for dopamine uptake sites both in vitro and in vivo, and inhibit DA uptake in vitro. These analogs also produce potent cocaine‐like behavioral effects in various procedures. The purpose of the present studies was to evaluate the iodinated WIN 35,065‐2 analog [125I] RTI‐55 as an in vivo ligand for the DA transporter. Following intravenous injection in mice, [125I] RTI‐55 showed highest accumulation in areas with high densities of dopamine uptake sites. Light microscopic autoradiography was used to examine binding with higher resolution. Displacement studies demonstrated that [125I] RTI‐55 binding in dopamine containing regions, striatum and olfactory tubercles, was saturable and inhibited by other cocaine analogs. GBR 12909 and WIN 35,428 significantly inhibited [125I] RTI‐55 binding in striatum, while paroxetine significantly inhibited hypothalamic binding but had little effect in striatum. The latter finding suggests that [125I] RTI‐55 also binds to the serotonin transporter. Haloperidol had no effect on [125I] RTI‐55 binding in any brain region measured. In addition, treatment of animals with the dopamine neurotoxin MPTP caused significant reductions in striatal [125I] RTI‐55 binding. The results of these studies indicate that [125I] RTI‐55 binds primarily to the dopamine transporter in the mouse striatum in vivo. Publish

ISSN:0887-4476    

DOI:10.1002/syn.890120105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractUsing conventional autoradiographic and tissue counting techniques, the experimental quantitation of in vivo kinetics of prospective or established radioligands for PET is animal and labour intensive. The present study tested the feasibility of using PET itself to quantitate the specific binding of [11C] raclopride to rat striatum and to study the effects of experimental manipulation of endogenous dopamine on binding parameters.Carbon‐11‐labeled raclopride was given i. v. to anaesthetised rats, positioned in a PET camera and dynamic emission scans acquired over 60 min. Time‐activity curves were generated for selected regions of interest, representing striatum and cerebellum and the striatal data fitted to a compartmental model, using cerebellum as the input function, thus circumventing the need for individual metabolite‐corrected plasma curves. In control rats, the binding potential (BP), defined as the ratio of the rate constants for transfer from “free to bound” and “bound to free” compartments, was of the order of 0.6. This was reduced threefold by predosing with nonraioactive raclopride. Increasing extracellular dopamine levels by predosing withd‐amphetamine resulted in a significant decrease in BP whereas reducing extracellular dopamine by predosing with γ‐butyrolactone caused a significant increase.Thus, despite the limitation in spatial resolution of PET, specific binding of raclopride could be assessed from regional time‐activity curves from individual rats. The system was sufficiently sensitive that changes in BP could be detected following modulation of endogenous dopamine levels, a finding of potential relevance to the interpretatio

ISSN:0887-4476    

DOI:10.1002/syn.890120106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe effects of short‐term (90 min), mid‐term (5 days), and long‐term (15 days) administration of ammonium acetate (5 mmol/Kg day i. p.) on the somatostatinergic neurotransmitter system of the rat hippocampus have been studied. Scatchard analysis of the binding of125I‐Tyr11‐somatostatin to hippocampal dissociated cells indicated that administration of ammonium acetate at the times studied were associated with a decrease in the number of somatostatin receptors in this brain area, whereas the affinity of the same receptors remained unchanged. Administration of ammonium acetate did not affect the levels of somatostatin‐like immunoreactivity in the hippocampus. Treatment with N‐carbamyl‐L‐glutamate (1 mmol/Kg, i. p.) plus L‐arginine (1 mmol/Kg), which lead to the conversion of ammonia into urea, prevented the ammonium acetate‐induced changes in somatostatin binding in this brain area. N‐carbamyl‐L‐glutamate plus L‐arginine alone had no observable effect on the somatostatinergic system. The decrease in the number of somatostatin receptors induced by ammonium acetate might reflect a decreased sensitivity of the target cells to somatostatin, a phenomenon that could contribute to the depressed neuronal excitability induced by ammonia in the rat hippoc

ISSN:0887-4476    

DOI:10.1002/syn.890120107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe regional distribution of mRNA coding for the neuropeptide somatostatin has been studied in the human brain by in situ hybridization histochemistry using32P‐labeled oligonucleotides. We show that somatostatin mRNA‐containing neurons are widely distributed in a number of nuclei and grey areas of the human brain, including neocortex, putamen, nucleus caudatus, nucleus accumbens, amygdala, midbrain, medulla oblongata, hippocampal formation, reticular nucleus of the thalamus, and posterior nucleus of the hypothalamus. No significant hybridization signal was observed in the substantia nigra, claustrum, globus pallidus, thalamus, and cerebellum. The topographic localization of neurons containing SOM mRNA in the human brain is in agreement with previous studies using immunocytochemical or radioimmunoassay techniques. These results show that in situ hybridization histochemistry with oligonucleotide probes can be used to map the distribution of neurons expressing SOM mRNA in human postmortem materials. © 1992 Wiley‐Lis

ISSN:0887-4476    

DOI:10.1002/syn.890120108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractIpsapirone, a high‐affinity ligand for the 5‐hydroxytryptamine1A(5‐HT1A) receptor subtype, has been shown to be a full agonist at presynaptic serotonergic sites and a partial agonist at postsynaptic sites. Several recent studies have examined the effects of chronic treatment with ipsapirone or other structurally related pyrimidinylpiperazine compounds, including buspirone and gepirone, on 5‐HT1Abinding sites with mixed results. Since the neural mechanism responsible for the anxiolytic and antidepressant properties of these compounds is currently uncertain, further investigation of this issue appeared warranted. [3H] 8‐hydroxy‐2‐(di‐n‐propylamino)‐tetralin ([3H] 8‐OHDPAT), a ligand specific for the 5‐HT1Asite, has been used successfully to label these sites using both membrane binding assays and autoradiography. Experiments were performed to determine whether chronic treatment with ipsapirone would differentially affect binding to 5‐HT1Areceptors at different brain sites. Rats were treated twice daily with ipsapirone (10 mg/kg i. p.) for 1 day or for 1, 2, or 3 weeks. Quantitative analyses were done of autoradiograms of in vitro [3H] 8‐OH‐DPAT binding to selected brain regions. Binding in vehicle‐treated rats was highest in the hippocampus, septal nucleus, interpeduncular nucleus, entorhinal cortex, and dorsal raphe nucleus. Following 3 weeks of treatment with ipsapirone, a large decline in binding was measured in the dorsal raphe nucleus. This decline was not seen with ipsapirone treatments for shorter periods. With the 3‐week treatment, there were less robust declines in [3H] 8‐OH‐DPAT binding in the entorhinal cortex and interpeduncular nucleus. Binding in the other brain regions analyzed was unaltered. These results, together with those in the literature, indicate the importance of dose and length of treatment in producing these alterations. The large decline in binding sites in the dorsal raphe is consistent with the view that the anxiolytic and antidepressant properties of ipsapirone are mediated by a downregulation of the somatodendritic 5‐HT

ISSN:0887-4476    

DOI:10.1002/syn.890120109

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

ISSN:0887-4476    

DOI:10.1002/syn.890120110

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

ISSN:0887-4476    

DOI:10.1002/syn.890120111

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY