摘要:

AbstractThe purpose of this study was to determine whether dopamine D4 receptors could be detected in the human brain striatum by means of an indirect ligand‐binding method, because no dopamine D4 receptor‐selective ligand presently exists. The antipsychotic clozapine is more selective for the dopamine D4 receptor than for other dopamine receptors. Although most antipsychotic drugs act in the striatum to elicit Parkinson‐like side‐effects, clozapine is atypical in that it does not produce Parkinsonism. To understand this atypical action of clozapine, it would be helpful to know whether the presumed target for clozapine, the dopamine D4 receptor, is or is not present in the human striatum. We measured dopamine D4 receptors indirectly, using [3H]emonaprideEmonapride (or YM‐09151‐2; eis‐N‐[(2RS,3RS)‐l‐benzyl‐2‐methylpyrrolin‐ 3‐yll‐5‐chloro‐2‐methoxy‐4‐∼methylamino‐benzamide]) contains two asymmetric carbon atoms and is, therefore, a racemate of four enantiomers, two of which, (R,R)YM‐O9151‐2 and (S,S)YM‐09151‐2, are active with identical potency (see Refs. in Seeman et al., 1992).and [3H]raclopride. Emonapride has a high affinity (K = 90 pM) for the dopamine D4 receptor, while raclopride has a very low affinity for this receptor (K = 240 nM); thus, any difference in the densities of these two [3H]ligands (in the absence of dopamine) could be attributed to the presence of dopamine D4 receptors. Since the binding of [3H]raclopride is sensitive to endogenous dopamine, we used Parkinson‐diseased tissue which has little dopamine. We found that the densities of the two ligands were identical in Parkinson striata, indicating a low density (<1 pmol/g) for dopamine D4 receptors in the human striatum. This low or undetectable density of dopamine D4 receptors in the striatum is consistent with other data indicating that clozapine does not have its major action in the human striatum. Thus, the atypical action of clozapine, insofar as clozapine does not elicit Parkinson side‐effects, may be based on its ability to avoid striatal dopamine D2 receptors and to target dopamine D4 receptors in non‐striatal brain regions. In schizophrenia striata the density of [3H]emonapride was almost two‐fold higher than that of [3H]raclopride. Considering that there are few dopamine D4 receptors in the human striatum, this two‐fold difference is best explained by endogenous dopamine interfering with the binding of [3H]raclo

ISSN:0887-4476    

DOI:10.1002/syn.890140402

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

年代:1993

数据来源: WILEY

摘要:

AbstractSince the high‐affinity state of dopamine D2 receptors may be abnormal in psychomotor diseases, it is desirable to develop a radioactive agonist to label this high‐affinity site for possible clinical diagnostic use. (+)PHNO is a selective D2 agonist used to treat Parkinson's disease. We prepared [3H](+)PHNO from allyl‐des‐propyl‐(+)PHNO. In binding to dopamine receptors in homogenates of canine brain striata, [3H](+)PHNO had a dissociation constant of 0.35 nM in the absence of NaCl, and 0.56 nM in the presence of NaCl. Dopamine agonists and antagonists inhibited the binding of [3H](+)PHNO at drug concentrations similar to those inhibiting other [3H]ligands at D2 receptors, but not similar to those acting at D4 receptors. Approximately 90% of the total [3H](+)PHNO binding was specific. Guanilylimidodiphosphate markedly inhibited [3H](+)PHNO binding, suggesting that [3H](+)PHNO was binding primarily to the high‐affinity state of dopamine D2 receptors rather than to D3 receptors. The density of the [3H](+)PHNO binding sites was equal to that of [3H]emonapride (or [3H]YM‐09151‐2), both densities of which were 1.5‐ to 2‐fold higher than that of [3H]spiperone, compatible with the idea that [3H](+)PHNO binds to monomers of D2, while [3H]spiperone binds to dimers of D2. Although [3H](+)PHNO has good selectivity and affinity for the high‐affinity state of D2, the [3H]ligand was sensitive to endogenous dopamine, since washing the tissue lowered the dissociation constant. For future in vivo labelling of D2 by an agonist, therefore, it will be essential to search for a related [3H]ligand with an even lower dissociation constant.

ISSN:0887-4476    

DOI:10.1002/syn.890140403

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

年代:1993

数据来源: WILEY

摘要:

AbstractQuantitative autoradiography was used to determine changes in GABABreceptor binding in the substantia gelatinosa of the lumbar spinal cord at 4 days and at 6 weeks after a midthoracic spinal transection in rats.In the 4 day lesion animals, there was no significant change in either the density or the affinity of the GABABbinding. At 6 weeks, however, there was a 35% increase in binding density, with no significant change in affinity. The results suggest that alterations in spinal synaptic mechanisms can slowly evolve following loss of descending input to the spinal cord. © 1993 Wiley‐Liss, I

ISSN:0887-4476    

DOI:10.1002/syn.890140404

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe distributions of the two synaptic vesicle proteins p65 [Matthew et al. (1981) J. Cell Biol., 91:257–269] and synapsin I [De Camilli et al. (1983) J. Cell Biol., 96:1337–1354]were compared in macaque monkey retina using pre‐embedding immunocytochemistry for both light and electron microscopy. The monoclonal antibody AB‐48 against p65 labeled ribbon‐containing synaptic terminals of cone, rod, and bipolar cells as well as many conventional synapses of amacrine cells. In contrast, a polyclonal antiserum against synapsin I (SYN I) labeled many amacrine conventional synapses but no photoreceptor or bipolar ribbon synaptic terminals. Horizontal cell pre‐ and post‐synaptic profiles in the outer plexiform layer were not labeled by either antibody. At the light microscopic level, the banding patterns in the inner plexiform layer also differed for the two antibodies, with four bands of AB‐48 immunoreactivity in sublayers S1, S2, S4, and S5 but only three bands of SYN I immunoreactivity in S1, S3, and S5. SYN I also labeled varicose fibers in both the inner nuclear layer and the outer plexiform layer that are probably processes of dopaminergic and GABAergic interplexiform cells. Varicose fibers in the ganglion cell layer were labeled by both antibodies. These results provide the first electron microscopic immunocytochemical labeling for AB‐48 and SYN I in intact retina and confirm that AB‐48 labels both ribbon and conventional synaptic terminals, whereas SYN I labels only conventional synapses. ©

ISSN:0887-4476    

DOI:10.1002/syn.890140405

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

年代:1993

数据来源: WILEY

摘要:

AbstractThree classes of muscarinic receptors in mammalian brain have been postulated on the basis of equilibrium and kinetic binding data. However, equilibrium binding assays alone have not permitted a clear demonstration of the localization of putative M1, M2, and M3 receptor subtypes in the brain because of the overlaping affinities of virtually all muscarinic antagonists. In the present study, the conditions for selective occupancy of the M1, M2, and M3 receptor subtypes in the brain of the rhesus monkey were based on the distinct kinetic and equilibrium binding properties of N‐[3H]‐methylscopolamine (NMS) at cloned m1–m4 muscarinic receptor subtypes expressed in A9L transfected cells. Quantitative autoradiography of the M1, M2, and M3 muscarinic receptor subtypes in the primate brain was performed according to the following strategy. The M1 (m1) receptor subtype was labeled directly with a non‐saturating concentration of [3H]‐pirenzepine. The M2 (m2) subtype was labeled by incubations consisting of short, two minute pulses of [3H]‐NMS after a preincubation with 0.3 μM pirenzepine to occlude m1, m3, and m4 sites. Selective occupancy of the M3 (m3) receptor (subtype) was achieved by pre‐incubation with 0.5 nM unlabeled NMS to partially occlude the m1, m2, and m4 sites, equilibrium with 0.5 nM [3H]‐NMS, followed by a 60 minute tracer dissociation in the presence of 1 μM atropine.In vitro autoradiography demonstrated that the M1 receptor subtype was confined to forebrain structures. M1 receptors were prevalent throughout the cerebral cortical mantle, amygdala, hippocampus, and the striatum. Low to background levels of the M1 receptor subtype were measured over the thalamus, hypothalamus, and brainstem. The M2 subtype was widely distributed with elevated densities of binding sites seen over all primary sensory cortical areas, and within discrete thalamic, hypothalamic, and brainstem nuclei. The distribution of the M3 receptor subtype was largely coincident with the pattern of the M1 sites labeled by non‐saturating concentrations of [3H]‐pirenzepine with some notable exceptions. Within the cerebral cortical mantle, the M3 receptor exhibited an elevated gradient over the orbitofrontal gyrus and the temporal lobe. Within the striatum, the M3 subtype was elevated over the anterior and dorsal part of the caudate nucleus, while the M1 receptors were most prevalent over the ventromedial sector. Selective labeling of M3 receptors was seen over the medial division of the globus pallidus and within the substantia nigra pars reticulata. In contrast to the pattern of the M1 receptor subtype, M3 receptors were prevalent also over midline nuclei of the hypothalamus. These results demonstrate that the distinct kinetic and equilibrium binding profiles of N‐methylscopolamine and pirenzepine for cloned muscarinic receptors provide a viable ligand autoradiographic strategy for mapping the distribution of M1, M2, and M3 receptors in brain.

ISSN:0887-4476    

DOI:10.1002/syn.890140406

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

年代:1993

数据来源: WILEY

摘要:

AbstractPrevious studies [Meller et al. (1990) Mol. Pharmacol., 37:231‐237] have shown that a large receptor reserve exists for the inhibition of serotonin synthesis in rat cortex and hippocampus by the 5‐HT1Aagonist 8‐hydroxy‐2(di‐n‐propylamino)tetralin (8‐OH‐DPAT), whereas little or no reserve exists for the lower efficacy agonists ipsapirone and BMY 7378. The current studies were undertaken to determine if the above drugs exhibit similar relative efficacies and receptor reserves in an electrophysiological model of 5‐HT1Areceptor activation, i. e., the inhibition of dorsal raphe cell firing. Intravenous dose‐response curves were constructed in untreated control rats, or in rats which received an injection of the irreversible receptor inactivator N‐ethoxycarbonyl‐2‐ethoxy‐1, 2‐dihydroquinoline (EEDQ, 6 mg/kg, s. c.) 24 hours before recording. All three drugs fully inhibited dorsal raphe cell firing in control rats (ED50's: 1.5 μg/kg, 8‐OH‐DPAT; 30.0 μg/kg, ipsapirone; 17.5 μg/kg, BMY 7378). However, unlike effects on serotonin synthesis, EEDQ treatments caused no depression of the maximal inhibitory response for any of the agonists, although all dose‐response curves were shifted to the right (ED50's: 10.1 μg/kg, 6.7‐fold shift, 8‐OH‐DPAT; 139.9 μg/kg, 4.7‐fold shift, ipsapirone; 53.8 μg/kg, 3.1‐fold shift, BMY 7378). Although the order of agonist efficacies was similar for both inhibition of serotonin synthesis and dorsal raphe cell firing (8‐OH‐DPAT>ipsapirone>BMY 7378), a large (>50%) receptor reserve was estimated for all three drugs in this electrophysiological system. This suggests that 5‐HT1Areceptor populations mediating the inhibition of transmitter synthesis and neuronal firing may be differently regulated or have different receptor‐effector coupling characteristics (G‐proteins, effecto

ISSN:0887-4476    

DOI:10.1002/syn.890140407

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

年代:1993

数据来源: WILEY

摘要:

AbstractRecent reports have indicated that weak activity in a test input, negatively correlated (out‐of‐phase) with tetanization of a separate, converging input, produces an NMDA‐independent, associative long‐term depression (LTD) of the test input synapses, in hippocampal field CA1 (Stanton and Sejnowski, 1989; Stanton et al., 1991). Associative LTD has also been observed in the dentate gyrus, in vivo, but only following “priming” of the test path with 5 Hz stimulation prior to associative conditioning (Christie and Abraham, 1992b). We have used these stimulus protocols, in vitro, in order to compare the induction of non‐associative and associative LTD in field CA1 of the adult rat hippocampus. Stimulation in normal solution evoked a small non‐associative LTD, but no associative LTD. Addition of picrotoxin to the medium facilitated the induction of NMDA‐dependent non‐associative LTD, but not associative LTD. Previously potentiated pathways were not different from naïve pathways in expression of LTD of either kind. Finally, ‘priming’ stimulation (5 Hz) of the test pathway produced a weak, selective enhancement of associative LTD that was, however, not significantly greater than non‐associative LTD. These results indicate that, for our experimental conditions, negatively correlated co‐activity during afferent tetanization does not induce a substantial associative LTD in area

ISSN:0887-4476    

DOI:10.1002/syn.890140408

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

年代:1993

数据来源: WILEY

摘要:

AbstractSeveral studies suggest that one of the most important factors contributing to cocaine dependence is an alteration in the actions of the neurotransmitter dopamine in the central nervous system. In order to understand some of the neuroreceptor consequences of cocaine administration, groups of rats were injected with cocaine (2 daily doses of 15 mg/kg) for 1 to 21 days. Binding of [3H]cocaine, [3H]SCH23390, [3H]raclopride, and [3H]BTCP in striatal and cortical tissue from the treated animals was compared to controls. [3H]Cocaine binding was increased by the drug in the striatum and cortex at days 14 and 21, respectively. The binding of [3H]SCH23390 to D1dopamine receptors was significantly increased at day 3 of cocaine exposure. In striatal membranes, [3H]BTCP binding to dopamine uptake sites was significantly increased after day 7, whereas binding in cortical membranes was increased from day 1. [3H]Raclopride binding to D2dopamine receptors remained unchanged throughout the study in both cortical and striatal tissues.These results indicate that repeated exposure to cocaine produces an upregulation (possible supersensitivity) in cortical D1, cocaine, and DA‐uptake sites which occurs in a time‐dependent manner. These increases are coupled with an upregulation in striatal D1, cocaine, and DA‐uptake sites, without simultaneous changes in D2receptors. Thus, cocaine's effects are not uniformly distributed across all brain regions, but rather are focused within areas of the dopamine system. © 1993 Wiley‐L

ISSN:0887-4476    

DOI:10.1002/syn.890140409

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

年代:1993

数据来源: WILEY

摘要:

AbstractThis study was undertaken to investigate the effect of chronic treatment with fluoxetine, a selective serotonin uptake inhibitor used widely in the treatment of depression, on the distribution and density of 5‐HT uptake sites, 5‐HT2receptors, and vesicular amine uptake sites in rat brain. Fluoxetine (10 mg/kg i. p.) was administered daily for 21 days. The density of 5‐HT uptake sites labelled by [3H]paroxetine, 5‐HT2receptors labelled by [3H]ketanserin in presence of tetrabenazine and vesicular amine uptake sites labelled by [3H]ketanserin in the presence of mianserin were measured by quantitative autoradiography in 22 areas of rat brain, using coronal tissue sections. Chronic administration of fluoxetine produced significant increases in the density of 5‐HT uptake sites in layers of frontoparietal cortex (by 32–43%), of striate cortex (by 55%), in CA1 field of hippocampus (by 111%) and in superior colliculus (by 20%). Fluoxetine treatment also resulted in upregulation of 5‐HT2receptors in layers of frontparietal cortex (31–38%) and in CA2‐3 fields of hippocampus (by 39%). The density of tetrabenazine‐sensitive vesicular amine uptake sites in the caudate‐putamen was also significantly increased (by 66%). The observed alterations in 5‐HT uptake site and 5‐HT2receptor densities are likely a part of adaptive neuronal changes that occur after chronic administration of fluoxetine and may be related to the antidepressant effect of the dru

ISSN:0887-4476    

DOI:10.1002/syn.890140410

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe percentages of females at critical steps in the academic career ladder were examined for one specific field, neuroscience. There was a slight attrition among females completing the Ph. D. However, the major drop‐off occurred when qualified post‐doctorates did not apply for faculty positions. Remedial actions should focus on not only the graduate school environment but also on the more critical postdoctoral experience. © 1993 Wiley‐Lis

ISSN:0887-4476    

DOI:10.1002/syn.890140411

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

年代:1993

数据来源: WILEY