摘要:

AbstractWe have examined the effects of various calcium channel blockers on stimulation‐induced changes in end‐plate potential (EPP) amplitude at the frog neuro‐muscular junction. We found that the addition of small concentrations (1–10 μM) of Cd2+to the low calcium bathing Ringer reduced both the control EPP amplitude and the increase in EPP amplitude that normally occurs during repetitive stimulation under low quantal conditions. These effects of Cd2+, which developed rapidly following its addition to the bathing solution and were equally rapidly reversed, resulted from changes in the amount of transmitter released from the nerve terminal. The major effect of Cd2+appeared to be on the facilitation and augmentation components of increased release. Cd2+had little or no effect on potentiation of release. The other divalent cations tested, Zn2+, Co2+, and Ni2+, also decreased both control EPP amplitude and the stimulation‐induced increase in EPP amplitude, but higher concentrations (>100 μM) of these cations were required. The order of effectiveness in reducing stimulation‐induced increases in EPP amplitude was: Cd2+>>>Co2+, Zn2+>Ni2+. The organic calcium channel blockers ver‐apamil (20–100 μM) and nimodipine (20–50 μM) had little effect on stimulation‐induced increases in EPP amplitude. The results of this study are consistent with previous suggestions that the different components of increased release represent different mechanisms. Furthermore, if Cd2+is acting by reducing Ca2+entry into the nerve terminal, then these results suggest that facilitation and augmentation are dependent in some way on Ca2+entry.

ISSN:0887-4476    

DOI:10.1002/syn.890150402

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe kinetic pattern of a11C‐labeled histamine H1receptor antagonist, [11C]pyrilamine, was investigated in the human brain by factor analysis of dynamic PET studies. Tissue time activity curves were also processed by compartment model curve fitting preceded by deconvolution analysis. Factor analysis revealed two statistically significant and physiologically meaningful kinetic patterns: one for specific and another for nonspecific binding of the radioligand. From these two factors a compartment model containing two tissue compartments (one for specific binding and another for nonspecific binding and free ligand) was constructed. The two‐compartment model was also supported by the impulse response function, which was obtained by deconvolution and showed two components. The factor image constructed from factor two demonstrated a distribution pattern characteristic for brain regions rich (frontal, parietal, and temporal lobes) or poor (occipital lobe and cerebellum) in H1receptors. Blockade of H1receptors with unlabeled pyrilamine, diphenhydramine, or hydroxyzine caused a significant reduction of this factor. Blockade produced no significant changes in factor one representing nonspecific binding.We conclude that the kinetics of [11C]pyrilamine in the brain can be described by two tissue compartments, one related to the distribution of the H1receptors. Factor analysis of dynamic studies can be used to locally separate these two compartments, for identification of regions rich and poor in H1receptors and for noninvasive quantitative investigation of the effects of H1receptor blockers such as pyrilamine, diphenhydramine, or hydroxyzine. © 1993 Wiley‐Lis

ISSN:0887-4476    

DOI:10.1002/syn.890150403

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

年代:1993

数据来源: WILEY

摘要:

AbstractFurther evaluation of the effects of BMY 14802 on dopamine (DA) neuronal activity in the rat substantia nigra pars compacta (A9) was conducted with single‐unit recording and microiontophoresis in anesthetized rats. Microiontophoretic administration of BMY 14802 (sigma, serotonin (5‐HT)‐1A and α‐1 adrenoceptor ligand) had no effect on DA neurons. Microiontophoretic administration of (+)‐3‐PPP (weak D2 agonist with high affinity for sigma receptors) and quinpirole (D2/D3 agonist) inhibited A9 DA neuronal activity. Coiontophoresis or i.v. pretreatment with BMY 14802 had no effect on the current‐response curves for the effects of microiontophoretic (+)‐3‐PPP or quinpirole on A9 DA neurons. Coiontophoretic administration of (−)‐sulpiride, a selective D2 antagonist, blocked the inhibitory effects of microiontophoretic (+)‐3‐PPP. The effects of BMY 14802 (0.25‐8 mg/kg, i.v.) on DA neurons (increased firing rate, increased burst‐firing, reduced regularity of firing pattern) were not altered by acute brain hemitransection, but were blocked by pretreatment with NAN‐190, an antagonist of 5‐HT‐1A and α‐1 receptors. The α‐1 receptor antagonist, prazosin, did not block these effects of BMY 14802.In conclusion, the effects of BMY 14802 on DA neuronal firing rate and firing pattern are indirect, perhaps due in part to the occupation of

ISSN:0887-4476    

DOI:10.1002/syn.890150404

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

年代:1993

数据来源: WILEY

摘要:

AbstractRecent postmortem studies have suggested that reduced γ‐aminobutyric acid (GABA)ergic activity in limbic cortex may be one component to the pathophysiology of schizophrenia. This hypothesis has underscored the importance of knowing whether midbrain dopamine afferents interact extensively enough with inhibitory interneurons to suggest a direct functional relationship. Toward this end, a double immunofluorescence approach combined with confocal laser scanning microscopy has been used to localize dopamine and GABA simultaneously in rat medial prefrontal cortex. The results confirm studies from other laboratories showing a rich network of dopamine‐immunoreactive fibers forming a gradient across the cortical laminae, with deeper layers having the highest density. When viewed with oil immersion optics, dopamine‐immunoreactive fibers were frequently found to be in close apposition with GABA‐immunoreactive cell bodies. The percentage of GABA‐containing neurons showing such contacts was highest in layer VI (65%) and progressively decreased toward layer I (9%). Varicose regions of the dopamine fibers were typically present at the point of contact with a GABA‐immunoreactive cell body. Using an immunoperoxidase technique to localize dopamine fibers and cresyl violet staining to visualize neurons simultaneously, two separate statistical analyses were performed to assess whether the frequency of contacts between dopamine fibers and cell bodies in general may be due to random effects. In layer VI, a high percentage of both pyramidal and nonpyramidal neurons were found to be in contact with dopamine varicosities (71% and 76%, respectively), but these were not significantly different from that observed for GABA‐containing cells (65%) in double‐immunofluorescence specimens. A Chi‐square statistical test was used to compare the observed and predicted number of varicosities forming cell body contacts. This analysis indicated that the percentage of dopamine varicosities (30%) that form appositions with cell bodies is much greater than would be expected if these appositions were due to random effects (15%). Moreover, using an estimate of intensity for a stationary Poisson process, it was again found that random effects can not account for these interactions (P = 0.01). Taken together with earlier electron microscopic studies from other laboratories, the present findings support the idea that GABAergic interneurons have extensive interactions with dopamine varicosities. While these interactions are not unique to GABAergic cell bodies, they suggest that inhibitory interneurons can play a direct role in mediating the effects of midbrain dopamine afferents in rat medial prefrontal cortex. © 1

ISSN:0887-4476    

DOI:10.1002/syn.890150405

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

年代:1993

数据来源: WILEY

摘要:

AbstractFentanyl and its congeners are of interest not only because of their clinical applications, but also because certain members of this series of opioid analgesics exhibit unique properties, such as acting as pseudoirreversible inhibitors of μ receptor binding, both in vitro and in vivo. Previous studies showed that pretreatment of membranes with (+)‐cis‐3‐methylfentanyl resulted in a lower affinity interaction of [3H]ohmefentanyl with the μ binding site, as well as an increased dissociation rate. The present study was undertaken to determine the stereochemical requirements for pseudoirreversible inhibition of μ receptor binding using the methylfentanyl congeners, (±)‐cis‐N‐[1‐(2hydroxy‐2‐phenylethyl)‐3‐methyl‐4‐piperidyl]‐N‐phenylpropanamide HCI (RTI‐4614‐4) and its four resolved enantiomers. A R configuration of the 2‐hydroxy group was essential for high affinity binding and pseudoirreversible inhibition. The two enantiomers with this configuration, lb (2R, 3R,4S)‐N‐[1‐(2‐hydroxy‐2‐phenylethyl)‐3‐methyl‐4‐piperidyl]N‐phenylpropanamide oxalate) and lc ((2R, 3S,4R)‐N‐[1‐(2‐hydroxy‐2‐phenylethyl)‐3methyl‐4‐piperidyl]‐N‐phenylpropanamide HC1), acted as pseudoirreversible inhibitors of the μ receptor as labeled with [3H ][D‐Ala2‐McPhe4, Gly‐ol5]enkephalin, [3H]fentanyl or [3H]etorphine. RTI‐4614‐4, lb, and 1c decreased the Bmax of [3H][D‐Ala2‐MePhe4, Glyol5]enkephalin binding sites without altering the dissociation rate. These drugs had a lesser effect on steady‐state [3H]fentanyl and [3H]etorphine binding but did produce statistically significant changes in the parameters of the two‐component dissociation model, which accurately described the dissociation of these [3H]ligands. Viewed collectively, these data indicate that the mechanism of the pseudoirreversible inhibition appears to depend on the radioligand used to label the μ receptor. To explain these data, a pseudoallosteric model is proposed that postulates that certain μ ligands bind to different domains of the drug recognition site of the μ receptor and that the prebinding of pseudoirreversible inhibitors to the recognition site changes the domains available to a radioligand, leading to alterations in steady‐state binding levels and dissociation kinetics. © 1993 Wiley‐Liss,

ISSN:0887-4476    

DOI:10.1002/syn.890150406

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

年代:1993

数据来源: WILEY

摘要:

AbstractDevelopment of the noradrenergic fiber innervation of the rat hippocampus by the locus coeruleus was examined immunohistochemically in fixed tissue from animals aged 4 days through 55 days postnatal. The presence of tyrosine hydroxylase (TH) and dopamine‐beta‐hydroxylase (DBH) immunoreactive cells and fibers was evaluated in sections of hippocampus and locus coeruleus. Large, multipolar TH‐ and DBH‐positive cells with long beaded fibers were visible within locus coeruleus at all ages; no immunopositive cell bodies were found in hippocampus. In hippocampal sections from mature animals (PN55), the highest density of DBH‐stained fibers was found in stratum lucidum of CA3 and in the hilus and inner molecular layer of the dentate gyrus. Whereas similar patterns of fiber positivity were found at PN21 and PN10 (although with somewhat reduced density of immunopositive fibers), the pattern was quite different at PN4. Although fiber staining was relatively sparse at PN4, relative density of DBH fibers was highest in stratum radiatum of CAI and subiculum. This change in staining pattern suggests that noradrenergic function in hippocampus may change as the rat matures.Double immunofluorescence techniques showed an overlap of DBH and TH positive fibers in all hippocampal regions at all ages. DBH immunostaining appeared to be somewhat more sensitive than the TH staining. These data made it impossible to confirm the presence of significant numbers of nonnoradrenergic, catecholamine‐containing fibers in hippocampus. © 1993 Wil

ISSN:0887-4476    

DOI:10.1002/syn.890150407

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

年代:1993

数据来源: WILEY

摘要:

AbstractDevelopment of the noradrenergic innervation of the rat hippocampus by the nucleus locus coeruleus was examined immunohistochemically in the roller tube organotypic cultured slice preparation. Slices of rat hippocampus and locus coeruleus were co‐cultured on glass coverslips for 2–6 weeks and evaluated for the presence of dopamine‐beta‐hydroxylase (DBH) and tyrosine hydroxylase (TH) immunoreactive cells and fibers. Large, multipolar DBH‐ and TH‐positive cells were visible within the locus coeruleus; an occasional cell appeared near or just within co‐cultured hippocampal tissue and in connecting fiber tracts. DBH‐positive cells tended to concentrate near the edges of locus coeruleus tissue. Locus coeruleus slices cultured alone showed little indication of fiber outgrowth in any direction. In co‐cultures, however, beaded DBH‐ and TH‐positive fibers were directed toward the hippocampus. The majority of these fibers entered the hippocampus in the hilar/CA3 region and formed extensive collateral branches. Light microscopy suggests that DBH‐positive fiber growth was densest at or near the pyramidal cell layer in CA3b and CA3c and in the infragranular region of the dentate hilus. This pattern of noradrenergic innervation of hippocampus by co‐cultured locus coeruleus in vitro appears very similar to the pattern established in vivo (see Moudy et al., companion article, this issue

ISSN:0887-4476    

DOI:10.1002/syn.890150408

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

年代:1993

数据来源: WILEY

摘要:

AbstractA recently developed benzamide compound which facilitates glutamate receptor‐mediated synaptic responses was used to test behavioral consequences of enhanced glutamatergic transmission. The drug was found to depress exploratory activity by rats in a novel environment. At a dose below threshold for causing such effects, drug‐treated and control rats exhibited no evident behavioral differences during the acquisition phase of a radial maze experiment. Yet, when tested 2.5 h later, experimental animals were more likely than controls to choose maze arms that had not been entered during the acquisition session, suggesting that the drug enhanced retention of information about prior choices and the maze environment. © 1993 Wiley‐Lis

ISSN:0887-4476    

DOI:10.1002/syn.890150409

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

年代:1993

数据来源: WILEY

ISSN:0887-4476    

DOI:10.1002/syn.890150401

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

年代:1993

数据来源: WILEY