摘要:

AbstractCyclase response elements (CREs) are located in the promoter regions of several neuropeptide and immediate early genes. Activation of the adenylate cyclase/ cAMP second messenger cascade leads to phosphorylation of CRE‐binding proteins (PCREBs) which bind to CREs in the promoter region of these genes and alter their rate of transcription. We have previously reported an increase in striatal immunoreactivity for P‐CREB (phosphorylated on Ser‐133) and Fos following intracerebroventricular (ICV) injection of H2O‐soluble forskolin, a direct activator of adenylate cyclase. Because CREs are located in the promoter regions of the opioid peptide genes, preproenkephalin (PPE) and preprodynorphin (PPD), we investigated what effect continuous ICV infusion of H2O‐soluble forskolin has on striatal PPE and PPD mRNA levels. Quantitative in situ hybridization histochemistry demonstrated that continuous activation of the adenylate cyclase/cAMP second messenger cascade results in a significant induction of striatal PPE and PPD mRNA at 6, 24, and 72 h. The sustained induction of striatal PPE and PPD mRNA indicates that pro‐opioid gene transcription is not desensitized following 72 h of continuous adenylate cyclase activation. Continuous ICV infusion of 1,9‐dideoxyforskolin, a forskolin analog which does not activate adenylate cyclase, did not induce striatal PPE and PPD mRNA. These data are consistent with cAMP‐dependent protein kinaseinduced phosphorylation and binding of CREBs to CREs in the promoter regions of pro‐opioid genes during sustained activation of adenylate cyclase. © 19

ISSN:0887-4476    

DOI:10.1002/syn.890190302

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

年代:1995

数据来源: WILEY

摘要:

AbstractNeuropeptide Y (NPY) and dynorphin elicit regionally selective presynaptic modulation in the hippocampal formation and the pars reticulata of the substantia nigra, respectively. We examined potential anatomical substrates for their presynaptic modulation by determining the distribution and size of large (80–120 nm) dense‐core vesicles (DCVs), organelles previously shown to be immunoreactive for each peptide. Throughout the hippocampal formation, NPY‐immunoreactive DCVs were located primarily in axon terminals and were more sparingly distributed in dendrites. In comparison with other portions of the hippocampal formation, NPY‐labeled DCVs were most abundant in axons and terminals of the CA1 region. The DCVs in the CA1 region of the hippocampus also more frequently had larger mean cross‐sectional diameters when located along portions of the terminal in contact with unlabeled axons. In both the CA1 region of the hippocampus and the dentate gyrus, NPY‐labeled DCVs in contact with portions of the axonal membrane apposed to astrocytes also were larger than those located more centrally in the axon terminal. Dynorphin‐immunoreactive DCVs in axon terminals 'of the substantia nigra were significantly larger when found near portions of the axonal membrane in contact not only with other axons and astrocytic processes, but also occasionally with postsynaptic dendrites. The parallels between diameters of DCVs and known selectivity of NPY for presynaptic modulation in the CA1 region of the hippocampus suggest a direct correlation between the size and distribution of immunoreactive DCVs and their sites of exocytotic release. By analogy, we can conclude that dynorphin in the pars reticulata of the substantia nigra is also principally a presynaptic modulator, but may additionally elicit functional changes through interactions with receptive sites on astrocytes or postsynaptic neurons. © 1995 W

ISSN:0887-4476    

DOI:10.1002/syn.890190303

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

年代:1995

数据来源: WILEY

摘要:

AbstractTo gain further insight into the operation of 5‐HT autoreceptor‐mediated feedback control of 5‐HT biosynthesis in serotonergic nerve terminal areas, the effect of the 5‐HT1Band the 5‐HT1Areceptor agonists, TFMPP and 8‐OH‐DPAT, respectively, were investigated in the rat central nervous system (CNS) using in vivo and in vitro neurochemical approaches. TFMPP suppressed 5‐HT synthesis (5‐HTP accumulation after decarboxylase inhibition) both in vivo and in vitro. In vivo, the 5‐HT synthesissuppressing effect of the drug (3.0 mg/kg, s.c.) proved resistant to either acute hemitransection or reserpine (5 mg/kg, i.p.; 90 min before) pretreatment. In vitro, in cortical, hippocampal and striatal slice preparations, TFMPP (0.1–10 μM) decreased 5‐HT synthesis under basal and stimulated (30 mM K+) conditions, an effect which was unaltered by prior in vivo reserpine‐induced 5‐HT depletion but was attenuated in the presence of 5‐HT1Breceptor antagonists such as methiothepin, cyanopindolol or propranolol. The 8‐OH‐DPAT (0.1 mg/kg, s.c.)‐induced decrease of 5‐HT synthesis in vivo was abolished by hemitransection but resistant to acute reserpine pretreatment; 8‐OH‐DPAT (10 μM) did not decrease 5‐HT synthesis in vitro. In conclusion, the present study confirms the importance of 5‐HT autoreceptors in the feedback control of nerve terminal 5‐HT biosynthesis. Specifically, our data indicate: (1) that the reduction of rat brain 5‐HT synthesis after TFMPP is mediated by 5‐HT1Bautoreceptors located on the serotonergic axon terminals, and (2) that the effect is directly mediated and occurs independently of 5‐HT neuronal fir

ISSN:0887-4476    

DOI:10.1002/syn.890190304

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

年代:1995

数据来源: WILEY

摘要:

AbstractA series of positron emission tomography (PET) imaging studies was conducted in a baboon with the benzamide derivatives [18F]2,3‐dimethoxy N‐9‐(4‐fluorobenzyl)‐9‐azabicyclo[3.3.1]nonan‐3β‐yl]benzamide ([18F]MABN) and [18F]2,3‐dimethoxy‐N‐[1‐(4‐fluorobenzyl)piperidin‐4‐yl]benzamide ([18F]MBP). Studies were also conducted with the butyrophenone [18F]N‐methylspiperone (NMSP) for comparison. Tissue‐time activity curves of [18F]MABN are similar to those of [18F]NMSP since both compounds displayed approximately the same uptake in the basal ganglia and displayed irreversible binding kinetics in vivo. However, the rapid rate of clearance from the cerebellum and high basal ganglia: cerebellum ratio of [18F]MABN indicate that this compound has a much lower amount of nonspecific binding than [18F]NMSP. [18F]MBP displayed a higher uptake in the basal ganglia relative to [18F]NMSP and [18F]MABN and exhibited reversible binding kinetics in vivo. This property of [18F]MBP is desirable since the uptake of radioactivity in D2‐rich ligands is less likely to be influenced by changes in cerebral blood flow. The current data suggest that both [18F]MABN and [18F]MBP are promising ligands for studying dopamine D2recept

ISSN:0887-4476    

DOI:10.1002/syn.890190305

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

年代:1995

数据来源: WILEY

摘要:

AbstractExperiments were performed to examine neurochemically the functional diversity of GABAAreceptors as measured by muscimol‐, 5α‐pregnane‐3α,21‐diol‐20‐one (THDOC)‐, and pentobarbital‐stimulated36C1−uptake, and region‐specific changes in muscimol THDOC‐ and THDOC‐induced potentiation of muscimol‐stimulated36CI– uptake in rats treated acutely or subacutely with a subconvulsive dose of bicuculline. The data, for stimulation of36C1– uptake by muscimol showed a single binding site interaction in the cerebral cortex, hippocampus and cerebellum. The concentration‐response curves for muscimol in the cerebral cortex and hippocampus were steep and indicated an increase of, approximately 130% at the maximum concentration. In contrast, the curve for the cerebellum was shallow and, exhibited a smaller maximal response (∽60%). Apparent affinity for muscimol also differed among these brain regions. The regional differences in36CI– uptake induced by THDOC and pentobarbital were not as apparent as those induced by muscimol; however, the maximal modulatory effect of pentobarbital, in the hippocampus was significantly higher than that in the cerebellum. In rats treated subacutely with a subconvulsive dose of bicuculline, a significant increase in muscimol‐stimulated36C1‐ uptake was observed in the cerebellum but not in the frontal cortex or hippocampus. Analysis of the concentration‐response curves for muscimol‐stimulated36CI−uptake in the cerebellum revealed that the Vmax for muscimol in the subacutely treated group was significantly higher than those for muscimol in the control and acutely treated groups without any differences in the KD value. In addition, THDOC‐induced potentiation of muscimol‐stimulated36CI−uptake in the subacutely treated group was significantly higher than those in the control and acutely treated groups when a lower concentration (10 nM) of THDOC was used. These results suggest that regional variation of36C1−uptake stimulated by muscimol is more apparent than those stimulated by THDOC and pentobarbital. The present results, along with our previous findings, also indicate that region‐specific bicuculline up‐regulation of GABAAreceptors in the cerebellum involves changes not only in binding characteristics but also in function of G

ISSN:0887-4476    

DOI:10.1002/syn.890190306

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

年代:1995

数据来源: WILEY

摘要:

AbstractMorphine dependence was experimentally induced in rats by daily injection of increasing doses of morphine for seven days. Withdrawal was precipitated in half of the morphine‐dependent rats by a single injection of naloxone on day 8. Behavioral signs of withdrawal weret evident in the morphine/naloxone group. Gene expression in locus coeruleus (LC) neurons was investigated using quantitative in situ hybridization analysis. Messenger RNA (mRNA) levels for tyrosine hydroxylase (TH), the rate‐limiting enzyme in catecholamine synthesis, and for precursors to galanin (GAL) and neuropep tide Y (NPY), peptides that coexist with norepinephrine in LC neurons, were not altered by chronic morphine treatment or naloxone‐precipitated withdrawal. In contrast, mRNA levels forc foswere dramatically elevated in the LC following naloxone‐precipitated withdrawal. Chronic morphine treatment caused a small decrease in levels of mRNA encoding the precursor to corticotropin‐releasing factor (CRF) in Barrington's nucleus. Although long‐term adaptations of LC neurons have previously been implicated in the development of morphine tolerance, dependence, and withdrawal, alterations in the levels of TH, GAL, or NPY mRNA in the LC apparently do not underlie this process. © 1995 Wil

ISSN:0887-4476    

DOI:10.1002/syn.890190307

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

年代:1995

数据来源: WILEY

摘要:

AbstractCocaine analogs such as 3β‐(4‐iodophenyl)tropane‐2β‐carboxylic acid methyl ester (RTI‐55 or βCIT) with a higher affinity for the dopamine transporter (DAT) may be potentially useful in interfering with cocaine's actions in brain. This study evaluates the time course of the effects of RTI‐55 on cocaine binding in baboon brain using PET and [11C]cocaine. [11C]Cocaine binding was measured prior to, and 90 minutes, 24 hours, 4–5 days and 11–13 days after RTI‐55 (0.3 mg/kg i.v.). Parallel studies with [3H]cocaine and RTI‐55 (0.5 mg/kg i.v. or 2 mg/kg i.p.) were performed in the mouse. RTI‐55 significalitly inhibited [11C]cocaine binding at 90 minutes and 24 hours after administration.The half‐life for the clearance of RTI‐55 from the DAT was estimated to be 2 to 3 days in the baboon brain. In the mouse brain, RTI‐55 significantly inhibited [3H]cocaine binding at 60 and 180 minutes after administration and recovery was observed at 12 hours. These results document long‐lasting inhibition of cocaine binding by RTI‐55 and corroborate that binding kinetics of RTI‐55 in striatum observed in imaging studies with [123I]RTI‐55 represents b

ISSN:0887-4476    

DOI:10.1002/syn.890190308

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

年代:1995

数据来源: WILEY

摘要:

AbstractTranscription factors are known to act as gene expression regulators, possibly linking extracellular stimuli to long‐term modifications at the neuronal level. Such modifications may potentially ‐underlie chronic psychostimulant‐ and stress‐induced behavioral alterations. This study illustrates how a 2 week, twice daily 7.5 mg/kg d‐amphetamine or saline regimen alters rat brain regional expression of transcription factor genes, includingc fos, fos‐B, jun‐B,c jun, andzif268, and seeks potential correlations between those changes and alterations in neurotransmitter levels and behavioral novelty responses.Amphetamine withdrawal‐induced decreases in transcription factor mRNA levels, assessed using Northern blot analysis, appear most prominent in prefrontal cortex, begin approximately 12 h after the last injection, and largely recover to control levels by 54 h. Prefrontal cortical and striatal dopamine content, assessed using HPLC, decrease and recover over a similar time course. Behavioral “stereotypy time” manifest by animals exposed to a novel environment, a measure sensitive to psychostimulant withdrawal, also decreases beginning 12 h after the last injection, is still significantly reduced at 54 h, and recovers at 72 h.Chronic saline injections are followed by a consistent decrease in transcription factor gene expression, observed 6 h after the last injection, followed by a “rebound” increase at 12 h. These changes are accompanied by dramatic, mostly biphasic alterations in prefrontal cortical biogenic amines and by a short‐lived increase in striatal dopamine turnover. At the same time, rats display much longer‐lasting decreases in locomotor responses when exposed to a novel environment, with recovery occurring only 54 h after the last injection.The delayed recovery of behavioral responses to novelty is consistent with potential involvement of changes in transcription factor‐mediated gene expression in neurochem‐ ical mechanisms underlying psychostimulant withdrawal and chronic injection stress‐ induced behavioral al

ISSN:0887-4476    

DOI:10.1002/syn.890190309

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

年代:1995

数据来源: WILEY

摘要:

AbstractUse of illicit and licit drugs during pregnancy is a major public health concern, as it can have adverse effects on the developing fetus. Infants born of women addicted to narcotics, cocaine, alcohol, or polydrugs often undergo a characteristic withdrawal syndrome and may have physical, behavioral, and/or neurological abnormalities. As it is not feasible to ascertain whether these functional changes in human infants are produced by abused substance(s) per se or by a combination of complex socioeconomic factors and polydrug use, researchers in recent years have developed and utilized various innovative animal models to assess drug‐induced alterations and their biological mechanisms during the developmental period under a controlled environment. To promote interdisciplinary communications as well as to assess the progress and the future needs in this area, the National Institute on Drug Abuse (NIDA) held a technical review at which biomedical researchers discussed their current findings in various physiological systems. This report summarizes the major findings and the methodological and experimental issues discussed at the conference. The meeting was held in Washington, DC, on May 25 and 26, 1994. © 1995 Wiley‐Liss,

ISSN:0887-4476    

DOI:10.1002/syn.890190310

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

年代:1995

数据来源: WILEY

ISSN:0887-4476    

DOI:10.1002/syn.890190301

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

年代:1995

数据来源: WILEY