摘要:

AbstractThe effects of withdrawal from continuous administration of cocaine on behavioral sensitivity to apomorphine and monoamine receptor density were examined in rats. Subdermal minipumps that delivered either saline or 20 mg/kg/day cocaine hydrochloride were implanted for 2 weeks. Apomorphine‐induced stereotypy (0.5 mg/kg, SC) was examined in separate groups of rats either 4 hr or 7, 28, or 60 days after removal of the minipumps. Transient enhanced sensitivity to apomorphine‐induced stereotypy occurred during the course of withdrawal. Animals withdrawn from cocaine for 4 hours did not differ from controls in their sensitivity to apomorphine, whereas animals withdrawn from cocaine for 7 days exhibited an increase in apomorphine‐induced oral stereotypy relative to controls. However, the enhanced stereotypy response was no longer evident in animals withdrawn for 28–60 days. The animals were sacrificed after behavioral testing, and their brains were assayed for changes in monoamine receptor density in the frontal cortex, caudate‐putamen, and nucleus accumbens. The density of3H‐SCH‐23390‐labeled D1 receptors was altered in all three regions examined in a time‐dependent manner that paralleled the changes in behavioral sensitivity to apomorphine. There was a transient decrease in D1 receptor density that was evident by 7 days following withdrawal from continuous cocaine administration and was no longer evident 28 or 60 days posttreatment. There were no changes in3H‐spiroperidol‐labeled D2 receptors,125‐pindolol‐labeled β‐adrenergic receptors, or3H‐ketanserin‐labeled 5‐HT2receptors in any of the regions examined at both 4 hr and 7 days after termination of the cocaine infusion. These findings are discussed in terms of their relevance to developing pharmacologic treatments for withdrawal fr

ISSN:0887-4476    

DOI:10.1002/syn.890160102

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

年代:1994

数据来源: WILEY

摘要:

AbstractLithium, a simple monovalent cation, represents one of psychiatry's most important treatments and is the most effective treatment for reducing both the frequency and severity of recurrent affective episodes. Despite extensive research, the underlying biologic basis for the therapeutic efficacy this drug remains unknown, and in recent years, research has focused on signal transduction pathways to explain lithium's efficacy in treating both poles of manic‐depressive illness. Critical to attributions of therapeutic relevance to any observed biochemical effect, however, is the observation that the characteristic prophylactic action of lithium in stabilizing the profound mood cycling of bipolar disorder requires a lag period for onset and is not immediately reversed upon discontinuation of treatment. Biochemical changes requiring such prolonged administration of a drug suggest alterations at the genomic level but, until recently, little has been known about the transcriptional and posttranscriptional factors regulated by chronic drug treatment, although long‐term changes in neuronal synaptic function are known to be dependent upon the selective regulation of gene expression. In this paper, we will present evidence to show that chronic lithium exerts significant transcriptional and posttranscriptional effects, and that these actions of lithium may be mediated via protein kinase C (PKC)‐induced alterations in nuclear transcription regulatory factors responsible for modulating the expression of proteins involved in long‐term neural plasticity and cellular response. Such target sites for chronic lithium may help unravel the processes by which a, simple monovalent cation can produce a long‐term stabilization of mood in individuals vulnerable to bipolar illness. © 1994 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United State

ISSN:0887-4476    

DOI:10.1002/syn.890160103

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

年代:1994

数据来源: WILEY

摘要:

AbstractWe evaluated the effect and action mechanisms of cocaine on electroencephalographic (EEG) activity in adult male Sprague‐Dawley rats anesthetized with chloral hydrate (400 mg/kg, i.p., with 80 mg/kg/h supplements). On‐line and real‐time power spectral analysis of the EEG activity continuously quantified its root mean square (RMS) and mean power frequency (MPF) values, and the power of its spectral frequency components (low frequency: 0–4 Hz; high frequency: 4–20 Hz). Administration of cocaine (1.5 or 3.0 mg/kg, i.v.) dose‐dependently induced EEG desynchronization, as manifested by a reduction in RMS and an elevation in MPF values, coupled with a differential decrease in both high and low frequency components. Samples collected by in vivo microdialysis at the medial prefrontal cortex (mPFC) and analyzed by HPLC showed that the elevation of cocaine and dopamine (DA) level in the dialysate reached its peak during the time interval when maximal activation of EEG occurred. This EEG activation was antagonized by microinfusion into the mPFC via reverse microdialysis of R(+)‐SCH 23390, a selective antagonist for D‐1 receptors; sulpiride, a selective antagonist for D‐2 receptors; or haloperidol, a nonspecific dopamine antagonist. These results suggest that dopaminergic neurotran:3mission at the mPFC may be intimately related to the specific spectral pattern of alteration in EEG activity elicited by cocaine in the rat and that both D‐1 and D‐2 receptors may be involved in the process.

ISSN:0887-4476    

DOI:10.1002/syn.890160104

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

年代:1994

数据来源: WILEY

摘要:

AbstractStimulation of the mesolimbic dopamine (DA) system is considered of major importance for the rewarding and dependence producing properties of nicotine (NIC). To identify the site of this stimulatory action, simultaneous microdialysis was performed in the ventral tegmental area (VTA) and the ipsilateral nucleus accumbens (NAC) of awake rats. Extracellular concentrations of DA and its metabolites were measured in the NAC. NIC (0.5 mg/kg, s.c.) increased DA and its metabolites by ∼50%.Concomitant infusion of the nicotinic receptor antagonist mecamylamine (MEC, 100 μ) through the VTA probe, starting 40 min before NIC injection, antagonized the NIC induced increases of DA and its metabolites. In contrast, similar MEC pretreatment (40 or 140 min) in the NAC did not affect DA or metabolite responses to systemic NIC. Infusion of NIC (1,000 μ) in the NAC or the VTA increased DA release by 49% and 48%, respectively, whereas only the VTA infusion increased metabolite concentrations by ‐25%. MEC infusion (1–1,000 μ) in the VTA did not affect DA or its metabolites, whereas the 1,000 μ concentration infused in the NAC increased DA by 77%. These results suggest that nicotinic receptors in the somatodendritic region may be of greater importance than those located in the terminal area for the stimulatory action of systemic NIC on the mesolimbic DA system. Furthermore, our findings support the notion that the mesolimbic dopaminergic system is phasically rather than tonically regulated by nicotinic receptor activation within the VTA. © 1994 Wiley

ISSN:0887-4476    

DOI:10.1002/syn.890160105

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

年代:1994

数据来源: WILEY

摘要:

AbstractThe single excitor motoneuron to the limb opener muscle in the crayfish Procambarus clarkii provides multiterminal innervation to individual muscle fibers. At low impulse frequencies, these neuromuscular synapses generate a threefold larger junctional potential in fibers of the proximal region of the muscle compared to those in the central region. Focal extracellular recording from synapse‐bearing “boutons” showed more quantal release at low frequencies in the proximal region. Structural correlates for the physiological differences were sought. Fluorescence microscopy of surface innervation stained with a vital fluorescent dye, 4‐Di‐2‐Asp, showed that density of innervation was not greater in the proximal region and thus could not account for the overall differences in synaptic strength. Freeze fracture studies showed that the intramembrane organization of excitatory synapses and their active zones was qualitatively similar in proximal and central sites. Serial section electron microscopy of several innervation sites in proximal and central regions showed homogeneity in number and size of synapses. However, presynaptic dense bars (at release sites, or active zones) were longer and occurred at a higher density in proximal than in central synapses. The differences in number and length of presynaptic dense bars correlate positively with the differences in synaptic strength represented by junctional potential amplitudes and quantal contents of individual surface recording sites. Since many individual proximal synapses have multiple dense bars, co‐operativity among these may serve to enhance transmitter output. It is concluded that occurrence of dense bars is a significant pre synaptic correlate of synaptic strength in this neuron. © 1994 W

ISSN:0887-4476    

DOI:10.1002/syn.890160106

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

年代:1994

数据来源: WILEY

摘要:

Abstract[3H]TCP, an analog of the dissociative anesthetic phencyclidine (PCP), binds with high affinity to two sites in guinea pig brain membranes, one that is MK‐801 sensitive and one that is not. The MK‐801‐sensitive site (PCP site 1) is associated with NMDA receptors, whereas the MK‐801‐insensitive site (PCP site 2) may be associated with biogenic amine transporters (BAT). Although several “BAT ligands” are known that bind selectively to PCP site 2 and not to PCP site 1 (such as indatraline), these compounds have low affinity for site 2 (Kivalues>1 μ). Here we demonstrate that the novel pyrrole RTI‐4793‐14 is a selective, high affinity ligand for PCP site 2. We determined the IC50values of RTI‐4793‐14 and several reference compounds [PCP, (+)‐MK801 and indatraline] for PCP site 1 (assayed with [3H](+)‐MK801), PCP site 2 (assayed with [3H]TCP in the presence of 500 nM (+)‐MK801) and a variety of BAT‐related measures ([3H]CFT binding to the DA transporter, [3H]nisoxetine binding to the norepinephrine transporter, [3H]dopamine uptake, [3H]serotonin uptake). In addition, we determined the ability of RTI‐4793‐14 to block NMDA responses in cultured hippocampal neurons under voltage clamp. (+)‐MK801 had high affinity for PCP site 1 (4.6 nM) and potently inhibited NMDA‐induced responses, but was much less potent in the BAT‐related measures (IC50s>10 μ). PCP had high affinity at PCP site 1 (IC50= 92 nM) and PCP site 2 (IC50= 117 nM), and was moderately potent in all BAT‐related measures except [3H]nisoxetine binding. Indatraline was potent in BAT‐related measures (IC50s, 2 to 5 nM), but weak in other measures (IC50s>1 μ). In contrast, RTI‐4793‐14 had high affinity for PCP site 2 (38 nM), low affinity for PCP site 1 (>36 μ), moderate IC50s for all BAT‐related measures, and negligible activity at NMDA receptors. Viewed collectively, these data indicate that RTI‐4793‐14 binds with high affinity and selectivity to PCP site 2 and provide further support for an associatio

ISSN:0887-4476    

DOI:10.1002/syn.890160107

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

年代:1994

数据来源: WILEY

摘要:

AbstractN‐methyl‐D‐aspartate (NMDA) receptors are important in many instances of synaptic plasticity. In hippocampal area CA1, long‐term potentiation (LTP) can be induced by both NMDA receptor‐dependent and ‐independent mechanisms. Using intracellular recordings and single‐electrode voltage clamp, we isolated and characterized NMDA receptor‐mediated synaptic responses. NMDA receptor‐mediated responses evoked by low frequency orthodromic stimulation were inhibited in a dose‐dependent manner by the competitive antagonist D,L‐2‐amino‐5‐phosphonovaleric acid (APV). High frequency (tetanic) stimulation, which facilitates synaptic release of glutamate, failed to overcome the blockade of NMDA receptors by APV. Using extracellular recordings of field potentials, we studied the contribution of NMDA receptors to LTP induced by different patterns of tetanic stimulation. LTP was inhibited in a dose‐dependent manner by APV, but was more sensitive to APV than were NMDA receptor‐mediated synaptic responses. This most likely reflects a threshold for NMDA receptor activation in LTP induction. A component of LTP that resisted blockade by APV was induced by high (200 Hz), but not low (25 Hz), frequency tetanization. This NMDA receptor‐independent component of LTP persisted for>4 hours and accounted for approximately half the potentiation induced by 200 Hz tetanization. Procedures necessary to induce LTP at the Schaffer collateral/ commissural synapses in area CA1 by both NMDA receptor‐dependent and ‐independent mechanisms are now well characterized. Using the same neuronal population, it will be possible to ask if processes involved in the maintenance of LTP are shared even when LTP is induced through two differe

ISSN:0887-4476    

DOI:10.1002/syn.890160108

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

年代:1994

数据来源: WILEY

ISSN:0887-4476    

DOI:10.1002/syn.890160109

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

年代:1994

数据来源: WILEY

ISSN:0887-4476    

DOI:10.1002/syn.890160101

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

年代:1994

数据来源: WILEY