摘要:

AbstractThe action of serotonin (5‐HT) on GABAergic synaptic transmission was investigated with intracellular recordings in CA3 pyramidal cells of rat hippocampal slices. Local application of 5‐HT (500 m̈M) hyperpolarized CA3 pyramidal cells, decreased cellular input resistance, and reduced slow afterhyperpolarizations. Serotonin attenuated the late (GABAB) component of polysynaptic inhibitory postsynaptic potentials (IPSPs; 47% of control) without affecting the early (GABAA) component. During bath application of the excitatory amino acid antagonists 6‐cyano‐7‐nitroquinoxaline‐2, 3‐di‐one (CNQX) (20 m̈M) and 2‐amino‐5‐phosphonovalerate (AP‐5) (40 m̈M), 5‐HT similarly decreased the amplitude of the late (GABAB) component (17% of control) of monosynaptic IPSPs but did not affect the early (GABAA) component. The mean reversal potentials of poly‐ and monosynaptic IPSPs were unaffected by 5‐HT. The conductance increases associated with the late component of poly‐ and monosynaptic IPSPs were reduced by 5‐HT.Hyperpolarizing responses evoked in CA3 pyramidal cells by somatic applications of gamma‐aminobutyric acid (GABA) were unaffected by 5‐HT. During bath application of bicuculline (20–50 m̈M), hyperpolarizing responses elicited by dendritic GABA application were reduced by 5‐HT (71% of control). The effect of 5‐HT on these direct GABABhyperpolarizations (29% decrease in response) does not appear sufficient to fully account for the effect of 5‐HT on late GABABIPSPs (53–83% decrease in response). Therefore, 5‐HT may reduce GABABIPSPs in CA3 pyramidal cells 1) by a postsynaptic action on pyramidal cells and 2) by a selective presynaptic action on GABAergic interneurons mediating the GABABIPSP. This presynaptic action of 5‐HT does not appear to involve excitatory afferen

ISSN:0887-4476    

DOI:10.1002/syn.890120302

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

年代:1992

数据来源: WILEY

摘要:

AbstractThe relationship between kappa opioid‐induced movement and output stations of the substantia nigra pars reticulata (SNpr) was examined using the rodent circling model. Contralateral rotation produced by intranigral microinjection of the kappa opiate U50,488 was lower in animals with ibotenic acid lesions of either the ipsilateral ventromedial thalamus or superior colliculas than in control animals without lesions. These results suggest that endogenous kappa opioids in the SNpr may influence movement through action on the nigrothalamic and nigrotectal pathways. In contrast, animals with ipsilateral lesions of the striatum showed an increase in circling relative to controls, possibly due to kappa receptor supersensitivity in the SNpr. © 1992 Wiley‐Liss,

ISSN:0887-4476    

DOI:10.1002/syn.890120303

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

年代:1992

数据来源: WILEY

摘要:

AbstractPutative sigma receptors are a current target for antipsychotic drug development. Novel antipsychotic agents which possess selective and high affinity for sigma binding sites may serve as an alternative to the principal neuroleptic drugs currently in clinical use which mediate extrapyramidal side effects and dyskinesias through their blockade of dopamine receptors. We have used in vitro autoradiography to localize putative sigma receptors labelled with (+)‐[3H]‐3‐(3‐hydroxyphenyl)‐N‐(1‐propyl) piperidine [(+)‐[3H]‐3‐PPP]in the brain of the rhesus macaque. The binding characteristics of (+)‐[3H]‐3‐PPP in the primate brain were comparable to those previously described in the rodent. Saturation analysis demonstrated a single class of sites in cerebellar and hippocampal membranes with a Kd value of 28 nM. Sigma receptors labeled with (+)‐[3H]‐3‐PPP in the primate brain displayed the appropriate rank order of potency and stereoselectivity in competition binding assays. Haloperidol displaced (+)‐[3H]‐3‐PPP binding in the low nanomolar range, and the (+) isomer of pentazocine was 50‐fold more potent than (‐) pentazocine. Computerized densitometric analysis of the autoradiograms demonstrated a striking enrichment of sigma binding sites over the paralimbic belt cortices, including the orbitofrontal, cingulate, insular, parahippocampal, and temporopolar gyri. Peak densities of sigma receptors were seen over the medial and central nuclei of the amygdala and were widely distributed within the hippocampal formation. Sigma binding sites densities were elevated over the suprachiasmatic and supraoptic nuclei of the hypothalamus. Moderate sigma receptor densities were observed over the ventromedial sectors of the caudate and the putamen. Sigma receptors were also elevated over autonomic relay nuclei of the brainstem, including the nucleus of the solitary tract and the dorsal motor nucleus of the vagus. The distribution of sigma receptors in the primate brain suggests that the paralimbic belt cortices, amygdala, hippocampus, hypothalamus, and autonomic relay nuclei of the brainstem may be interrelated by a topographic chemical linkage. The autoradiographic visualization of sigma receptor distributions in the primate brain provides further support for a role of sigma receptor mechanisms in the functions of

ISSN:0887-4476    

DOI:10.1002/syn.890120304

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

年代:1992

数据来源: WILEY

摘要:

AbstractSelective activation of metabotropic glutamate receptors withtrans‐1‐amino‐1, 3‐cyclopentanedicarboxylic acid (trans‐ACPD) stimulates phosphoinositide hydrolysis and elicits three major physiological responses in area CA1 of the hippocampus. These include direct excitation of pyramidal cells, blockade of synaptic inhibition, and decreased transmission at the Schaffer collateral‐CA1 pyramidal cell synapse. Physiological effects oftrans‐ACPD are thought to be mediated by activation of phosphoinositide hydrolysis. However, it is now clear that multiple metabotropic glutamate receptor subtypes exist, some of which are not coupled to phosphoinositide hydrolysis. Thus, we performed a series of studies aimed at determining whether the physiological effects oftrans‐ACPD in the hippocampus are mediated by activation of the predominant phosphoinositide hydrolysis‐linked glutamate receptor. We report thatL‐2‐amino‐3‐phosphonopropionic acid (L‐AP3), an antagonist oftrans‐ACPD‐stimulated phosphoinositide hydrolysis, does not inhibit the physiological effects oftrans‐ACPD in area CA1 at concentrations that maximally inhibittrans‐ACPD‐stimulated phosphoinositide hydrolysis in this region. Furthermore, 1S, 3S‐ACPD activates the phosphoinositide hydrolysis‐linked glutamate receptor but does not reduce evoked field excitatory postsynaptic potentials (EPSPs) in area CA1. However, we report that the physiological effects of 1R, 3S‐ and 1S, 3R‐ACPD are consistent with the hypothesis that these effects are mediated by activation of a metabotropic glutamate receptor. Thus, our data are consistent with the hypothesis that the physiological effects oftrans‐ACPD in area CA1 of the hippocampus are mediated by metabotropic glutamate receptors that are distinct from the AP3‐sensitive phosphoinositide hydrolysis

ISSN:0887-4476    

DOI:10.1002/syn.890120305

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

年代:1992

数据来源: WILEY

摘要:

AbstractIn vivo electrophysiological recording techniques were employed to examine responses of ventral pallidum/substantia innominata (VP/SI) neurons to systemic and local administration of morphine. Using a cumulative dosing protocol, intravenous administration (0.1–30 mg/kg i. v.) produced a suppression of firing in 82% of neurons tested. The suppression was dose‐related and blocked by the opioid antagonist, naloxone. In contrast, microiontophoretic applications of morphine resulted in current‐related suppression (32% of neurons tested) or excitation (26%). Concurrent application of naloxone attenuated or blocked both effects of local morphine applicatio. It was demonstrated that acute tolerance did not develop with repeated morphine exposures following either systemic or local administration. The present findings establish the sensitivity of VP/SI neurons to morphine and provide functional relevance at the level of a single neuron for opioid peptides and their receptors in this region. As reported for most other opioid receptive brain areas, neuronal rate suppression was the predominate response observed, and it is proposed that excitations to iontophoresed morphine reflect a disinhibitory phenomenon. The differntial morphine‐induced rate changes, and number of responding neurons, observed with systemic vs. iontophoretic morphine administration suggest that extra‐VP/SI regions that also are opioid sensitive can subsequently direct neuronal responsivensess to opioids within the VP/SI. © 1992 Wiley

ISSN:0887-4476    

DOI:10.1002/syn.890120306

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

年代:1992

数据来源: WILEY

摘要:

AbstractRecent studies have suggested that cocaethylene, an active metabolite of cocaine found in blood and postmortem brain of individuals self‐administering 2 drugs. We have used positron emission tomography (PET) and carbon‐11 (t1/2: 20.4 min) labeled cocaine and cocaethylene to compare the short‐term kinetics of cocaine and cocaethylene in baboon brain. The regional uptake of [11C]cocaine ([11C]COC) and [11C]cocaethylene ([11C]CE), 5–8 mCi and 4–6 m̈g, in baboon brain (n = 7) were similar but clearance from whole brain (global, GL) and from striatum (SR), thalamus (TH), and cerebellum (CB) was slower for cocaethylene. Steady‐state distribution volumes (DV) were not significantly different in the striatum but were greater for cocaethylene in the thalamus, cerebellum, and whole brain. Debenzoylation of cocaethylene proceeded at about one‐third the rate of cocaine, as determined by in vitro incubation of labeled cocaethylene and labeled cocaine with baboon plasma and with purified horse butyryl‐cholinesterase (EC 3. 1. 1. 8). Even though the slower clearance of cocaethylene could lead to longer tissue exposures and potentially accentuated or different physiological effects relative to cocaine, the difference between the 2 drugs is not large. Thus it is more likely that the direct actions of cocaine and alcohol on some organs, rather than cocaethylene, account for this enhanced toxicity. © 199

ISSN:0887-4476    

DOI:10.1002/syn.890120307

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

年代:1992

数据来源: WILEY

摘要:

AbstractThere is increasing evidence that the combined use of cocaine and alcohokl produces enhanced behaviroal and toxic effects. We have used PET and tracer doses of [11C]cocaine in 7 normal human volunteers to assess if the dostribution and clearance of cocaine are altered by alcohlol intoxication. Each subject received 2 PET studies with [11C]cocaine (3–11 m̈g), one before and one during alcohol intoxication (1 g/kg). Regions of interest included dthe brain (n= 3) and heart (n = 4). arterial plasma was assayed for unchanged cocaine and for labelaed cocaethylene, a metabolite of cocaine found in individuals usig cocaine and alcohol in combination (hearn et al., 1991a). Alcohol intoxication did not change uptake and clearance or the steady‐state distribution volume of [11C]cocaine in brain (striatum, thalamus, and cerebellum) or in heart. Moreover, labeled cocaethylene was not detedted in the 10 minute plasma sample. These results suggest that the acute dnhancement of behavior and toxicity associated with the combined use of cocaine and alcohol is not due to an alteration in cocaine's organ distribution or to cocaethylene formation but may be related to an additive effect resulting from the direct actaons of each of these drugs. Published 1992 Wiley‐Lis

ISSN:0887-4476    

DOI:10.1002/syn.890120308

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

年代:1992

数据来源: WILEY

摘要:

AbstractIodobenzamide (IMB) labeled with either [11C] or [125I] was studied in mice and baboons. Pharmacological studies demonstrated an in vivo binding profile compatible with D2dopamine receptors. Mouse biodistribution studies with both [11C]IMB and [125I]IMB showed a similar brain distribution of radioactivity. Mouse [125I]IMB studies with amphetamine and reserpine pretreatment suggested that IMB may be less susceptible to endogenous dopamine competition for D2receptor binding in vivo as compared to raclopride. Preliminary baboon studies showed haloperidol competition for IMB binding sites. © 1992 Wiley‐Liss, I

ISSN:0887-4476    

DOI:10.1002/syn.890120309

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

年代:1992

数据来源: WILEY

摘要:

AbstractWe studied levels of neurofilament (NF) proteins in the ventral tegmental area (VTA), and other regions of the central nervous system, of two genetically inbred rat strains, Lewis (LEW) and Fischer (F344) rats. These strains represent genetically divergent populations of rats that have been used to study possible genetic factors involved in a variety of biological processes, including drug addiction: compared to F344 rats, LEW rats show a much higher preference for several classes of drugs of abuse. We found 30–50% lower levels of three NF proteins, NF‐200 (NF‐H), NF‐160 (NF‐M), and NF‐68 (NF‐L), in the VTA of LEW compared to F344 rats by use of immunolabeling and Coomassie blue staining. These strain differences were highly specific to this brain region, with no differences observed elsewhere in brain or spinal cord. Interestingly, chronic treatment of F344 rats with morphine decreased levels of these three NF proteins in the VTA, as found previously in outbred Sprague‐Dawley rats (Beitner‐Johnson, D., Guitart, X., and Nestler, E. J.: J. Neurosci., 12:2165–2176,1992), whereas morphine had no effect on NF levels in the VTA of LEW rats. A similar strain difference was observed in chronic morphine regulation of tyrosine hydroxylase, with morphine increasing enzyme immunoreactivity in the VTA of F344 rats (as has been observed previously in Sprague‐Dawley rats [Beitner‐Johnson, D., and Nestler, E. J.: J. Neurochem., 57:344–347, 1991]), but not in LEW rats. In view of the observations that LEW and F344 rats show different levels of preference for several types of drugs of abuse, and of the evidence supporting a central role of the mesolimbic dopamine system in drug reward mechanisms, the results of the current study suggest the possibility that levels of NFs and tyrosine hydroxylase may mediate some aspects of drug reinforcement and contribute to individual genetic differences in vulnerability to drug addictio

ISSN:0887-4476    

DOI:10.1002/syn.890120310

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.890120301

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

年代:1992

数据来源: WILEY