摘要:

AbstractParoxetine, a selective inhibitor of serotonin uptake and an antidepressant, was used in conjunction with quantitative ex vivo autoradiography to study the feasibility of imaging serotonin terminals in the living brain. Tritiated paroxetine was injected in the rat tail vein, and the brain was processed for quantitative autoradiography 3 hours later. Animals received either [3H]paroxetine alone (100 μCi/animal) or a mixture of labeled paroxetine (100 μCi) and an excess of unlabeled drug (0.5 or 2 mg/kg intravenously [i.v.]). Computerized image analysis of the resulting autoradiograms revealed high densities of radioactivity in brain regions known to contain high densities of serotonergic terminals and high specific binding of [3H]paroxetine in vitro, such as the raphe nuclei, interpeduncular nucleus, basolateral amygdala, substantia nigra, and some hypothalamic nuclei. Radioactivity uptake in these brain regions was effectively blocked (50‐72%) by coadministration of excess unlabeled paroxetine. However, cortical and hippocampal binding of paroxetine in vivo was moderately high, in contrast to the relatively sparse serotonergic innervation in these regions. Only a relatively small proportion of cortical and hippocampal binding (20‐40%) could be blocked by excess unlabeled paroxetine, indicating that most of the radioactivity in these regions is not associated with serotonin terminals or uptake sites. The usefulness of [3H]paroxetine as an in vivo ligand for imaging serotonin terminals in the human brain is limited by these nonserotonergic binding sites. © 1993 Wiley‐L

ISSN:0887-4476    

DOI:10.1002/syn.890130102

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe effects of trifluoperazine (TFP), a phenothiazine antipsychotic, on hippocampal activity were studied in the CA1 subfield, both in situ and in slices. In the extracellular studies in situ and in vitro, both somatic population spikes and dendritic excitatory postsynaptic potentials (EPSP) fields were depressed reversibly by TFP, applied by microiontophoresis or in the bath (50‐100 μM). Similar effects were also seen during iontophoretic applications of sphingosine in situ. Like TFP (at micromolar concentrations) sphingosine is a dual Ca2+/calmodulin‐dependent kinase and protein kinase C (PKC) inhibitor. In intracellular recordings from slices, 50‐100 μM TFP induced a slow depolarization and a decrease in input resistance (RN), probably through a β‐aminobutyric acid (GABA)‐mediated increase in Cl−conductance (GCl). TFP also reduced the slow afterhyperpolarization (AHP) as well as electrically evoked inhibitory postsynaptic potentials (IPSPs), but EPSPs were augmented in both amplitude and duration. When CA1 neurons were voltage clamped, TFP elicited a corresponding inward current (consistent with depolarization), increased the leak conductance, and enhanced excitatory synaptic currents; whereas inhibitory synaptic currents and high‐threshold Ca2+currents were reduced. In conclusion, these effects of TFP–which cannot be readily explained by its potent antidopamine action–are in keeping with other evidence that both Ca2+/calmodulin‐dependent kinase and PKC can modulate GCl‐conductance and high‐threshold Ca2+‐conductance, as well as inhibitory and excitatory postsynaptic curr

ISSN:0887-4476    

DOI:10.1002/syn.890130103

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe effect of chronic cocaine administration on the in vivo occupation of dopamine (DA) receptor subtypes was examined using the irreversible receptor blocker N‐ethoxycarbonyl‐2‐ethoxy‐1, 2‐dihydroquinoline (EEDQ). Rats were given continuous infusions of cocaine (vehicle, 2.5, 7.5, or 22.5 mg/day) via subcutaneous implants of Alzet osmotic minipumps for 14 days. Some groups were also given the D1 antagonist SCH 23390 and/or the D2 antagonist raclopride for this same time period. DA receptor binding techniques were used 24 hours post‐EEDQ injection (Day 15, 5 mg/kg, intraperitoneally [ip]) in order to examine changes in D1 and D2 receptor densities in the striatum. Half of the rats were killed in the day with the other half killed at night in order to examine day/night differences in the effects of cocaine treatment. Results showed that chronic cocaine increased the protection of D1 receptors from EEDQ inactivation in a dosedependent fashion during the day, and decreased D1 protection from EEDQ at night. Since EEDQ has a low affinity for the DA receptor relative to endogenous DA or the exogenous ligands in this study, only receptors that are vacant are inactivated thereby allowing for an estimate of DA receptor occupation in vivo. Cocaine can therefore be said to increase D1 receptor occupation by DA in vivo during the day and decrease it at night. Coadministration of the DA antagonists eliminated this cocaine‐induced day/night difference and, in the case of the D1 antagonist, produced opposite D1 receptor effects when administered alone. Chronic SCH 23390 treatment protected D1 receptors from EEDQ denaturation while D2 receptors were protected by chronic raclopride. In addition, raclopride was found to affect the affinity of both the D1 and the D2 receptors to the [3H]SCH 23390 and [3H] spiperone ligands, respectively. Since no day/night differences were found in D2 receptor density with respect to chronic cocaine treatment these findings have implications for a phasic D1/tonic D2 receptor hypothesis such that cocaine treatment selectively alters the level of DA at sites containing D1 receptors with differential effects depending on the day/night cycle. © 1993 W

ISSN:0887-4476    

DOI:10.1002/syn.890130104

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

年代:1993

数据来源: WILEY

摘要:

AbstractRecent in vitro radioligand binding studies have shown that several cytochrome P‐450 inhibitors can displace [3H] sigma ligands, suggesting that these ligands might bind to the cytochrome P‐450 superfamily of enzymes. Using an in vivo electrophysiological model of extracellular recordings performed in the CA3region of the rat dorsal hippocampus, we have previously shown that intravenous administration of low doses of several sigma ligands, such as 1, 3‐di(2‐tolyl) guanidine (DTG), JO‐1784, and (+)pentazocine potentiate the neuronal response induced by microiontophoretic applications ofN‐methyl‐D‐aspartate (NMDA) without affecting those induced by quisqualate and kainate, suggesting that they act as sigma agonists. Conversely, the sigma ligands haloperidol, (+)3‐PPP, and BMY‐14802, which have no effect by themselves on the NMDA response, prevent and suppress the potentiating effect of sigma agonists on the NMDA response, suggesting that they act as sigma antagonists. The present studies were undertaken to determine if cytochromes P‐450 could be involved in the modulation of the NMDA response by sigma ligands. For this purpose, two cytochrome P‐450 inhibitors, proadifen (SKF‐525A) and piperonyl butoxide (PB), have been tested in our model.Unlike sigma agonists, at low doses, neither SKF‐525A nor PB affected the NMDA response of CA3dorsal hippocampus pyramidal neurons. Unlike sigma antagonists, neither of these drugs reversed or prevented the DTG‐induced potentiation of the NMDA response. In addition, following high doses of SKF‐525A or PB, sufficient to induce a complete inactivation of cytochromes P‐450, DTG still potentiated the NMDA response.The present data suggest that cytochrome P‐450 inhibitors do not modulate the NMDA response like sigma agonists or antagonists do in this brain region. Furthermore, they rule out the involvement of cytochromes P‐450 in the modulation of the NMDA response by

ISSN:0887-4476    

DOI:10.1002/syn.890130105

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

年代:1993

数据来源: WILEY

摘要:

AbstractIntracellular injections of Lucifer Yellow were utilized to evaluate the incidence of dye‐coupling among dorsolateral septal nucleus (DLSN) neurons recorded from slice preparations of adult rat septal nuclei. Twenty percent of single injections of Lucifer Yellow resulted in pairs of labeled neurons. These dye‐coupled cells were morphologically heterogeneous and did not exhibit any morphological characteristics that could be used to distinguish them from non dye‐coupled neurons. The spatial separation of cell bodies and close apposition of dendrites within each pair indicated that the dye transfer site(s) were situated at dendrodendritic and/or dendrosomatic rather than somatosomatic junctions. The main axon of some dye‐coupled neurons gave rise to intrinsic axon collaterals prior to exiting the nucleus indicating that these coupled neurons function as projection neurons as well as local circuit interneurons.Electrophysiological recordings of the passive membrane properties and spontaneous activity of individual dye‐coupled neurons revealed no significant difference from non dye‐coupled cells in the DLSN. Some neurons exhibited spontaneously occurring fast potentials which presumably represent electrotonic potentials. These fast potentials were often tightly coupled with action potentials but could be distinguished from synaptic potentials by their shape and their lack of voltage‐dependent changes in amplitude.These morphological and supportive electrophysiological data provide the first indirect evidence for electrotonic coupling of dorsolateral septal neurons. The functional significance of this coupling may lie in the potential for synchronization of the output of the DLSN which could play an important role in the septal maintenance and modulation of hippocampal Theta rhythm. © 1993 W

ISSN:0887-4476    

DOI:10.1002/syn.890130106

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe effects of differential rearing on synaptic morphology and neuronal size were examined in the medial amygdaloid nucleus (MAN) of adult rats. Forty‐day‐old male rats were housed in one of three ways: individually (isolated condition, IC); with four males per cage (unisexual condition, UC); or with two males and two females per cage (social condition, SC). After 2 months, the animals were prepared for electron and light microscopy Although there was no statistically significant difference in number of synapses per unit volume in MAN, the number of perforated (P) synapses, which are characterized by discontinuities in the postsynaptic density, were significantly greater in the UC and the SC than in the IC. The length of synaptic contact zone of P synapses was also longer in both the UC and the SC compared with the IC, whereas the length of nonperforated synapses was longer only in the SC. Some area was also larger in the SC compared with the IC. These results demonstrate that exposure to different rearing conditions, in which the pheromonal environment can be substantially different, can induce striking morphological changes in both synapses and neurons in the MAN of adult rats. © 1993 Wiley‐Lis

ISSN:0887-4476    

DOI:10.1002/syn.890130107

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

年代:1993

数据来源: WILEY

摘要:

AbstractThe efficacy of decamethonium as an agonist at the nicotinic acetylcholine receptor has never been determined. Here, we demonstrate how patch clamp recording during rapid perfusion of agonists to outside‐out patches from BC3H‐1 cells can be used to provide an unambiguous estimate of the efficacy of decamethonium. First, we obtain the decamethonium concentration‐response relationship between 10 and 1,000 μM decamethonium. The maximum channel open probability is small (<0.02) and occurs at about 100 μM. This suggests two alternative explanations: decamethonium is a poor agonist or decamethonium is an efficacious agonist but a potent channel blocker. To distinguish between these alternatives, we perfuse mixtures of decamethonium and acetylcholine to generate acetylcholine concentration‐response curves in the presence of 30, 100, and 1,000 μM decamethonium. We use a model for activation and block of the acetylcholine receptor by both agonists to fit these data and determine the binding affinity, efficacy, and blocking affinity of decamethonium. We conclude that the efficacy of decamethonium is low 0.016. Decamethonium is a true partial agonist. © 1993 Wile

ISSN:0887-4476    

DOI:10.1002/syn.890130108

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

年代:1993

数据来源: WILEY

摘要:

AbstractIntracranial self‐stimulation (ICS) is thought to activate neuronal systems involved in processing natural reinforcing agents. Metabolic mapping studies have previously demonstrated a subset of CNS structures specifically engaged by ICS in animals receiving stimulation actively vs. passively. Since opiates are known to enhance JCS behavior and presumably its reinforcing properties, the current study addressed the question of the role of opioid peptides as mediators of ICS. Rats were trained on a fixed ration (FR) 20 schedule of responding maintained by ICS. Following response stabilization, rats were assigned either to an active or a corresponding yoked stimulation group at 1 of 2 schedules of reinforcement (i. e., FR1‐YFR1, FR20‐YFR20, or sedentary control), and opioid peptide release was inferred from in vivo receptor occupancy. Autoradiographic analyses identified 3 groups of structures. Treatment‐induced alterations in occupancy were seen in the medial dorsal nucleus of the thalamus, basolateral amygdala, ventral pallidum, medial habenula, dorsal raphe, posterior hypothalamus, substantia nigra pars compacta, agranular preinsular cortex, and zona incerta. Depending upon the structure, peptide release was dependent upon stimulus contingency (active vs. yoked) and/or schedule (FR1 vs. FR20). Evidence for ICS‐induced inhibition of peptide release was found in the habenula and preinsular cortex. Nine additional structures, all components of, or receiving projections from, the limbic system, revealed complex interactions between ICS treatment and the electrode side. Finally, a widespread ipsilateral increase in receptor binding was seen rostrally from the cingulate, olfactory tubercle, and nucleus accumbens, along the lateral hypothalamus and hippocampus, and extending caudally to the substantia nigra and ventral tegmentum. These later effects appear to be related to stimulation‐induced changes in blood flow and subsequent ligant presentation increases. Collectively, these data point towards the ability of rewarding brain stimulation to activate discrete neuronal opioid systems contingent upon specific behavioral as well as stimulus conditions. © 1993 Wil

ISSN:0887-4476    

DOI:10.1002/syn.890130109

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

年代:1993

数据来源: WILEY

摘要:

AbstractGABAAreceptors in plasma membranes of neurons are integral oligomers which form chloride channels. The binding of GABA molecules at recognition sites for channel opening triggers a transient increase in transmembrane chloride ion flux. The multiplicity and drug specificity of GABAAreceptor, kinetics of channel opening, and desensitization of GABAAreceptor and its short‐ and long‐term regulation have been investigated by the use of tracer amounts of the radioactive chloride isotope,36Cl−ion. Results and new insights from36Cl−ion flux measurements have been reviewed. © 1993 Wiley

ISSN:0887-4476    

DOI:10.1002/syn.890130110

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.890130111

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

年代:1993

数据来源: WILEY