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E Sanders-Bush

Publications and source records attributed to E Sanders-Bush.

At least 91 records · Page 5Linked to original sources
PubMed1985

Serotonin-stimulated phosphoinositide turnover: mediation by the S2 binding site in rat cerebral cortex but not in subcortical regions.

In rat cerebral cortex, serotonin (5-HT) stimulates phosphoinositide turnover with an EC50 of 1 microM in the presence of pargyline. The EC50 is 16-fold higher in the absence of pargyline. Selective S2 antagonists inhibit 5-HT-stimulated phosphoinositide turnover. Schild analysis of the blockade by ketanserin of the 5-HT effect gives an estimated Kd of ketanserin for the phosphoinositide-linked receptor of 11.7 nM, which agrees with the Kd (3.5 nM) of [3H]ketanserin for the S2 site. Furthermore, MK-212, 5-HT and 5-fluorotryptamine stimulate phosphoinositide turnover with potencies that resemble their potencies at the S2 but not the S1 binding site. Of 11 agonists tested, the tryptamine derivatives tend to be more efficacious than the piperazine derivatives. The selective S1 agonist 8-hydroxy-2-(di-N-propylamino)tetralin is inactive at stimulating phosphoinositide turnover. No significant relationship exists between the regional distributions of 5-HT-stimulated phosphoinositide turnover and S2 binding sites. Furthermore, the S2 antagonist ketanserin is less potent and less efficacious in hippocampus and limbic forebrain than in cerebral cortex. These data suggest that 5-HT-stimulated phosphoinositide turnover is linked to the S2 binding site in rat cerebral cortex. However, 5-HT increases phosphoinositide turnover in subcortical regions by mechanisms other than stimulation of the S2 receptor.

Animals↗
PubMed1984

Clozapine blocks disruptive and discriminative stimulus effects of quipazine.

Clozapine was tested in two serotonin-dependent behavioral measures. One group of rats was trained to discriminate the serotonin agonist, quipazine, from saline in a two-lever operant choice task. Pretreatment with clozapine completely blocked the discrimination of quipazine. Another group of rats was trained to bar press for milk on a variable interval schedule of reinforcement. Quipazine decreased the response rate in these animals and pretreatment with clozapine completely reversed this effect. Thus, clozapine acted as a serotonin antagonist in both measures of serotonin function.

Animals↗
PubMed1984

Selective 5HT-2 antagonists inhibit serotonin stimulated phosphatidylinositol metabolism in cerebral cortex.

Evidence suggests that the serotonin 5HT-1 receptor site is functionally linked to adenylate cyclase in the brain, but a biochemical effector system which is linked to the serotonin 5HT-2 receptor site has not been found. In the present paper we report an investigation of 5HT stimulated phosphatidylinositol (PI) hydrolysis in rat cerebral cortex and have found that selective 5HT-2 antagonists (pizotifen and ketanserin) block 5HT's effect upon PI metabolism. These data suggest that 5HT stimulated PI hydrolysis is mediated by the 5HT-2 binding site.

Animals↗
PubMed1984

Discriminative stimulus properties of quipazine: mediation by serotonin2 binding sites.

The relative abilities of putative serotonin (5-HT) antagonists to block the quipazine discriminative cue were compared with their relative potencies to compete for the 5-HT1 and 5-HT2 binding sites in the brain. Male Sprague-Dawley rats were trained to discriminate 2.5 mg/kg of quipazine from saline. Once training was complete, antagonists were administered 90 min before a 5-min test with 1 mg/kg of quipazine, a dose which gave 75% responding on the quipazine lever. A dose-response curve was generated for each antagonist and an ID50 value (dose that inhibits responding to 50% on the quipazine lever) was determined by log-logit analysis. The binding of [3H]-5-HT to the 5-HT1 site and of [3H]spiperone to the 5-HT2 site was determined in crude membranes prepared from frontal cortex ( [3H]spiperone) or pons-medulla ( [3H]-5-HT) of naive rats. IC50 values for the antagonists were determined by log-logit analyses of competition binding curves. The ID50 values for the blockade of the quipazine discrimination by the 5-HT antagonists correlated significantly with their affinities for the 5-HT2 binding site (r = 0.87). In contrast, no correlation existed between effects on the behavioral measure and affinities for the 5-HT1 site (r = 0.15). These results suggest that the quipazine cue is mediated by an action at central 5-HT2 sites.

Animals↗
PubMed1983

Additional evidence that L-5-hydroxytryptophan discrimination models a unique serotonin receptor.

The purpose of the present studies was to investigate further the role of central serotonin (5-HT) in mediating the L-5-hydroxytryptophan (L-5-HTP) discriminative cue. Rats were trained to discriminate the stimulus properties of 35 mg/kg L-5-HTP combined with RO 4-4602, a peripheral decarboxylase inhibitor. Considering that several 5-HT antagonists were unable to block the L-5-HTP discriminative cue in our earlier studies, we extended these studies to include the two other presumed 5-HT antagonists mianserin and BC-105 (pizotyline). Only BC-105 completely blocked the training dose of L-5-HTP. Furthermore, the blockade of the L-5-HTP cue was both graded and surmountable by increasing the dose of L-5-HTP, suggesting a competitive antagonism. In neurochemical studies, the regional brain levels of 5-HT, norepinephrine and dopamine were determined after the injection of the training dose of L-5-HTP. Marked changes in the levels of 5-HT were found, while the levels of the catecholamines were changed only slightly or not at all. Furthermore, dose-response studies of L-5-HTP demonstrated an orderly dose-related increase in the levels of 5-HT in brain and in the percent responding on the L-5-HTP lever, while no such relationship was found for brain catecholamines. These results agree with previous pharmacological studies and suggest that the L-5-HTP discrimination is mediated by a central 5-HT receptor that has pharmacological properties distinct from those receptors identified in previous behavioral models of 5-HT receptor stimulation.

5-Hydroxytryptophan↗
PubMed1983

Acute and chronic effects of serotonin (5HT) antagonists on serotonin binding sites.

The administration of 14 daily doses of cyproheptadine, BC-105, metergoline and methysergide induced a marked decrease in the number (Bmax) of 3H-spiroperidol binding sites (5HT2 sites) in frontal cortex, when assayed 48 h after the last dose; the apparent affinity (KD) of 3H-spiroperidol was not changed. The same treatment schedules failed to modify the KD and Bmax values for 3H-5HT binding to the 5HT1 site in the hippocampus. Cyproheptadine, BC-105 and methysergide, but not metergoline, decreased the density of 5HT2 sites in frontal cortex 48 h after a single dose. Additional studies of the decrease in 3H-spiroperidol binding after in vivo treatment with cyproheptadine showed that the extent of binding loss was unaltered by repeated washing. Furthermore, cyproheptadine added in vitro to membranes isolated from frontal cortex inhibited the binding of 3H-spiroperidol in a competitive manner; Scatchard plots were linear with the same maximum binding (Bmax) and different slopes. Therefore, these preliminary studies suggest that the loss of 5HT2 binding sites after in vivo treatment with cyproheptadine and with other 5HT antagonists may reflect an adaptive response. This apparent paradoxical effect suggests that the action of these drugs at the 5HT2 binding sites should be reevaluated.

Animals↗
PubMed1982

Discriminative stimulus properties of L-5-hydroxytryptophan: behavioral evidence for multiple serotonin receptors.

Rats were trained to discriminate the stimulus properties of L-5-hydroxytryptophan (L-5-HTP) (30 mg/kg SC), the immediate precursor of serotonin (5-HT). The peripheral decarboxylase inhibitor R04-4602, administered prior to L-5-HTP, greatly attenuated the disruptive effects observed on responding when L-5-HTP alone was injected. Following acquisition, the discrimination was dose-dependent and generalized to fenfluramine, a 5-HT-releasing drug, but not to amphetamine, a catecholamine-releasing agent. Further evidence for the involvement of 5-HT receptor stimulation in mediating the discrimination was that pretreatment with fluoxetine, a highly specific 5-HT uptake inhibitor, markedly potentiated the cue. Nevertheless, the classical 5-HT antagonists methysergide, cyproheptadine, metergoline, and methiothepin did not block the L-5-HTP-related discriminative stimulus. This finding suggested that the cue properties of L-5-HTP might be mediated by a population of 5-HT receptors previously identified electrophysiologically in limbic structures. As in the present experiment, the putative 5-HT antagonists did not block the synaptic effects of 5-HT in these structures.

5-Hydroxytryptophan↗
PubMed1982

Comparison of the pharmacological characteristics of 5 HT1 and 5 HT2 binding sites with those of serotonin autoreceptors which modulate serotonin release.

The abilities of various 5-hydroxytryptamine (5 HT) receptor agonists to inhibit the K+-evoked release of 3H-5 HT from prelabelled synaptosomal preparations of rat hypothalamus were studied. In addition, the abilities of various 5 HT receptor agonists and antagonists to compete with 3H-5 HT and 3H-spiperone binding to 5 HT1 and 5 HT2 sites, respectively, were determined. The orders of potency of the agonists for inhibiting K+-evoked 3H-5 HT release and for inhibiting 3H-5 HT and 3H-spiperone binding were then compared. Likewise, the abilities of the antagonists to block the inhibitory effect of 5 HT on its own K+-evoked release (data from previous studies) were compared to the affinities of these compounds for the 3H-5 HT and 3H-spiperone binding sites. A significant correlation was obtained between the effects of the agonists on K+-evoked 3H-5 HT release and 3H-5 HT binding but not 3H-spiperone binding. Furthermore, the antagonists which have been demonstrated to block the inhibitory effect of 5 HT on its own release (methiothepin, methysergide, metergoline and quipazine) had higher affinities for the 3H-5 HT binding site than the other antagonists. A similar correlation could not be made between antagonist activity at the 5 HT autoreceptor and affinity for the 3H-spiperone binding site. These results demonstrate that the 5 HT autoreceptor and the 5 HT1 binding site have similar pharmacological characteristics. On this basis, it is suggested that 5 HT autoreceptor and the 5 HT1 binding site may be related 5 HT receptor sites.

Animals↗
PubMed1982

The serotonin autoreceptor: antagonism by quipazine.

The purpose of this study was to attempt to reproduce previous findings regarding the antagonist specificity of the 5HT autoreceptor and to find additional antagonists of this receptor. Crude synaptosomal preparations of the rat hypothalamus were loaded with [3H]5HT, placed on glass microfiber filters and superfused with modified Krebs--Henseleit buffer at 37 degrees C. The release of [3H]5HT was stimulated by raising the buffer K+ concentration and was Ca2+-dependent. In the presence of 100 nM fluoxetine (a selective 5HT uptake inhibitor), exogenous 5HT inhibited the K+-induced release of [3H]5HT but did not affected basal [3H]5HT release. The K+-induced [3H]5HT release was maximally inhibited by 30 nM 5HT to a level of 66.4 +/- 4.0% of control. The concentration of 5HT required to inhibit half-maximally K+-induced [3H]5HT release was approx. 7 nM. Methiothepin and quipazine were found to block the inhibition of K+-induced [3H]5HT release by exogenous 5HT (30 nM). The IC50S for blockade of the effects of 5HT were approx. 3.8 and 670 nM for methiothepin and quipazine, respectively. Several other putative 5HT antagonists, the dopamine receptor antagonist, spiperone and the alpha receptor antagonist, phentolamine, were without effect. Thus, the 5HT autoreceptor appears to have a unique specificity for certain 5HT antagonists. In addition, blockade of 5HT autoreceptors may be one mechanism by which quipazine produces behavioral effects characteristic of a 5HT receptor agonist.

Animals↗
PubMed1982

Serotonin receptor sensitivity after acute and chronic treatment with mianserin.

The chronic administration of mianserin for 14 days leads to a marked decrease in the maximal number of serotonin2 (5-HT2) binding sites in brains of rats and mice with no change in the KD values. The decrease in [3H]spiroperidol binding to the 5-HT2 site in rats was most pronounced in the frontal cortex with only minor changes in hippocampus and pons-medulla. The 5-HT1 site was largely unaffected. The decrease in the Bmax for 5-HT2 site also occurred after a single dose of mianserin, although mianserin was more potent when given chronically. Maximal inhibition of binding occurred with a chronic dose of 0.5 mg/kg. The greatest decrease was found 48 hr after single or repeated doses with a gradual return to normal levels within 10 days. The administration of mianserin also leads to a decrease in 5-methoxy-N,N-dimethyltryptamine-induced head twitches in mice assayed 48 and 96 hr after a single or repeated doses, which is presumably correlated with the decrease in the 5-HT2 binding site assayed in vitro.

Animals↗
PubMed1981

Multiple serotonin receptors: regional distribution and effect of Raphe lesions.

These studies confirm and extend the recent work suggesting that [3H]lysergic acid diethylamide (LSD) labels two distinct binding sites in rat brain resembling serotonin (5HT) receptors. Although Scatchard analyses of [3H]LSD binding to membranes prepared from cortex/hippocampus were linear, the heterogeneity of the [3H]LSD binding sites was clearly demonstrated in displacement studies. The displacement curves for both 5HT and spiperone were bisigmoidal with the concentration required to saturate the high affinity components nearly 3 orders of magnitude lower than the concentration necessary to saturate the low affinity components. Additivity studies suggested that the sites with high affinity for 5HT and spiperone are different, independent sites. These sites are referred to as 5HT, and 5HT2, respectively. Regional analyses showed, that in the frontal cortex, the density of the 5HT2 site was slightly greater than the 5HT1 site, whereas the 5HT1 site was predominant in all other brain areas, including the spinal cord. The pharmacological properties of the two sites have features in common with 5HT receptors; however, electrolytic lesions of the midbrain raphe nuclei did not change the densities or binding constants of the two apparent 5HT receptor subtypes, even though the number of high affinity 5HT uptake sites was markedly reduced.

Animals↗
PubMed1980

Long-term effects of continuous exposure to amphetamine on brain dopamine concentration and synaptosomal uptake in mice.

Continuous release of p-chloroamphetamine from subcutaneously implanted minipumps for 3 days decreased brain 5-hydroxytryptamine, but not norepinephrine or dopamine, when analyzed 2 weeks later. In contrast, 2 weeks after infusion of amphetamine, whole brain dopamine but not 5-hydroxytryptamine or norepinephrine, was decreased. Also, the high affinity uptake of [3H] dopamine was markedly and selectively reduced in striatal synaptosomes. Thus, neurotoxicity is apparently not unique to halogenated amphetamine derivatives, but is produced by amphetamine itself if administered continuously.

Amphetamine↗