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T A Reader

Publications and source records attributed to T A Reader.

At least 55 records · Page 3Linked to original sources
PubMed1997

Alterations in the turnover rate of dopamine D1 but not D2 receptors in the adult rat neostriatum after a neonatal dopamine denervation.

Adult rats that were treated with intracerebral ventricular injection of 6-hydroxydopamine (6-OHDA) as neonates exhibit a profound loss of nigrostriatal dopamine innervation in addition to a variety of other neurochemical and anatomical changes, including alterations in the number of neostriatal D1 and D2 receptor binding sites. In the present study, the turnover of neostriatal dopamine D1 and D2 receptors was measured in rats previously treated with 6-OHDA or ascorbic acid vehicle as neonates at various time intervals after peripheral N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ, 10 mg/kg) administration. Dopamine receptors were labelled with [3H]SCH23390 (D1) and [3H]raclopride (D2), while the degree of dopamine denervation was assessed by the measurement of neostriatal dopamine, homovanillic acid and dihydroxyphenylacetic acid content. Two days after acute EEDQ treatment, the maximal binding capacity (Bmax) of [3H]SCH23390 and [3H]raclopride binding was significantly decreased to 58 and 32% of control values, respectively, without any significant alteration in their equilibrium dissociation constants (Kd). A time-dependent increase in the density of [3H]SCH23390 and [3H]raclopride binding was observed in both treatment groups following a single dose of EEDQ. The rate of recovery of D1 receptors was significantly slower in the 6-OHDA-lesioned animals as compared to controls with a half-life of 103 compared to 53 h, respectively. No differences were observed in the rate of recovery of D2 receptors in these two treatment groups. These data are consistent with the findings of decreased expression of D1 receptors in neonatal 6-OHDA-lesioned rats owing to decreased receptor synthesis, and further suggest that in this model the up-regulation of D2 receptors is a result of a post-transcriptional mechanism, such as an increased rate of post-synthetic maturation.

Aging↗
PubMed1997

Effects of chronic neuroleptic treatments on dopamine D1 and D2 receptors: homogenate binding and autoradiographic studies.

The antipsychotic effects of neuroleptics are believed to be mediated via dopamine D2 receptor blockade; however, the anatomical and pharmacological targets of these drugs remain somewhat controversial. The purpose of this study was to examine the effects of chronic clozapine (CLZ) and haloperidol (HAL) treatments on the densities of DA D1 and D2 receptors. Adult male Sprague-Dawley rats (300-350 g) were treated for 21 days with either HAL (1 mg/kg/day, i.p.), CLZ (20 mg/kg/day, i.p.) or saline. Three days after ending the treatments, the brains were removed and used for biochemical assays of tissue DA and metabolites as well as for receptor studies. DA D1 and D2 receptors were labelled with [3H]SCH23390 and [3H]raclopride, respectively, and measured in the neostriatum by binding studies, and in autoradiograms of forebrain sections by quantitative densitometry. The autoradiographic measurements revealed significant increases in the densities of D2 receptors in nucleus accumbens, in the medio-ventral, latero-dorsal and latero-ventral quadrants of the rostral neostriatum, in caudal neostriatum and in globus pallidus of both HAL-(28-44%) and CLZ-treated (15-85%) animals. The HAL-induced up-regulation of D2 receptors in rostral and caudal neostriatum was homogenous, but CLZ produced a more uneven increase, with the highest absolute densities measured in latero-dorsal neostriatum, as well as with changes in the medio-dorsal rostral neostriatum. For D1 receptors, only CLZ and not HAL, produced significant increases in five regions, namely nucleus accumbens (43%) latero-dorsal rostral neostriatum (16%), caudal neostriatum (30%), globus pallidus (67%) and substantia nigra (12%). The observation that CLZ, contrary to HAL, also has an effect on D1 receptor densities may explain the greater therapeutic and selective efficacy with fewer side-effects of this agent, in comparison to other neuroleptics.

Animals↗
PubMed1997

The human 5-HT1A receptor: comparison of its binding properties in transfected cells and cortical tissue.

1. The binding characteristics of tritium labeled 8-hydroxy-dipropyl-aminotetralin, or [3H]8-OH-DPAT, to the serotonin1A (5-HT1A) receptor in the stably transfected HeLa cell clone HA6 and in human cortical tissue were examined and compared. 2. A series of kinetic studies of [3H]8-OH-DPAT binding to the transfected HA6 cell line demonstrated two components in both the association and the dissociation reactions. 3. In saturation experiments, at least two affinity states were unequivocally detected in the HA6 cell line and the human cortical tissue. Using isotopic dilutions, the binding isotherms were best fitted to a two-site model, and similar affinity values were obtained in both systems (KH approximately 1.1 nM and KL approximately 12-223 nM). 4. Most of the drugs used in competitions inhibited [3H]8-OH-DPAT binding, following a two-site model, and maintained their rank order of binding potency in both systems; that is, 5-HT > or = 8-OH-DPAT > buspirone > pindolol. Inconsistencies, however, were found for the antagonists NAN-190 and pindolol; only one inhibition constant was determined for HA6 cells, but two affinities were detected with cortical tissue. 5. The results indicate that, although data from binding studies using the cell expression system reflect, to a certain extent, those obtained with the cortical tissue, some discrepancies remained. 6. Finally, and in contrast with what is observed with the 5-HT1A receptor expressed in the HA6 cell line, it is possible that different receptors, or subtypes of one receptor, or even uptake sites normally expressed in cortical tissue, could interact with [3H]8-OH-DPAT or the competing drugs or both, thus leading to the observation of additional binding sites.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

Effects of a chronic lithium treatment on cortical serotonin uptake sites and 5-HT1A receptors.

The objectives of this study were to characterize the effects of a chronic lithium (Li+) treatment on serotonin (5-HT) uptake sites and on 5-HT1A receptors, and to determine the eventual reversibility of the treatment. The experiments were carried out with membranes from rat cerebral cortex using 8-hydroxy-2-(propylamino)tetralin, or [3H]8-OH-DPAT, and [3H]citalopram to label 5-HT1A receptors and 5-HT uptake sites, respectively. Endogenous levels of 5-HT and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured by high-performance liquid chromatography in the cingulate cortex. The saturation curves with [3H]8-OH-DPAT were always best fitted a two-site model. After a treatment with Li+ for 28 days, no alterations in the binding parameters of [3H]8-OH-DPAT to the high- and low-affinity binding sites could be documented. However, competition curves with 5-HT to inhibit [3H]8-OH-DPAT binding revealed a decreased proportion of sites with high affinity for the agonist, together with an increased density of sites with low affinity for 5-HT, suggesting an alteration in the coupling efficacy between 5-HT1A receptors and their transduction systems. Saturation studies with [3H]citalopram showed an increase (> 40%) in the density of 5-HT uptake sites after chronic Li+, suggesting a more efficient 5-HT uptake process for the treated animals, in accord with clinical observations. Although 5-HT contents in cingulate cortex remained unchanged after the treatment, 5-H[AA levels decreased (> 30%), leading to a diminished (almost 50%) 5-HT turnover; and also reflecting a more efficient uptake in the treated rats, so that less 5-HT could be degraded by extracellular monoamine oxidase. All the effects revealed by [3H]8-OH-DPAT and [3H]citalopram were reversed following a recovery period of two days without Li+. Since symptoms of bipolar affective disorders may reappear if the chronic Li+ treatment is interrupted, the reversibility of the observed effects further supports the importance of central 5-HT synaptic transmission in the pathophysiology and treatment of human affective disorders.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Dopamine receptor agonists regulate levels of the serotonin 5-HT2A receptor and its mRNA in a subpopulation of rat striatal neurons.

The effects of dopamine receptor agonists on the levels of the striatal serotonin 5-HT2A receptor and its mRNA were investigated in rats lesioned with 6-OHDA as neonates. The mRNA encoding for the 5-HT2A receptor was detected by in situ hybridization histochemistry and the binding of 5-HT2A receptors was revealed with [125I](2,5-dimethoxy-4-iodophenyl)2-aminopropane ([125I]DOI). In adult control unlesioned rats, labeling with the 5-HT2A cRNA probe and with [125I]DOI was concentrated in medial sectors of the striatum. In 6-OHDA-lesioned rats, labeling with the 5-HT2A cRNA probe or with [125I]DOI was increased in the striatum, particularly in its lateral subdivisions. These increases were abolished after chronic systemic administration of the dopamine receptor agonists apomorphine or SKF-38393. The mRNA levels encoding for the 5-HT2A receptor were further measured in individual striatal neurons after double-labeling of sections with a 5-HT2A and a preproenkephalin (PPE) cRNA probe. In control unlesioned rats, 5-HT2A mRNA labeling was distributed in PPE-labeled as well as in PPE-unlabeled striatal neurons. In 6-OHDA-lesioned rats, increased 5-HT2A mRNA labeling was found only in PPE-unlabeled neurons and it was abolished after apomorphine or SKF-38393 administration. These results demonstrate that agonists of dopamine receptors inhibit the expression of 5-HT2A receptors in a subpopulation of presumed striato-nigral neurons. We propose that this regulation plays an important role in the control of motor activity by dopamine and 5-HT in the basal ganglia.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1996

Changes in extracellular levels of dopamine metabolites in somatosensory cortex after peripheral denervation.

This study examined the effects of a nerve transection on monoamine release from primary somatosensory cortex. The technique of microdialysis was employed to sample extracellular levels of norepinephrine (NE), 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindole-3-acetic acid (5-HIAA) and homovanillic acid (HVA) in the barrel field of freely moving rats following the surgical transection of the contralateral infraorbital nerve. Microdialysates obtained 3, 4, and 5 days after deafferentation were analyzed using high-performance liquid chromatography with electrochemical detection. We found a significant increase in the release of the dopamine metabolites, DOPAC and HVA from the deafferented cortex. Three days after deafferentation the release of DOPAC was three-fold higher in the deafferented than in the control animals, and remained about 100% higher in the next two days in this group of animals. The release of HVA showed a gradual increase following the deafferentation procedure, since a 92% larger value on day 3 increased to a 338% difference on day 5. On the other hand, the release rate of NE and the levels of the serotonin metabolite 5-HIAA were not significantly affected by the deafferentation procedure. These results are discussed in the context of the possible participation of dopamine in the reorganization of the deafferented somatosensory cortex.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Alkylation of [3H]8-OH-DPAT binding sites in rat cerebral cortex and hippocampus.

The binding of tritiated 8-hydroxy-2-(di-n-propyl-amino)tetralin, or [3H]8-OH-DPAT, to membranes from rat cerebral cortex and hippocampus could be inhibited by serotonin (5-HT) and buspirone, and by the 5-HT antagonists propranolol, NAN-190, pindolol, pindobind-5-HT(1A), WAY1OO135, spiperone and ritanserin. All competition curves, except for ritanserin, best fitted a two-site model. In vitro treatment of the membranes with N-ethylmaleimide (NEM), to alkylate sulfhydryl groups, caused dose-dependent decreases of binding; the inhibition curves were biphasic, and the effects irreversible. Reduction of disulfide bonds with L-dithiothreitol (L-DTT) also decreased binding, but in a monophasic way; these effects were fully reversible in cortex, but only partially reversible in hippocampus. In the latter region, but not in cerebral cortex, previous occupancy by [(3)H]8-OH-DPAT partially protected binding from the effects of both L-DTT and NEM, suggesting that the thiol groups in the receptor recognition site(s) of this brain region are readily accessible. The binding characteristics were examined with the aid of saturation curves, carried out with increasing concentrations, up to 140 nM, of [(3)H]8-OH-DPAT. The saturation data were suggestive of a two-site receptor model incorporating a high-affinity site (K(H) of 0.3-0.5 nM) corresponding to the 5-HT(1A) receptor, and a low-affinity site (KL of ca 25 nM). After in vivo alkylations, carried out by treating rats with N-ethoxycarbonyl-2-ethoxy-1,2-dihydro-quinoline (EEDQ), the saturation curves from both control and EEDQ-treated rats were again best fitted to a two-site model. For EEDQ-treated animals, a drastic decrease of 5-HT(1A) receptor binding activity was noted; this loss was greater in hippocampus than in cerebral cortex. Since the decrease in 5-HT(1A) receptors was not associated with changes in low-affinity binding, the results suggest independent regulations of the two [(3)H]8-OH-DPAT binding proteins. Altogether, the present data further supports the notion that [(3)H]8-OH-DPAT, besides labelling 5-HT(1A) receptors, also binds to other structures in rat cerebral cortex and hippocampus.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Regional distribution of the 5-HT innervation in the brain of normal and lurcher mice as revealed by [3H]citalopram quantitative autoradiography.

The neurological cerebellar mutant lurcher is characterized by a primary degeneration of Purkinje cells as well as retrograde secondary partial degeneration of cerebellar granule cells and inferior olivary neurons. Since serotonin (5-HT) has been implicated in the modulation of excitatory amino acid systems of the cerebellum, the 5-HT innervation of the normal and lurcher mice was examined by quantifying uptake sites using [3H]citalopram autoradiography, and by biochemical assays of the indoles 5-HT, 5-hydroxy-L-tryptophan and 5-hydroxyindole-3-acetic acid using high-performance liquid chromatography. Comparable results were found between [3H]citalopram binding and 5-HT tissue concentrations in different brain regions. The highest [3H]citaslopram labelling was observed in defined structures of the mesencephalic and upper pontine regions, in limbic strutures, in hypothalamus and in discrete thalamic divisions, while the lowest labelling of uptake sites was documented in cerebellum and brainstem reticular formation. In lurcher mutants, the histology confirmed cell degeneration and the reduction in width, leading to 65%, 45% and 25% atrophies of total cerebellum, deep nuclei and inferior olivary nucleus, respectively. The [3H]citalopram labelling corrected for surface loss was 45% and 20% higher to cerebellar deep nuclei and red nucleus, respectively, but remained unchanged in the cerebellar cortex and inferior olivary nucleus. Moreover, higher labelling was found in nucleus raphe dorsalis, ventral tegmental area, inferior colliculus, locus coeruleus, pontine central grey and anterior thalamic nuclei, areas known to be part of cerebellar afferent and efferent systems. The present results indicate that in such pathological conditions as described for the lurcher mutant, the 5-HT system may modulate motor function not only at the level of the cerebellum, but also in other forebrain structures functionally related to the motor system.

Animals↗
PubMed1996

[3H]8-OH-DPAT binding and serotonin content in rat cerebral cortex after acute fluoxetine, desipramine, or pargyline.

Cortical serotonin1A (5-HT1A) receptors in the rat were studied following acute (24 hours) intraperitoneal administrations of the 5-HT uptake inhibitor fluoxetine (10 mg/kg), the antidepressant desipramine (20 mg/kg), or the monoamine oxidase (MAO) inhibitor pargyline (75 mg/kg). The 5-HT1A receptors were labelled in total cortex membrane homogenates with [3H]8-OH-DPAT, and the monoamines measured in cingulate cortex by high-performance liquid chromatography. As expected, after pargyline administration tissue concentrations of 5-HT, noradrenaline (NA) and dopamine (DA) were markedly increased due to MAO inhibition with a concomitant decrease of the metabolites 5-hydroxyindole-3-acetic acid and homovanillic acid. However, neither desipramine nor fluoxetine changed monoamine concentrations. Saturation binding with [3H]8-OH-DPAT revealed that, for the control animals (saline treated), the curves were best fitted to a 2-site model. Following drug administration, the saturation curves were still best fitted to a 2-site model, with no changes in affinities or bonding capacities. In competition experiments with 5-HT, buspirone, and pindolol, the curves were always best fitted to a 2-site model. Following fluoxetine administration, the inhibition curves revealed decreases in the affinity of the low-affinity site (KiL) for the agonist buspirone, and in the relative proportion of these sites. In addition, following pargyline, there was an increase in the affinity of the high-affinity site (KiH) for 5-HT but with a decrease of the relative proportion of high-affinity sites. The results confirm that [3H]8-OH-DPAT binding is to a 2-site model, and reveal an absence of downregulation of 5-HT1A receptors following increases in tissue 5-HT after MAO inhibition or antidepressant administrations. Moreover, the data may reflect an alteration of the coupling efficacy between cortical 5-HT1A receptors and their associated G proteins.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Effect of probenecid on 5-hydroxyindoleacetic acid in cisternal cerebrospinal fluid of rats with portacaval anastomosis.

Portal-systemic encephalopathy (PSE) is characterized by a neuropsychiatric disorder progressing through personality changes, to stupor and coma. Previous studies have revealed alterations of serotonin and of its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in brain tissue and CSF in experimental (rat) and human PSE. Increased brain 5-HIAA concentrations could result from its decreased removal rather than to increased serotonin metabolism. In order to evaluate this possibility, CSF 5-HIAA concentrations were measured using an indwelling cisterna magna catheter technique at various times following end-to-side portacaval anastomosis in rats (the most widely used animal model of PSE) treated with probenecid, a competitive inhibitor that blocks the active transport of acid metabolites out of the brain and CSF. Following portacaval anastomosis and probenecid treatment, CSF concentrations of 5-HIAA were increased to a greater extent than in sham-operated controls. When data were expressed as per-cent baseline values, the relative increase of CSF 5-HIAA in portacaval shunted rats following probenecid treatment was not significantly different from sham-operated controls. These findings confirm that increased 5-HIAA in the CNS in experimental PSE results from increased 5HT metabolism or turnover and that the probenecidsensitive acid metabolite carrier is intact in PSE.

Animals↗
PubMed1995

Regional alterations of dopamine and its metabolites in rat brain following portacaval anastomosis.

Hyperammonemia and changes in brain monoamine metabolism have been proposed to contribute to the pathogenesis of the neuropsychiatric symptoms characteristic of human portal-systemic encephalopathy (PSE) resulting from chronic liver disease. Portacaval anastomosis (PCA) in the rat leads to sustained hyperammonemia and mild encephalopathy. In order to evaluate the role of dopamine (DA) metabolism in PSE, levels of DA and its metabolites were measured by HPLC with electrochemical detection in brain regions of rats with PCA at various stages of encephalopathy precipitated by ammonium acetate administration. Following ammonium acetate administration, rats with PCA rapidly develop severe neurological signs of encephalopathy progressing through loss of righting reflex to coma; sham-operated control animals administered ammonium acetate showed no such neurological deterioration. Concentrations of the DA metabolites DOPAC and HVA as well as [DA metabolites]/[DA] ratios, an indirect measure of DA turnover in brain, were increased in caudate-putamen, in cingulate and pyriform entorhinal cortices as well as in raphe nucleus and locus coeruleus. Increased DA metabolites, however, did not worsen at coma stages of PSE. Increased DA turnover thus appears to relate to early neuropsychiatric and extrapyramidal symptoms of PSE.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Hypersensitivity to serotonin and its agonists in serotonin-hyperinnervated neostriatum after neonatal dopamine denervation.

Neonatal destruction of the nigrostriatal dopamine projection by intraventricular 6-hydroxydopamine leads to a serotonin (5-hydroxytryptamine, 5-HT) hyperinnervation of the adult neostriatum accompanied by increased radioligand binding to 5-HT1B, 5-HT1nonAB and 5-HT2 receptors. The consequences of such 5-HT receptor changes on neuronal responsiveness to 5-HT and corresponding receptor agonists were assessed with a quantitative iontophoretic approach. For comparative purposes, similar data were also obtained from rats 6-hydroxydopamine lesioned as adults, showing severe neostriatal dopamine denervation but no 5-HT hyperinnervation. In controls, 5-HT and its receptor agonists, m-chlorophenylpiperazine (mCPP; 5-HT1B/2C agonist) and dimethoxy-iodophenyl-aminopropane (DOI; 5-HT2A/2C agonist), depressed the firing rate of a majority of the unit tested. Three months after neonatal 6-hydroxydopamine lesion (5-HT-hyperinnervated tissue), inhibitory responses to all three agents were significantly increased and comparable results were obtained for 5-HT and DOI in the rostral versus caudal neostriatum. After 6-hydroxydopamine lesion in adults, neither responsiveness to 5-HT, mCPP or DOI nor the density of 5-HT1B or 5-HT2A binding were significantly different from control. Thus, the up-regulation of 5-HT1B, 5-HT2A and possibly 5-HT2C receptors accompanying the 5-HT hyperinnervation after neonatal but not after adult dopamine denervation was associated with increased responsiveness (IT50) of neostriatal neurons to iontophoresed 5-HT and its receptor agonists. Under these conditions, neostriatal 5-HT transmission might be enhanced in spite of a basal release seemingly comparable to normal (Jackson and Abercrombie, 1992, J. Neurochem. 58, 890).(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamines↗
PubMed1994

Ca(2+)-sensitive and insensitive omega-conotoxin GVIA binding sites in rat brain.

The autoradiographic distribution of Ca(2+)-sensitive high- and low-affinity binding sites for the N-type calcium channel ligand, [125I]omega-conotoxin GVIA, has been examined in rat brain. Both classes of sites were rather evenly distributed, exhibiting their highest density in cell body rich layers, such as the pyramidal layer of Ammon's horn and the granular layer of the dentate gyrus. In cerebellum, the granular layer was more densely labelled than the molecular layer at low ligand concentration, and this pattern was reversed at high concentration. The presence of 30 mM Ca2+ in the incubation medium revealed the existence of a third class of sites, insensitive to Ca2+, comparably distributed at both concentrations, and apparently absent from cell body rich layers.

Animals↗
PubMed1994

Effects of chronic lithium treatments on central dopaminergic receptor systems: G proteins as possible targets.

Numerous biochemical and electrophysiological studies have proposed a role for dopamine (DA) in the therapeutic efficacy of lithium (Li+) salts. The effects of ex vivo chronic Li+ treatments on neostriatal DA receptors, as well as on the G protein adenylyl cyclase complex and on tissue cAMP levels were investigated in adult rats. The animals were administered LiCl in their drinking water (1 g/l) for varying periods of time, i.e. 1, 15 and 28 days. After sacrifice by decapitation, their brains were removed and the neostriatum dissected out to assay DA receptors and adenylyl cyclase activity. The antagonists [3H]SCH23390 and [3H]raclopride were employed to label D1 and D2 receptors, respectively. Chronic Li+ treatments did not modify the saturation binding of either ligand. However, competition studies of the same antagonists by DA revealed biphasic curves, and the inhibition constant of the high-affinity site was significatively increased after chronic Li+. The data suggest an alteration in the coupling efficacy between G proteins and DA receptors. Moreover, chronic (28 day) Li+ treatment, but not a 1 day Li+ administration, lead to a reduction of the GTP-induced and DA-sensitive adenylyl cyclase activity, without changes in the basal activity or in forskolin-induced cAMP production. The results demonstrate that chronic Li+ treatments diminish neostriatal dopaminergic activity, probably through a direct action on the G protein itself. The underlying mechanisms do not appear to involve modifications in either the D1 or the D2 receptor primary ligand recognition sites, but may represent alterations in both the coupling process and the capacity of the G proteins, once activated, to stimulate adenylyl cyclase.

Adenylyl Cyclases↗
PubMed1994

Platelet-induced vasomotion of isolated canine coronary artery in the presence of halothane or isoflurane.

To determine the effect of 1.5 MAC of two volatile anesthetics (halothane and isoflurane) on platelet-induced contraction of canine coronary artery, isolated, denuded coronary rings were suspended between two stirrups, placed into organ chambers filled with an oxygenated Krebs-Ringer solution, and connected to an isometric force transducer. Human platelets were obtained from healthy donors and introduced into the organ chambers in increasing amounts to reach 20,50 and, 70 x 10(9) platelets/L. The tension generated in both the control and anesthetic-treated rings was recorded; only halothane reduced the tension induced by platelet activation in the organ chambers. In some experiments, aliquots of Krebs-Ringer solution were taken to determine the amount of 5-HT and TB2 released by 70 x 10(9) human platelets in the presence and absence of the anesthetics. Only halothane reduced TA2 production by the activated platelets. Finally, the contractile response of isolated denuded canine coronary artery rings to U46619, a thromboxane analog, was measured in the presence and absence of the anesthetics. Neither halothane nor isoflurane attenuated the response. In another series of experiments, in vitro platelet aggregation was induced by epinephrine, collagen, ADP, or arachidonic acid in the presence or absence of 1.5 MAC isoflurane or halothane. Both anesthetics significantly reduced the aggregation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1994

Heterogeneity of cortical and hippocampal 5-HT1A receptors: a reappraisal of homogenate binding with 8-[3H]hydroxydipropylaminotetralin.

The selective serotonin (5-HT) agonist 8-hydroxydipropylaminotetralin (8-OH-DPAT) has been extensively used to characterize the physiological, biochemical, and behavioral features of the 5-HT1A receptor. A further characterization of this receptor subtype was conducted with membrane preparations from rat cerebral cortex and hippocampus. The saturation binding isotherms of [3H]8-OH-DPAT (free ligand from 200 pM to 160 nM) revealed high-affinity 5-HT1A receptors (KH = 0.7-0.8 nM) and low-affinity (KL = 22-36 nM) binding sites. The kinetics of [3H]8-OH-DPAT binding were examined at two ligand concentrations, i.e., 1 and 10 nM, and in each case revealed two dissociation rate constants supporting the existence of high- and low-affinity binding sites. When the high-affinity sites were labeled with a 1 nM concentration of [3H]8-OH-DPAT, the competition curves of agonist and antagonist drugs were best fit to a two-site model, indicating the presence of two different 5-HT1A binding sites or, alternatively, two affinity states, tentatively designated as 5-HT1AHIGH and 5-HT1ALOW. However, the low correlation between the affinities of various drugs for these sites indicates the existence of different and independent binding sites. To determine whether 5-HT1A sites are modulated by 5'-guanylylimidodiphosphate, inhibition experiments with 5-HT were performed in the presence or in the absence of 100 microM 5'-guanylylimidodiphosphate. The binding of 1 nM [3H]8-OH-DPAT to the 5-HT1AHIGH site was dramatically (80%) reduced by 5'-guanylylimidodiphosphate; in contrast, the low-affinity site, or 5-HT1ALOW, was seemingly insensitive to the guanine nucleotide. The findings suggest that the high-affinity 5-HT1AHIGH site corresponds to the classic 5-HT1A receptor, whereas the novel 5-HT1ALOW binding site, labeled by 1 nM [3H]8-OH-DPAT and having a micromolar affinity for 5-HT, may not belong to the G protein family of receptors. To further investigate the relationship of 5-HT1A sites and the 5-HT innervation, rats were treated with p-chlorophenylalanine or with the neurotoxin p-chloroamphetamine. The inhibition of 5-HT synthesis by p-chlorophenylalanine did not alter either of the two 5-HT1A sites, but deafferentation by p-chloroamphetamine caused a loss of the low-affinity [3H]8-OH-DPAT binding sites, indicating that these novel binding sites may be located presynaptically on 5-HT fibers and/or nerve terminals.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Altered dopamine and serotonin metabolism in the dopamine-denervated and serotonin-hyperinnervated neostriatum of adult rat after neonatal 6-hydroxydopamine.

3,4-Dihydroxyphenylalanine (L-DOPA), 5-hydroxy-l-tryptophan (5-HTP), dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites were measured in the rostral neostriatum of adult rats neonatally lesioned with 6-hydroxydopamine (6-OHDA) after treatment with NSD-1015 (aromatic L-amino acid decarboxylase inhibitor), pargyline (monoamine oxidase inhibitor) or probenecid (blocker of acidic metabolite efflux). Binding experiments with DA and 5-HT transporter ligands allowed us to relate observed changes to the number of DA and 5-HT terminals. One and 3 months after the lesions were made, DA, 3,4-dihydroxyphenylacetic acid (DOPAC)- and homovanillic acid (HVA)-content as well as [3H]N-[1-(2-benzo(b)-thiophenyl)cyclohexyl]piperidine ([3H]BTCP) binding were lowered to 1% to 2% of control values, reflecting a permanent DA denervation. After 1 month, 5-HT content was increased by 96% and 5-hydroxyindole-3-acetic acid (5-HIAA) was increased by 50% in the presence of control levels of [3H]citalopram binding, suggesting that there was an increased amount of 5-HT per neostriatal 5-HT terminal. At 3 months, 5-HT content had increased by 205%, 5-HIAA remained increased by 50% and [3H]citalopram binding had reached 170% of control values, indicating a persistent increase in 5-HT content within an excessive number of 5-HT terminals (hyperinnervation). At both survival times, neostriatal L-DOPA accumulation after NSD-1015 was low, but ratios of L-DOPA to DA and of L-DOPA to [3H]BTCP were greatly elevated. 5-HTP accumulation was increased, but ratios of 5-HTP to 5-HT were lower than control, despite unchanged ratios of 5-HTP to [3H]citalopram.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗