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K M Dewar

Publications and source records attributed to K M Dewar.

At least 37 records · Page 2Linked to original sources
PubMed1991

[3H]paroxetine binding and serotonin content of rat and rabbit cortical areas, hippocampus, neostriatum, ventral mesencephalic tegmentum, and midbrain raphe nuclei region.

The high-affinity binding of [3H]paroxetine to membranes was measured in different regions of the rat and rabbit brain: cingulate, frontal, parietal, piriform, entorhinal, and visual cortical areas; dorsal and ventral hippocampus; rostral and caudal halves of neostriatum (rat) or caudate nucleus and putamen (rabbit); ventral mesencephalic tegmentum; and midbrain raphe nuclei region. The tissue concentrations of serotonin (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA) and 5-hydroxy-l-tryptophan (5-HTP) were also determined by high-performance liquid chromatography (HPLC) in the same brain samples. The regional density of [3H]paroxetine binding varied in both species; the highest values (Bmax) were found in the midbrain raphe region and ventral mesencephalic tegmentum. The cortical values ranged from moderate to low, with a significantly higher density in the cingulate cortex of the rat compared with rabbit. In the rat, there was also a higher density in the ventral than dorsal hippocampus, and the caudal than rostral neostriatum. In the rabbit, the hippocampal and neostriatal values were generally lower and more uniform. In both species, there was an excellent correlation between regional 5-HT levels and specific [3H]paroxetine binding (r = 0.87 in the rat and 0.96 in the rabbit). Considering the available quantitative data on the number of 5-HT nerve cell bodies and axon terminals in different regions of the rat brain, it appears likely that the high amount of [3H]paroxetine binding in the midbrain raphe region and ventral mesencephalic tegmentum reflects the presence of 5-HT uptake sites on 5-HT nerve cell bodies and dendrites as well as axon terminals. In other brain regions, the heterogeneous distribution of [3H]paroxetine binding parallels that of the number of 5-HT axon terminals, emphasizing the potential usefulness of this radioligand as a marker of 5-HT innervation density.

5-Hydroxytryptophan↗
PubMed1990

Elevation of dopamine D2 but not D1 receptors in adult rat neostriatum after neonatal 6-hydroxydopamine denervation.

Monoamine levels and the binding properties of [3H]SCH23390, a D1-specific ligand, and [3H]raclopride, a D2-specific ligand, were measured in the rostal and caudal neostriatum to investigate the fate of dopamine receptors following bilateral cerebroventricular injection of 6-hydroxydopamine in 3-day-old rats. After survival times of 15, 30 or 90 days, measurement of monoamine levels and of [3H]SCH23390 binding were also obtained from the cerebral cortex. At all three survival times, dopamine content was reduced by more than 90% of control values in both the rostral and caudal neostriatum; in cerebral cortex, the dopamine depletion was less profound (80%) and noticeable only after 1 and 3 months. In the rostral but not the caudal neostriatum, serotonin and 5-hydroxyindoleacetic acid concentrations were markedly increased at 1 and 3 months; cortical serotonin also was augmented at 3 months. There were no changes in neostriatal [3H]SCH23390 binding at any of the survival times, but a transient elevation occurred in the cortex at 1 month. In the rostral but not the caudal neostriatum, [3H]raclopride binding showed a slight elevation at 1 month and a further, highly significant increase at 3 months. As measured in individual rats, this increase in [3H]raclopride binding was linearly correlated with the increase in serotonin turnover (ratio of 5-hydroxyindoleacetic acid/serotonin). Such an up-regulation of D2 receptors, restricted to the rostral neostriatum which was also the site of a serotonin hyperinnervation, was probably indicative of a serotonin control on the expression of D2 receptors after dopamine denervation.

Animals↗
PubMed1990

Effects of monovalent cations on neostriatal dopamine D2 receptors labeled with [3H]raclopride.

Specific [3H]raclopride binding to dopamine D2 receptors in the rabbit neostriatum was investigated in the presence of the monovalent cations sodium, lithium and potassium. NaCl and LiCl produced concentration-dependent elevations in specific [3H]raclopride binding with sodium inducing approximately 50% more binding than lithium. Inhibition of [3H]raclopride binding by the antagonist (+)-butaclamol was unaffected by the presence of sodium or lithium in the incubation medium. In contrast, the potency of dopamine to compete with [3H]raclopride was decreased by these two ions. This effect was more pronounced in the presence of sodium than lithium and was observed for both the high- and low-affinity states of the D2 receptor. The guanine nucleotide derivative 5'-guanylylimidodiphosphate (Gpp(NH)p) reduced the potency of dopamine to compete with [3H]raclopride binding in both the presence and absence of cations; however, this effect of Gpp(NH)p was a shift of the D2 receptors from a high to a lower affinity state. Saturation binding curves in the presence of sodium or lithium were compared with experiments carried out in the absence of monovalent cations (sucrose) and demonstrated that these ions increased the affinity (judged by the equilibrium dissociation constant Kd) of the neostriatal [3H]raclopride binding sites. While NaCl produced a significantly greater change in the Kd of [3H]raclopride binding as compared to LiCl, no differences were apparent in the maximum binding capacity (Bmax) values determined in the presence of these two cations. In conclusion, the results indicate that [3H]raclopride binding to rabbit neostriatal membranes exhibits a sensitivity to monovalent cations that is consistent with the ionic regulatory properties of the D2 receptor. Moreover, although lithium and sodium influence specific [3H]raclopride binding in a similar manner, there appear to be quantitative differences between these two ions.

Animals↗
PubMed1990

[3H]ketanserin binds to non-5-HT2 sites in rabbit cerebral cortex and neostriatum.

A characterization of [3H]ketanserin ([3H]KTS) binding in the frontal cortex (fCTX) and neostriatum (caudate-putamen, CPU) of rabbit was carried out to determine whether this ligand labels a non-serotoninergic receptor. The association and dissociation kinetics in fCTX were rapid, and could be fitted to two-site models, suggesting [3H]KTS is labeling two cortical sites. Using the serotonin-2 (5-HT2) antagonist mianserin to determine nonspecific binding, the saturation curves revealed a single high-affinity binding site. In contrast, when unlabeled ketanserin was used for nonspecific counts, the Scatchard plots were best fitted to a two-site model but the binding parameters of the high-affinity site were similar to that obtained in the presence of mianserin. The 5-HT2 antagonists mianserin, methysergide and ritanserin inhibited [3H]KTS binding in fCTX at nanomolar concentrations, however, the curves were best fitted to two-site models. In contrast, [3H]KTS binding to membrane preparations from the CPU could only be inhibited by high (micromolar) concentrations of these antagonists. Low micromolar concentrations of the monoamine uptake blockers GBR12909, desipramine, nomifensine, cocaine and fluoxetine competed with [3H]KTS in both fCTX and CPU. This study demonstrates that [3H]KTS labels a non-serotoninergic recognition site in the rabbit fCTX and CPU similar to that found in the rat neostriatum, i.e.: probably a monoamine transport site.

Animals↗
PubMed1989

Acute and chronic effects of methylphenidate on cortical adrenoceptors in the rat.

The effects of acute and chronic treatments with methylphenidate were examined on cortical adrenoceptors. A single dose of methylphenidate increased the affinity of [3H]prazosin and [3H]idazoxan binding sites. Acute and chronic methylphenidate treatments caused a down-regulation of alpha 1-adrenoceptors. There were no changes in cortical beta-adrenoceptors measured with [3H]dihydroalprenolol nor in endogenous monoamine levels. The alterations in alpha-adrenoceptors can be attributed to an indirect action of methylphenidate possibly through an accrued release of noradrenaline or tyramine.

Animals↗
PubMed1989

Distribution of dopamine D1 and D2 receptors in rabbit cortical areas, hippocampus, and neostriatum in relation to dopamine contents.

The densities of dopamine D1 and D2 receptors were measured by using [3H]SCH23390 and [3H]raclopride, respectively, in the rabbit cingulate, visual, sensorimotor, and entorhinal-piriform cortical areas; the dorsal and ventral hippocampus; and the putamen as well as the medial and lateral caudate. Endogenous dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 4-hydroxy-3-methoxyphenylacetic acid (HVA), and 3-methoxytyramine (3-MT) were assayed by HPLC with electrochemical detection. The distributions of [3H]SCH23390 and [3H]raclopride binding were heterogenous with the greatest densities in the neostriatum. The concentrations of DA and its metabolites were also highest in this structure. Regions with low DA content, i.e., cortex and hippocampus, had lower densities of [3H]SCH23390 and [3H]raclopride binding. Furthermore, these sites were differentially localized within the various regions and there were substantially more D1 than D2 receptors. The functional significance and heterogeneities in the distribution of D1 and D2 receptors are discussed in relation to the dopaminergic innervation and the turnover estimated by the ratios between endogenous DA and its metabolites.

Animals↗
PubMed1989

Dopamine D1 receptors labelled with [3H]SCH23390 in rabbit cerebral cortex and neostriatum. Equilibrium binding, kinetics and selectivity.

The binding characteristics of the novel benzazepine compound SCH23390 were studied using membrane preparations from rabbit cerebral cortex (CTX) and neostriatum (CPU; caudate putamen). The association kinetics of [3H]SCH23390 to membranes from CTX and CPU were rapid, while the dissociation kinetics were extremely slow and only around 40-60% of the binding was displaced two hours after the addition of either S(+)-butaclamol or 30 volumes of buffer. The saturation curves revealed that [3H]SCH23390 bound with high affinity in both tissues, with densities of 133 fmol/mg protein for CTX (Kd 25 degrees C = 0.31 nM) and 664 fmol/mg protein for CPU (Kd = 0.13 nM). the specificity of binding to the cortical D1 receptor was verified in competition experiments with a variety of dopaminergic agents. The rank order of potency of these compounds was consistent with the pharmacology of the dopaminergic D1 site. All competition curves were better fitted to a one-site model with Hill coefficients around one, indicating that [3H]SCH23390 was binding to a single cortical site. The stereoselectivity of the cortical [3H]SCH23390 binding site could be demonstrated by the use of enantiomer pairs of dopaminergic drugs. This study provides compelling evidence that [3H]SCH23390 binds to dopamine D1 receptors in the neostriatum and cerebral cortex of the rabbit.

Animals↗
PubMed1989

Endogenous homovanillic acid levels differ between rat and rabbit caudate, hippocampus, and cortical regions.

Endogenous dopamine (DA) levels and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3MT) and homovanillic acid (HVA) were measured by high-performance liquid chromatography in the entorhinal-piriform (EnPi), cingulate (CIN), sensorimotor (SSM) and visual (VIS) cortices as well as is the caudate (CAU) and hippocampus (HIP) of Sprague-Dawley (SD) rats and New Zealand (NZ) rabbits. The DA, DOPAC and 3MT contents were similar in both species. The HVA levels however, although they followed DA distribution, were several-fold higher in NZ rabbits than in SD rats for all cortices, HIP and CAU. In addition, total metabolite contents and DA turnover (estimated from 'DA metabolite/DA' ratios) were significantly higher in NZ rabbits than in SD rats, suggesting an increased release and/or metabolism in the former species. The HVA/DA ratios were much higher for NZ rabbit regions than for SD rats, indicating an increased DA release in the former species since the DOPAC/DA ratios (index of intraneuronal degradation) were similar.

Animals↗
PubMed1989

Distribution of monoamines and metabolites in rabbit neostriatum, hippocampus and cortex.

The monoamines noradrenaline (NA), dopamine (DA), adrenaline (AD) and 5-hydroxytryptamine (5-HT) were assayed in the putamen (PUT), the lateral (lCAU) and medial (mCAU) portions of the caudate, the dorsal (dHIP) and ventral (vHIP) hippocampus, as well as in four cortical areas, i.e., anterior cingulate (CIN), entorhinal-piriform (EnPi), sensorimotor (SSC; somatosensory) and primary visual (VIS). The use of an HPLC procedure enabled us to perform these measurements in microdissected samples and to assay as well monoamine metabolites. The DA levels were highest in the neostriatum, moderate in the EnPi and CIN and very low in the SSC, VIS and hippocampus. The distribution of NA was more uniform, although higher concentrations were measured in the neostriatum, hippocampus and EnPi. The largest amounts of 5-HT were in the EnPi, while moderate concentrations were found in the other regions. The ratios between the neurotransmitters and their metabolites were used as an index of turnover and indicate that the terminal fields of the monoamine systems are heterogenous within the neostriatal, hippocampal and cortical subdivisions.

Animals↗
PubMed1989

Specific [3H]SCH23390 binding to dopamine D1 receptors in cerebral cortex and neostriatum: role of disulfide and sulfhydryl groups.

Receptor binding studies were performed in cerebral cortex (CTX) and neostriatum (CPU; caudate-putamen) using the dopamine D1 antagonist [3H]SCH23390. Because receptors are of protein nature, we examined the role of disulfide bonds (--SS--) and sulfhydryl groups (--SH) in the specific binding of [3H]SCH23390. Furthermore, membrane preparations contain a certain amount of lipid, so that treatments with --SH and --SS-- reagents could determine whether the fixation of the radioligand was to protein or to the lipid moiety. Pretreatment of CTX and CPU membranes with dithioerythritol, L-dithiothreitol, or 5,5'-dithiobis(2-nitrobenzoic acid), as well as with the alkylating agent N-ethylmaleimide, produced dose-dependent decreases of specific [3H]SCH23390 binding in membrane preparations from both tissues. These changes were not reversible after up to two washes, but could be prevented in part if the treatments were performed in the presence of dopamine. Additional protection experiments were conducted with (+)- and (-)-butaclamol, as well as with (+)- and (-)-SKF38393. A series of saturation experiments (with pretreated membranes in the absence of reactives) demonstrated that the alkylation of --SS-- groups reduced specific [3H]SCH23390 binding mainly through an affinity change, but L-dithiothreitol and 5,5-dithiobis(2-nitrobenzoic acid) decreased the number of binding sites. The affinity of the receptor to agonists was examined with the two enantiomers of SKF38393; the inhibition curves showed that residual binding was not affected and stereospecificity was conserved. The present results provide evidence for the participation of both --SS-- and --SH groups in the recognition site of the dopamine D1 receptor in both the CTX and the CPU.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Dopamine D2 receptors labeled with [3H]raclopride in rat and rabbit brains. Equilibrium binding, kinetics, distribution and selectivity.

The binding properties of the substituted benzamide raclopride to dopamine D2 receptors were studied with membrane preparations from rat and rabbit neostriatum. An analysis of the association kinetics suggested a single binding site but the data from the dissociation experiments were better described by a two-site model. Examination of saturation curves at equilibrium revealed a single class of binding sites in the neostriatum from both species (rat: maximum binding capacity (Bmax) = 247 fmol/mg of protein; rabbit: Bmax = 337 fmol/mg of protein). In cortical regions known to possess a distinct dopaminergic innervation (piriform-entorhinal areas and cingulate cortex) the Bmax values ranged between 9 and 22 fmol/mg of protein. [3H]Raclopride binding sites (less than 12 fmol/mg of protein) were also detectable in the dorsal and ventral hippocampus as well as in the somatosensory and visual cortices. The selectivity in the neostriatum was examined by competition experiments with dopaminergic drugs. The rank of potency of agonists and antagonists to displace [3H]raclopride binding revealed its selectivity for the dopamine D2 receptor and was essentially the same for both species. Antagonist competition curves could be fitted to a single site but inhibition by agonists was better described assuming a two-site model. The stereospecificity of binding was demonstrated by the use of the enantiomer pairs. These results validate the utilization of the novel benzamide [3H]raclopride as a selective marker of dopamine D2 receptors.

Animals↗
PubMed1988

Distribution, morphology and habenular projections of adenosine deaminase-containing neurons in the septal area of rat.

Adenosine deaminase (ADA) was localized within several types of neurons within the septum and in septal efferent projections to the habenula by immunohistochemical, biochemical, retrograde tracing and lesion methods. Numerous ADA-immunoreactive (ADA-IR) neurons were observed in the septofimbrial nucleus, the triangular septal nucleus and the bed nucleus of the anterior commissure, while considerably fewer numbers were seen in the lateral septal area. Based on their size, shape and dendritic features, 4 morphologically distinct types of ADA-IR neurons were recognized in these septal structures. In addition, fine, non-varicose, ADA-IR fibers appeared to emanate from the postcommissural cell groups and these coalesced within the stria medullaris, continued caudally within this fiber bundle, and gave rise to a dense field of very fine immunoreactive elements within a restricted zone of the dorsal half of the medial habenula. Comparisons of the habenular localization of ADA-IR and enkephalin-IR elements showed that fibers labelled for either ADA or enkephalin occupied distinct, non-overlapping regions within the dorsal half of the medial habenula. After injections of Fluoro-gold (FG) into the medial habenula, the majority of ADA-IR neurons in the septofimbrial nucleus, triangular septal nucleus, and the bed nucleus of the anterior commissure were retrogradely labelled with this fluorescent tracer, whereas no ADA-positive FG-labelled neurons were observed in the lateral septal region. Unilateral transections of the stria medullaris caused substantial depletions of ADA-immunoreactivity and reduced enzymatically determined ADA activity by up to 80% in the medial habenula on the lesioned compared with the contralateral control side. These results demonstrate that ADA-IR neurons in the septum are heterogeneously distributed and that populations of positive neurons within the postcommissural septal nuclei give rise to dense, focal projections to the medial habenula. These projections appear to be restricted to a portion of the medial habenula known to contain substance P-IR neurons and are subregionally segregated from enkephalin-positive septohabenular projections ending within this same portion. In addition to pointing out a unique capacity for adenosine catabolism within some septal neurons, possibly related to purinergic neuromodulation, the results indicate the utility of ADA-immunohistochemistry for the delineation of anatomical relationships between the septum and the medial habenula.

Adenosine Deaminase↗
PubMed1988

Involvement of brain trace amines in the behavioural effects of phenelzine.

The MAO inhibitor phenelzine (PLZ) at a dose of 25 mg/kg does not affect the behavior of rats. In contrast, the equivalent dose of a deuterated analog (alpha, alpha, beta, beta-tetradeutero-PLZ, d4PLZ) elicits a biphasic behavioral syndrome in rats. In an attempt to correlate changes in cerebral monoamines with behavior, the concentration of various amines were measured at various times after the administration of either d4PLZ or PLZ (25 mg/kg). In general, PLZ and d4PLZ caused elevations in brain amine levels, particularly in the time period 2-12 hours after drug administration. Furthermore, d4PLZ increased the concentrations of serotonin (5-HT), phenylethylamine (PE), tryptamine (T), meta-tyramine (mTA), and 3-methoxytyramine (3-MT) to a greater extent than PLZ. Since the time course of behavioral excitation closely parallels the elevations in T and PE levels in the brain and since the percentage increases in PE and T levels following d4PLZ compared to PLZ treatment were substantially greater than those of the other amines, it was postulated that PE and T are involved in d4PLZ-induced behaviors.

Animals↗
PubMed1986

Inhibition of aromatic L-amino acid decarboxylase and tyrosine aminotransferase by the monoamine oxidase inhibitor phenelzine.

The concentration of p-tyramine in the rat striatum was increased significantly by intraperitoneal injection of phenelzine (5 or 100 mg/kg). Unlike other monoamine oxidase (MAO) inhibitors, phenelzine had no effect on p-tyramine levels in the first 1-2 h following injection. The high dose of phenelzine increased the p-tyramine levels much more than the low dose. In addition, the high dose of phenelzine increased striatal p-tyrosine levels significantly 12 h after injection. Further studies showed that phenelzine inhibited the tyrosine aminotransferase activity of rat liver homogenates; the IC50 was 50 microM. Phenelzine also inhibited the aromatic L-amino acid decarboxylase activity of rat brain homogenate with an IC50 of 25 microM. Following intraperitoneal injection of 100 mg/kg phenelzine, the initial concentration of phenelzine in the striatum appears to be high enough to inhibit aromatic L-amino acid decarboxylase. It is suggested that the multiple enzyme inhibition caused by administration of high doses of phenelzine accounts for its unusual effects on striatal p-tyramine levels compared with other MAO inhibitors, i.e., its initial lack of effect on p-tyramine levels followed later by very large increases in p-tyramine levels.

Animals↗
PubMed1985

Changes in brain catecholamine levels following DL-dopa are not potentiated by deuterium substitution.

Adult male Wistar rats were treated with either DL-dopa, D3-DL-dopa or vehicle and sacrificed at various time intervals after treatment. Brain dopamine and noradrenaline concentrations were measured using quantitative mass spectrometric analysis. After treatment with DL-dopa or D3-DL-dopa, total dopamine levels increased above control values; however, no differences were observed between the two drug treatments. Total noradrenaline levels were not significantly altered by treatment with either DL-dopa or D3-DL-dopa. Deuterium substitution did not appear to affect catecholamine deamination or beta-hydroxylation in vivo.

Animals↗
PubMed1983

Potentiation of the behavioural effects of the antidepressant phenelzine by deuterium substitution.

Phenelzine in the rat induced biphasic behavioural stimulation, which was profoundly potentiated by deuterium substitution. Doses of 12.5 or 25.0 mg/kg phenelzine had little or no effect on spontaneous activity, whereas the same doses of deuterated phenelzine produced hyperactivity, wet-dog shakes, forepaw padding, splayed hind limbs, backward walking, sniffing and stereotyped grooming 2-12 h after injection. Similarly, the behavioural response induced by 50.0 mg/kg phenelzine was strongly potentiated by deuterium substitution. It appears likely that the increased behavioural response induced by deuterated phenelzine may be due to its greater potency as a monoamine oxidase inhibitor compared to undeuterated phenelzine. Since phenelzine is an antidepressant that is particularly efficacious in the treatment of severe anxiety, a deuterated analogue of the drug seems likely to be clinically useful.

Animals↗
PubMed1980

Comparison of the effects of spinal anaesthesia and general anaesthesia on postoperative oxygenation and perioperative mortality.

One hundred patients presenting for surgical treatment of fractured neck of femur were allocated to receive either spinal (SAB) or general (GA) anaesthesia. Before operation, the mean PaO2 was 9.04 kPa. There was a significant decrease in PaO2 of 0.68 kPa in GA group at 1 h after operation, while blood-gas values were unchanged in SAB group. Eight patients (15.7%) in GA group and five patients (10.2%) in SAB group died within 4 weeks of surgery. The difference was not statistically significant.

Acid-Base Equilibrium↗