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S B Ross

Publications and source records attributed to S B Ross.

At least 91 records · Page 5Linked to original sources
PubMed1986

Cortical beta- and alpha 2- adrenoceptor binding, hypothalamic noradrenaline and pineal melatonin concentrations measured at different times of the day after repeated treatment of rats with imipramine, zimeldine, alaproclate and amiflamine.

The effect of repeated treatment of rats for 21 days with the monoamine reuptake inhibitors imipramine, zimeldine, alaproclate (in each case 10 mumol/kg b.i.d.) and the reversible monoamine oxidase-A inhibitor amiflamine (3 mumol/kg b.i.d.) on brain noradrenergic mechanisms measured at different times of the day and night was investigated. Imipramine treatment produced a down-regulation of the Bmax for 3H-dihydroalprenolol binding to cortical beta-adrenoceptors that was not dependent upon the time of day the animals were killed. Zimeldine, on the other hand, reduced both Bmax and Kd of binding for day-time, but not night-time samples. Alaproclate and amiflamine were without effect on the binding. Twenty-four hour mean values for 1 nM 3H-p-aminoclonidine binding to alpha 2-adrenoceptors were lower for the zimeldine-treated rats than for the saline-treated rats. Pineal melatonin concentrations, which are regulated by beta-adrenoceptors, showed a pronounced diurnal rhythm, with the highest concentrations being found at 02:00. At this time point, a lower pineal melatonin content was found after amiflamine treatment, whereas imipramine, zimeldine and alaproclate were without significant effect. The importance of the use of more than one time point and the use of more than one biochemical test for the determination of the effects of repeated antidepressant treatment on central noradrenergic systems measured ex vivo is discussed.

Alanine↗
PubMed1986

Alpha 1-adrenoceptor function in the rat hippocampus as assessed by noradrenaline-stimulated inositol phospholipid breakdown after destruction of noradrenergic neurons by neonatal 6-hydroxydopamine treatment.

Neonatal 6-hydroxydopamine treatment of male Sprague-Dawley rats resulted in a large depletion of noradrenaline 84-87 days later, as demonstrated by an 82% reduction in the intra-synaptosomal deamination of [14C]noradrenaline within noradrenergic synaptosomes with only marginal effects upon the extrasynaptosomal deamination. The hippocampal stimulation of inositol phospholipid breakdown by noradrenaline was, however, unaffected by the neonatal 6-hydroxydopamine treatment.

Animals↗
PubMed1986

Single-site model of the neuronal 5-hydroxytryptamine uptake and imipramine-binding site.

Recently, a high affinity [3H]imipramine-binding site of protein nature that appeared to be related to the 5-hydroxytryptamine (5-HT, serotonin) uptake mechanism was demonstrated. This binding site was only part of desipramine-displaceable [3H]imipramine binding, which contained a significant amount of additional binding not related to 5-HT uptake. The present study further investigates the [3H]imipramine-binding site of protein nature in the rat brain. Displacement by 5-HT and 6-methoxytetrahydro-beta-carboline (6-MeO-TH beta C) revealed monophasic displacement patterns with 60% displaceable binding. This binding fraction was abolished by protease treatment of the brain tissue prior to binding assay. Saturation studies of [3H]imipramine binding (1-30 nM) in rat cortex showed that the binding displaced by 30 microM 5-HT [Bmax 322 +/- 16 fmol/mg of protein, Kd 4.17 +/- 1.07 nM (means +/- SE)] was not different from the binding displaced by 1.0 microM norzimeldine (Bmax 349 +/- 15 fmol/mg of protein, Kd 4.47 +/- 1.07 nM) or 30 microM 6-MeO-TH beta C (Bmax 439 +/- 28 fmol/mg of protein, Kd 5.49 +/- 1.09 nM). When 100 microM desipramine was used in saturation studies, the binding was different from that displaced by 5-HT with Bmax 608 +/- 42 fmol/mg of protein and Kd 6.68 +/- 1.09 nM. Both displacement and saturation studies in which two displacing agents were combined indicated that most of the binding competed by 5-HT (30 microM) and norzimeldine (1.0 microM) is identical. Similarly, the binding displaced by 5-HT or norzimeldine is subsumed within 6-MeO-TH beta C (30 microM)-displaceable binding. Lesion studies with parachloroamphetamine, a selective toxin for 5-HT terminals, which resulted in a 83% reduction of [3H] 5-HT uptake ( [3H]noradrenaline uptake unaffected), abolished cortical [3H]imipramine binding displaced by 30 microM 5-HT or 1.0 microM norzimeldine. (greater than 80% reduction). However, with 100 microM desipramine as displacer, 40% of the binding remained in lesioned animals. The [3H]imipramine binding displaced by 30 microM 5-HT or 1.0 microM norzimeldine was sodium dependent, and an increase in NaCl concentration from 0 to 120 mM resulted in a 10-fold increase in affinity without effect on Bmax, whereas no change in binding was observed with increasing concentrations of LiCl.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Active and passive avoidance following the administration of systemic DSP4, xylamine, or p-chloroamphetamine.

Groups of rats were administered either DSP4 (50 mg/kg, ip), xylamine (50 mg/kg, ip), or p-chloroamphetamine (2 X 10 mg/kg, ip), either 2 weeks or 1 week before the testing of two-way active avoidance. DSP4 and xylamine, the selective noradrenaline (NA) neurotoxins, caused a two-way avoidance impairment but p-chloroamphetamine, the selective 5-hydroxytryptamine (5-HT) neurotoxin, did not do so. Pretreatment with desipramine (20 mg/kg, ip) blocked the avoidance impairment caused by DSP4 and xylamine treatment. Neither DSP4 nor xylamine caused any alteration of passive avoidance retention. The biochemical analyses indicated severe NA, but not 5-HT, depletions in the DSP4 and xylamine conditions and drastic 5-HT, but not NA, depletions in the p-chloroamphetamine conditions. These results confirm and extend earlier findings concerning the role of NA in avoidance behavior.

Amphetamines↗
PubMed1985

Concentration and uptake of 5-hydroxytryptamine in platelets from cluster headache and migraine patients.

Concentrations of 5-hydroxytryptamine (5-HT) in platelets were determined in 33 cluster headache patients (17 males) and in 34 migraine patients (16 males) outside attacks. The 5-HT uptake into platelets was measured and the kinetic constants Vmax and Km determined in 26 cluster patients (14 males) and in 30 migraine patients (13 males). Significantly lower 5-HT concentrations in whole blood were found in cluster headache and migraine patients than in 50 healthy controls (19 males). The Vmax and Km values of the 5-HT uptake were significantly lower in cluster headache and migraine patients compared with 22 healthy controls (9 males). The 5-HT concentrations and the kinetics of the 5-HT uptake did not differ between cluster headache and migraine. In healthy controls a significant positive correlation was found between the 5-HT uptake rate at 0.25 microM and Km but not in cluster headache and migraine patients. The 5-HT concentrations in whole blood correlated positively with Vmax and Km, respectively, in cluster headache and with Km in healthy controls but not with Vmax nor with Km in migraine. There was no obvious relation between the kinetics of platelet monoamine oxidase (MAO) and the 5-HT uptake except for an increased incidence of low Vmax of MAO and low Km of the 5-HT uptake in cluster headache. The kinetics of the 5-HT uptake was apparently not related to the state of migraine. The results indicate a possible constitutional trait in cluster headache and migraine expressed as low 5-HT concentrations in whole blood and low Vmax and Km of the 5-HT uptake into platelets.

Adolescent↗
PubMed1985

"Specific" binding of [3H]imipramine to protease-sensitive and protease-resistant sites.

A number of 5-hydroxytryptamine (5-HT) uptake inhibitors have been shown to displace the binding of [3H]imipramine to rat cortical membranes in a complex manner with Hill slopes less than unity. Norzimeldine displaced the binding of [3H]imipramine in a biphasic manner with IC50 values for the two components of about 30 nM and 30 microM. This latter site alone was found in tissues that had been treated with a protease. Binding to both of these sites was displaced by 10 microM desipramine. The protease-sensitive [3H]imipramine binding sites were found to be saturable, high-affinity binding sites with a KD of 8 nM. The number of these sites varied between brain regions and was positively correlated with the regional distribution of [14C]5-HT but not [3H]noradrenaline uptake. This was not the case however for the protease-resistant but desipramine-displaceable binding sites. Since most previous [3H]imipramine binding studies have been performed with high concentrations of desipramine (10 microM) to define "specific binding," these data would suggest that either protease-sensitivity or displacability by 1 microM norzimeldine would give more reliable estimates of the specific binding.

Animals↗
PubMed1985

Inhibition of monoamine oxidase in 5-hydroxytryptaminergic neurones by substituted p-aminophenylalkylamines.

A series of substituted p-aminophenethylamines and some related compounds were examined with regards to the inhibition of monoamine oxidase (MAO) in vivo inside and outside 5-hydroxytryptaminergic neurones in the rat hypothalamus. This was recorded as the protection against the irreversible inhibition of MAO produced by phenelzine by determining the remaining deaminating activity in the absence and presence of citalopram using a low (0.1 microM) concentration of [14C]-5-hydroxytryptamine (5-HT) as substrate. Some of the phenethylamines were much more potent inside than outside the 5-hydroxytryptaminergic neurones. This neuronal selectivity was antagonized by pretreatment of the rats with norzimeldine, a 5-HT uptake inhibitor, which indicates that these compounds are accumulated in the 5-HT nerve terminals by the 5-HT pump. Selectivity was obtained for compounds with dimethyl, monomethyl or unsubstituted p-amino groups. An isopropyl group appears to substitute for the dimethylamino group but with considerably lower potency. Compounds with 2-substitution showed selectivity for aminergic neurones and this effect decreased with increased size of the substituent. The 2,6-dichloro derivative FLA 365 had, however, no neuronal selective action but was a potent MAO inhibitor. Substitutions in the 3- and 5-positions decreased both potency and selectivity. Prolongation of the side chain with one methylene group abolished the preference for the MAO in 5-hydroxytryptaminergic neurones although the MAO inhibitory potency remained. The selectivity disappeared by increasing the alpha-substituent to an ethyl group but remained for the alpha,alpha-dimethyl substituted derivatives. It is concluded that compounds which are (1) transported by the 5-HT pump and (2) potent reversible MAO-A inhibitors produce pronounced inhibition of MAO in 5-hydroxytryptaminergic neurones.

Animals↗
PubMed1985

Effects of amiflamine and related compounds on the accumulation of biogenic monoamines in rat brain slices in vitro and ex vivo in relation to their behavioural effects.

The inhibition of the accumulation of serotonin, noradrenaline and dopamine in rat brain (occipital cortex and striatum) slices by amiflamine and its two major metabolites FLA 788(+) and FLA 668(+) was examined and compared with that of amine releasing compounds e.g. p-chloroamphetamine (PCA) and alpha-ethyltryptamine and uptake inhibitors, e.g. alaproclate, citalopram, desipramine, fluoxetine and norzimeldine. It was found that amiflamine and FLA 788(+) inhibited the accumulation of serotonin and noradrenaline but only slightly that of dopamine in vitro and ex vivo with a mechanism similar to that of PCA and alpha-ethyltryptamine, i.e. with higher potency in reserpinized rats than in normal animals suggesting amine releasing mechanisms. Similar to alpha-ethyltryptamine and PCA, amiflamine and FLA 788(+) caused behavioural changes (serotonin syndrome) which were particularly pronounced in reserpinized rats but also observed after a second administration of amiflamine in normal rats. Upon repeated administration of amiflamine the behavioural changes disappeared which indicates a functional down-regulation of the serotonin receptors responsible for this syndrome. FLA 668(+) inhibited the accumulation of noradrenaline in vitro and ex vivo but had less effect on the accumulation of dopamine and particularly that of serotonin. It is concluded that amiflamine and FLA 788(+) inhibit the accumulation of serotonin and noradrenaline by releasing mechanisms and that the released serotonin triggers the behavioural changes observed.

Animals↗
PubMed1985

Antagonism of 5-methoxy-N,N-dimethyltryptamine-induced changes in postdecapitation convulsions in rats by repeated treatment with drugs enhancing 5-hydroxytryptamine neurotransmission.

Repeated administration of drugs that increase tryptaminergic neurotransmission antagonized the increase in latency to onset and the duration of postdecapitation convulsions (PDCs) induced by an acute 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) injection; Zimelidine (2 X 5 mg kg-1), fluoxetine (2 X 5 mg kg-1), amiflamine (2 X 2.5 mg kg-1) and alpha-ethyltryptamine (2 X 2.5 mg kg-1) administered orally over 10 days caused a substantial blockade of the increase in latency to onset and duration of PDCs following 5-MeODMT, whereas alaproclate (2 X 5 mg kg-1), clorgyline (1 X 1 mg kg-1) and pargyline (2 X 2.5 mg kg-1) caused a lesser blockade. Repeated 5-MeODMT (3 X 2 mg kg-1) administration blocked the acute effects of 5-MeODMT (2 and 4 mg kg-1) upon PDCs completely. These findings indicate down-regulation of the 5-hydroxytryptamine receptors which mediate the action of 5-MeODMT on the PDCs and offer a simple model system for studying 5-HT receptor sensitivity changes at the spinal level.

Animals↗
PubMed1984

Effects of acute and repeated administration of amiflamine on monoamine oxidase inhibition in the rat.

The inhibitory effect on monoamine oxidase (MAO) of the reversible MAO-A inhibitor (+)-4-dimethylamino-2,alpha-dimethylphenethylamine [amiflamine, FLA 336(+)] was evaluated in the rat after acute and repeated (twice daily for two weeks) oral treatment. MAO activity was measured ex vivo in slices from the hypothalamus and the duodenum for both MAO-A and MAO-B. Amiflamine selectively inhibited the A form of MAO after repeated as well as after acute treatment (ED50 approximately 7 mumoles/kg both acute and repeated). In the brain slices this inhibition corresponded to a decrease in the concentration of 5-hydroxyindoleacetic acid (5-HIAA) and to an increase in the concentration of 5-HT in the hypothalamus, the hippocampus and the striatum. The concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) was decreased in the striatum to the same extent as the decrease in the 5-HIAA concentrations. The effect on the homovanillic acid (HVA) concentration was somewhat weaker as was the increase in the concentration of dopamine. No essential difference was found after acute and chronic treatment on the amine and metabolite levels. The MAO activity returned to normal 24 hours after final dosing. A large difference between the neuronal and the extraneuronal protection against the phenelzine-induced irreversible MAO inhibition in the hypothalamus was found after both acute and repeated treatment. The ED50 of the protection within the serotonergic neurons was 1.3 mumoles/kg p.o. (acute) and 0.75 mumoles/kg p.o. (repeated). Amiflamine was 3 times less potent within noradrenergic neurons than within serotonergic neurons. A brain to plasma ratio of about 20:1 was found for amiflamine and its metabolites. The plasma and the brain concentrations of the N-demethylated metabolite [FLA 788(+)] exceeded that of amiflamine after a single dose, whereas the N,N-demethylated [FLA 668(+)] was found in low concentrations. The effect on MAO-A correlated significantly with the plasma and the brain concentration of FLA 788(+).

Animals↗
PubMed1984

Retention deficits induced by acute p-chloroamphetamine following fear conditioning in the rat.

Rats were given four inescapable shocks (1.0 mA) when confined to the right-hand corner of a modified shuttlebox. p-Chloroamphetamine (PCA) injected just before the retention test 24 h later completely blocked the immobile posture that was observed after saline injections. This retention deficit was shown to be selectively associated with 5-hydroxytryptamine (5-HT) release, since the administration of the 5-HT uptake inhibitors zimelidine and citalopram 60 min prior to PCA antagonized this effect. The 5-HT specificity of the deficit was further established by the findings that 5-HT-depleted rats (PCA, 2 x 10 mg/kg, and fenfluramine, 2 x 25 mg/kg), but not NA-depleted rats (DSP4, 1 x 50 mg/kg), or rats treated with zimelidine (2 x 20 mg/kg) 60 min before PCA (2 x 10 mg/kg), showed an almost complete blockade of the retention failure. The data presented may provide a useful experimental model for investigating the efficacy of functional 5-HT activity in the treatment of phobic anxiety.

Amphetamines↗
PubMed1984

The effect of acute zimeldine and alaproclate administration on the acquisition of two-way active avoidance: comparison with other antidepressant agents, test of selectivity and sub-chronic studies.

The dose-dependent effect of acute zimeldine and alaproclate treatment upon the acquisition of two-way and one-way active avoidance in the rat was studied in a single-session and in a repeated-sessions design. Zimeldine (5-20 mg/kg, IP), but not alaproclate, caused disruptions of two-way avoidance acquisition. Acquisition deficits were also caused by citalopram and fluoxetine but not the other antidepressant drugs tested. Zimeldine, but not alaproclate or desipramine, caused a slight but non-significant impairment of one-way active avoidance; neither zimeldine nor alaproclate produced any effects upon fear conditioning and retention testing. The long-term action of p-chloroamphetamine (2 X 10 mg/kg) antagonised the acute zimeldine effect totally, and chronic treatment with zimeldine (15 days, 1 X 50 mumol/kg) and chlorimipramine (15 days, 2 X 10 mumol/kg) also caused some partial blockade of the two-way avoidance deficit. These data seem to suggest some involvement of serotonin (5-HT) in the observed disruptions of two-way active avoidance caused by acute zimeldine treatment.

Alanine↗
PubMed1984

Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants on beta-adrenoceptors and 5-HT2 binding sites in the rat cerebral cortex.

The dependence of intact noradrenergic and serotonergic nerve terminals for the decrease in the number of beta-adrenoceptors and 5-HT2 binding sites in the cerebral cortex produced by long-term treatment of rats with antidepressant drugs was examined. Noradrenergic nerve terminals were destroyed with the selective noradrenaline neurotoxin DSP4, and serotonergic nerve terminals were destroyed with p-chloroamphetamine (PCA). It was found that lesioning of the noradrenergic nerve terminals abolished the decrease in beta-adrenoceptors produced by desipramine, mianserin and zimeldine and partially antagonized that of the beta-adrenoceptor agonist clenbuterol. PCA pretreatment did not antagonize the long-term effects on the beta-adrenoceptor produced by these compounds. Lesioning of serotonergic nerve terminals affected the down-regulation of 5-HT2 binding sites produced by long-term treatment with mianserin, desipramine and amiflamine. DSP4 pretreatment partially abolished the down-regulation of 5-HT2 binding sites produced by long-term treatment with desipramine, while the effects of mianserin and amiflamine were unaffected by pretreatment with DSP4.

Alanine↗
PubMed1984

Role of olfactory bulbectomy and DSP4 treatment in avoidance learning in the rat.

Olfactory bulbectomized rats and DSP4-treated rats were studied on a two-way active avoidance task as well as on step-down passive avoidance and fear conditioning and retention tasks in three experiments. The DSP4-treated, but not olfactory bulbectomized, rats were impaired in acquiring two-way avoidance; bulbectomized, but not DSP4-treated, rats were found to show notable passive avoidance and fear retention deficits. Bulbectomized rats treated with DSP4 did not show passive avoidance and fear retention deficits, nor did these animals evidence the two-way avoidance impairment of the DSP4-treated rats. No alteration of dopamine-beta-hydroxylase activity in the frontal cortex and hippocampus as a result of the bulbectomy operation was indicated. The double dissociation between bulbectomized and DSP4-treated rats is discussed in terms of opponent behavioral processes, influenced by olfactory bulbectomy and DSP4, which may permit insights into experimental investigations of stress, anxiety, and depression.

Amines↗
PubMed1984

A parametric study of the effects of the noradrenaline neurotoxin DSP4 on avoidance acquisition and noradrenaline neurones in the CNS of the rat.

The effects of various doses of DSP4 on two-way active avoidance acquisition in rats and on central noradrenaline neurones were compared. Doses of DSP4 from 3 mg kg-1 i.p. and upwards injected one week before the onset of the avoidance trials significantly impaired two-way avoidance learning. The learning impairment caused by DSP4 (50 mg kg-1 i.p.) lasted for at least 10 weeks. Desipramine (20 mg kg-1) injected either 30 or 60 min before DSP4 (50 mg kg-1) antagonized the active avoidance impairment. A high dose of DSP4 (50 mg kg-1 i.p.) produced profound decreases in dopamine-beta-hydroxylase activity in the frontal cortex and in the concentrations of noradrenaline in various brain regions indicating degeneration of the locus coeruleus noradrenaline system. Low doses of DSP4 (3 and 6 mg kg-1 i.p.) produced small but significant decrease in the concentrations of noradrenaline (NA) in some regions, e.g. cerebral cortex, hippocampus, olfactory bulb and spinal cord. The avoidance impairment caused by the low dose of DSP4 (3 mg kg-1) was absent when rats were tested 10 weeks after treatment nor was NA depletion present when NA was analysed 3 months after treatment.

Amines↗
PubMed1984

Attenuation of the post-decapitation convulsions after repeated treatment of rats with desipramine, imipramine and maprotiline.

The effects of repeated treatment of rats with the antidepressant or potential antidepressant agents alaproclate, citalopram, clomipramine, desipramine, imipramine, maprotiline, mianserin and zimeldine on the convulsions released by decapitation were examined. The noradrenaline uptake inhibitors desipramine, imipramine and maprotiline increased significantly the latency of onset of the post-decapitation convulsions (PDC's) after repeated administration of 10 mumol/kg orally twice daily, or 66 mumol/kg orally once daily (desipramine), for 15 days. The duration of the PDC's was slightly prolonged by these agents. A single acute dose of desipramine (20 mg/kg) administered at various time intervals before decapitation (1 to 24 hours) had no effect on the PDC's nor did repeated treatment with the other compounds examined, alaproclate, citalopram, clomipramine, mianserin and zimeldine, have any effect upon the PDC latency. The results are interpreted as evidence for noradrenaline receptor subsensitivity following chronic treatment.

Alanine↗
PubMed1984

Activation of monoamine oxidase by high molecular weight fractions of human plasma.

The activation of human platelet monoamine oxidase (MAO) and rat brain mitochondrial MAO ( RBM -MAO) by human plasma were studied. The deamination of two different substrates, tyramine and phenethylamine (PEA) was investigated. The increase in MAO activity in the presence of human plasma can be explained by the observed decrease in the apparent Km for the amine (tyramine, PEA). This activation pattern was the same both for human platelet MAO and RBM -MAO. The activating properties of human plasma were recovered in high molecular weight fractions after gel filtration.

Animals↗