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Biomedical subjects

B E Leonard

Publications and source records attributed to B E Leonard.

At least 55 records · Page 3Linked to original sources
PubMed1999

Onset of the effects of the 5-HT1A antagonist, WAY-100635, alone, and in combination with paroxetine, on olfactory bulbectomy and 8-OH-DPAT-induced changes in the rat.

5-HT1A receptor antagonists have recently been shown to accelerate the effects of some antidepressant drugs in clinical trials. In this study we investigate the effects of combining a full antagonist at the 5-HT1A receptor, WAY 100635 (0.2 mg/kg, SC) with the selective serotonin reuptake inhibitor (SSRI) paroxetine (5 mg/kg. SC) in the olfactory bulbectomized (OB) rat, an animal model of chronic (but not acute) antidepressant activity. Ambulation scores were measured in the open-field apparatus, following 3, 7, and 14 days of treatment. Further to the OB study, we simultaneously studied adaptive changes in 5-HT1A receptor function, utilizing alterations in the hypothermic response to the 5-HT1A receptor agonist 8-OH-DPAT. Paroxetine, in combination with WAY 100635, attenuated the hypothermic effects of 8-OH-DPAT as early as 3 days, with a full reversal evident following 7 days, whereas paroxetine, although attenuating the hypothermic effects in OB group by day 7, only reversed it fully after 14 days. Paroxetine alone and in combination with the antagonist reversed the olfactory bulbectomy-induced hyperactivity in the open field following 14 days of treatment only, this being the normal time of an "antidepressant" response in this model. However, there was no significant attenuation at any of the earlier time points. This further demonstrates that the reversal of this aspect of the olfactory bulbectomy-induced behavioral syndrome is insensitive to the potential faster onset of antidepressant action induced by 5-HT1A receptor antagonists. Nonetheless, WAY 100635, unlike previous studies with pindolol, did not interfere with the effects of the antidepressant in the model. The ability of the combination group to attenuate the hypothermic effects of 8-OH-DPAT faster than paroxetine alone, further emphasizes the role of the 5-HT1A receptor in the mechanism of action of antidepressants, and as a target for the development of faster acting antidepressants.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

The effect of treatment with a new antidepressant, INN 00835, on platelet serotonin uptake in depressed patients.

BACKGROUND: INN 00835 (4-fluoro-L-phenylalanyl-trans-4-hydroxy-L-prolyl-L-arginyl-glycyl-trypt ophanamide ditrifluoroacetate) is a synthetic pentapeptide antidepressant with a potential for rapid onset of action. We were interested to see if such action could be correlated with serotonin uptake by platelets. METHODS: In a phase II clinical trial, unipolar depressed patients were administered active drug, INN 00835 or placebo, subcutaneously, at 0.2 mg/kg, once daily for 5 consecutive days. Efficacy of treatment was evaluated by psychometric tests (HAMD, MADS, CSRS, CGI and total VAS). Changes in platelet uptake rates of serotonin (3H-5HT) were measured in plasma from the patients participating in the phase II clinical trial, prior to and immediately after treatment with INN 00835 (19 patients) or placebo (16 patients), to evaluate the effect of treatment with INN 00835 on the rate of platelet 5-HT uptake. RESULTS: The data evaluated by using the psychometric tests indicated a significant response to treatment with INN 00835 after 5 days of dosing. The rates of platelet 5-HT uptake were lower prior to treatment (baseline), and increased after the 5-day treatment period. The change in the uptake rate (deltaVmax) following treatment was significantly larger in the active group than in the placebo group (P < 0.05). The difference between the placebo group and the patients who responded to treatment was even larger. LIMITATIONS: Small number of subjects. CONCLUSION: The data tend to substantiate the use of platelet serotonin uptake as a biochemical marker of effective treatment of depression.

Adult↗
PubMed1999

Differential effect of a single high dose of the tricyclic antidepressant imipramine on interleukin-1beta and tumor necrosis factor-alpha secretion following an in vivo lipopolysaccharide challenge in rats.

Tricyclic antidepressants (TCAs) of which imipramine is one, are commonly used in the treatment of depressive disorders and other forms of psychiatric illness. There have been many reports regarding the suppressive effects of TCAs on immune function. However, information is still limited regarding the effects of TCAs on the immune system, as many of the studies conducted to date have concentrated on in vitro exposure to such drugs, or ex vivo measures of immunity following drug administration. Thus in the present investigation, an in vivo challenge with bacterial lipopolysaccharide (LPS) (100 microg/kg; i.p.) was used to assess immunocompetence following administration of a single high dose of the TCA, imipramine (100 mg/kg, p.o.). The results demonstrated that imipramine pretreatment inhibits LPS-induced increases in serum concentrations of the proinflammatory cytokine, tumor necrosis factor (TNF)-alpha both 3 and 6 h, following administration. However, LPS-induced interleukin (IL)-1beta secretion was not significantly altered following imipramine treatment at either of the timepoints examined. In addition, serum concentrations of corticosterone and the antiinflammatory cytokine IL-10 were measured, and imipramine treatment failed to alter either basal, or LPS-induced increases in these immunosuppressive agents. In conclusion, although IL-1beta and TNF-alpha are both macrophage-derived proinflammatory cytokines, the present study demonstrates a differential sensitivity of these cytokines to the suppressive effects of the TCA imipramine. Furthermore, the suppressive effects of imipramine on LPS-induced TNF-alpha secretion could not be attributed to either increased glucocorticoid levels, or increased secretion of the antiinflammatory cytokine IL-10. The relevance of these findings to antidepressant-induced immunotoxicity are discussed.

Animals↗
PubMed1999

An investigation of the antidepressant properties of lofepramine and its desmethylated metabolites in the forced swim and olfactory bulbectomized rat models of depression.

The purpose of this study was to examine the metabolites of lofepramine (LOF), namely desipramine (DMI), desmethyl desipramine (DDMI) and desmethyl lofepramine (DML) in the forced swim and olfactory bulbectomized (OB) rat models of depression. In the first study, subacute treatment with DMI (10 mg/kg) and DML (20 mg/kg), but not LOF, reduced the immobility time in the forced swim test. In the "open field", chronic (14 day) treatment with all drugs attenuated the hyperactivity associated with olfactory bulbectomy. In the second experiment, a lower dose of DML (10 mg/kg) demonstrated activity following subacute treatment in the forced swim and following chronic treatment in the OB model. In addition, DDMI (10 mg/kg) was active in both models. From these results, it can be concluded that, at the doses employed, LOF and it's desmethylated metabolites, DMI, DML and DDMI, exhibits activity in the OB model. In contrast, lofepramine but not it's desmethylated derivatives is inactive in the forced swim test, perhaps suggesting the requirement of metabolic conversion of LOF to reveal antidepressant activity in this model.

Animals↗
PubMed1999

Effects of acute and chronic antidepressant administration on phencyclidine (PCP) induced locomotor hyperactivity.

Previously it was found that both acute and chronic antidepressant pre-treatment enhanced the locomotor hyperactivity induced by a challenge injection of the non-competitive NMDA receptor antagonist, dizocilpine (MK-801). In the present study the effects of acute and chronic antidepressant administration on phencyclidine (PCP)-induced locomotor hyperactivity were examined. Phencyclidine (PCP), a non-competitive NMDA receptor antagonist increased locomotor activity in rats. Fluoxetine given acutely increased and prolonged the PCP-induced locomotor hyperactivity, while citalopram, sertraline and paroxetine had no effect on the PCP-induced behavioural effect. Repeated treatment with fluoxetine, citalopram and paroxetine increased the PCP-induced locomotor hyperactivity. In contrast, chronic sertraline administration attenuated the locomotor response to a PCP challenge. These results indicate that these antidepressants which are presumed to have a similar pharmacological profile, differ in their ability to alter PCP-induced hyperactivity. Whether these differences have any bearing on the therapeutic or adverse effects of these drugs remains to be shown.

Animals↗
PubMed1999

Acute toxicity profile of maprotiline in the rat.

The aim of the present study was to examine the toxic effects of single oral administrations of the antidepressant maprotiline at 150 mg/kg or 300 mg/kg using female Sprague-Dawley rats. Body-weight gain was significantly reduced in the group receiving 300 mg/kg on days 1-5 of the study (P<0.01). A significant reduction in food and water intake was observed on days 1 and 2 of the study (P<0.01) in the 300 mg/kg group and on day 1 in the 150 mg/kg group (P<0.05). There was a significant decrease in nocturnal home cage activity over the first five days of the study in the 300 mg/kg group (P<0.01). A significant hypothermic response was observed in both 150 and 300 mg/kg groups at 1, 2 and 4 hr after dosing (P<0.01), that had returned to control values within 8 hr following administration. This study demonstrates that a multi-parameter approach is appropriate for the investigation of high doses of antidepressants in rodents.

Animals↗
PubMed1999

Comparative effects of serotonergic agonists with varying efficacy at the 5-HT(1A) receptor on core body temperature: modification by the selective 5-HT(1A) receptor antagonist WAY 100635.

A reduction in core body temperature is one of the characteristic consequences of 5-HT1A receptor activation in rodents. In this study, we characterized the hypothermic effects of four 5-HT1A receptor ligands with varying affinity and selectivity at the 5-HT1A receptor. 8-OH-DPAT and flesinoxan (full agonists); ipsapirone (selective partial agonist) and eltoprazine (non selective partial agonist), all induced a dose-dependent reduction in core body temperature, which was maximal 30 min subsequent to administration. This response differed quantitatively between the agonists, in both the extent and the duration of its effects. The selective 5-HT1A receptor antagonist WAY 100635 (0.15 mg/kg), attenuated the hypothermia induced by the partial agonists, ipsapirone (10 mg/kg) and eltoprazine (10 mg/kg). In contrast, the higher dose of WAY 100635 (1 mg/kg) antagonized the effects of all agonists. This study therefore further confirms the utility of hypothermia as a simple, robust in-vivo probe of 5-HT1A receptor function. This paradigm, which was enhanced by use of specific antagonists such as WAY 100635, may prove useful for the detection and characterization of novel 5-HT1A receptor ligands.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Combining pindolol and paroxetine in an animal model of chronic antidepressant action--can early onset of action be detected?

The realisation that pindolol may accelerate the effects of some antidepressant drugs in clinical trials has added extra impetus to the search for faster acting antidepressants. Currently, no animal model of depression can identify potential faster acting antidepressant drugs or drug combinations. In this study, we investigate the effects of combining pindolol (2 mg/kg, s.c., bid) with the antidepressant paroxetine (2.5 mg/kg, i.p., bid) in the olfactory bulbectomised rat, an animal model of chronic (but not acute) antidepressant activity. Ambulation scores were measured in separate groups of rats, following 3, 7 and 14 days of treatment. Further, we simultaneously study adaptive changes in 5-HT1A receptor function, utilising alterations in the hypothermic response to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Pindolol in combination with paroxetine attenuated the hypothermic effects of 8-OH-DPAT as early as 3 days with a full reversal evident following 7 days, whereas paroxetine alone did so after 14 days only. Likewise, paroxetine alone reversed the olfactory bulbectomy-induced hyperactivity in the open field following 14 days of treatment only, this being the normal time of an 'antidepressant' response in this model. However, the group treated with both paroxetine and pindolol failed to reverse the hyperactive response. This suggests that a factor intrinsic to pindolol antagonises the behavioural effects of paroxetine in the olfactory bulbectomised rat. It also demonstrates that the reversal of this aspect of the olfactory bulbectomy-induced behavioural syndrome is insensitive to the potential faster onset of antidepressant action induced by pindolol. The ability of the combination group to attenuate the hypothermic effects of 8-OH-DPAT much faster further emphasises the role of the 5-HT1A receptor in the mechanism of action of antidepressants and as a target for the development of faster acting antidepressants. However, an animal model sensitive to the effects of any such compound and the actions of pindolol remains elusive.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

The functional sensitisation of sigma receptors following chronic selective serotonin reuptake inhibitor treatment.

The purpose of the present study was to investigate the potential impairment of normal motor function following chronic selective serotonin reuptake inhibitor treatment that may result from sensitisation of sigma receptors. Rats were chronically treated with either sertraline, citalopram, paroxetine or fluvoxamine and a selective sigma receptor ligand, di-o-tolylguanidine (DTG), for 28 days. All animals then received an acute intra-rubral injection of either DTG or saline. Following the direct injection of DTG into the red nucleus, rats chronically treated with DTG exhibit a maximal behavioural response characterised as a pronounced dystonia. Animals chronically treated with sertraline and citalopram elicited a response similar to that of control animals following the acute DTG challenge, whereas chronic treatment with paroxetine and fluvoxamine significantly decreased and increased the dystonic response, respectively. Facial spasticity and vacuous chewing movements were associated with, and reflected the extent of, the DTG-induced dystonia. Changes in regional biogenic amine concentrations were also determined. The concentrations of serotonin and noradrenaline were determined in the brain stem and cerebellum following the intra-rubral injection of either saline or DTG in animals that had been chronically treated with a selective serotonin reuptake inhibitor or DTG. There was a significant increase in serotonin concentration in the brain stem as a result of chronic DTG and fluvoxamine treatments. The increase in serotonin correlated with the reported potentiation of dystonia in animals that received 28 days treatment with these drugs. The potentiation of dystonia following chronic DTG and fluvoxamine treatments suggests that these drugs sensitise the sigma2 receptors, an effect that does not appear to be shared by citalopram, sertraline or paroxetine.

Animals↗
PubMed1998

Comparison between the effects of sigma receptor ligand JO 1784 and neuropeptide Y on immune functions.

Recent evidence suggests that sigma receptor ligands and neuropeptide Y may act through the same pathways to modulate centrally mediated immune function. The present study demonstrated that both the sigma receptor ligand igmesine: (+)-N-cyclopropylmethy-N-methyl-1, 4-diphenyl-1-yl-but-3-en-1-ylamine, hydrochloride (JO 1784) (10(-7) and 10(-5) M) and neuropeptide Y (10(-9) and 10(-7) M) in vitro significantly reduced neutrophil phagocytosis and decreased mitogen stimulated lymphocyte proliferation. By contrast, central administration of JO 1784 (0.5 and 5 microg/5 microl) significantly reduced the activity of neutrophil phagocytosis, but enhanced lymphocyte proliferation without changing the serum concentration of corticosterone. Neuropeptide Y (10(-9) and 10(-7) M), following intracerebroventricular infusion, also decreased the neutrophil response, but significantly raised the corticosterone concentration. These results indicate that different mechanisms (involving various neurotransmitters and their receptors, changes in the activity of the hypothalamic-pituitary-adrenal axis, or sigma receptor subtypes) may be involved in the central effects of JO 1784 and neuropeptide Y.

Animals↗
PubMed1998

Depression, stress and immunological activation: the role of cytokines in depressive disorders.

Traditionally, both stress and depression have been associated with impaired immune function and increased susceptibility to infectious and neoplastic disease. However over the last number of years a large body of evidence suggests that major depression is associated with signs of immunological activation. Moreover it has been suggested that cytokine hypersecretion may be involved in the aetiology of depressive disorders. The present article reviews the evidence from both clinical and experimental studies which implicates immunological activation and particularly hypersecretion of cytokines in the onset and maintenance of depressive illness. Both clinical and experimental studies indicate that stress and depression are associated with increased circulating concentrations of cytokines such as IL-1beta, IL-6 and gamma-IFN and positive acute phase proteins, and hyperactivity of the HPA-axis. In addition, it has been reported that immunological activation induces "stress-like" behavioural and neurochemical changes in laboratory animals. Although for many years it has been suggested that stress acts a predisposing factor to depressive illness, the precise mechanisms by which stress-induced depressive symptoms occur are not fully understood. Nevertheless, behavioural changes due to stress have often been explained in terms of changes in neurotransmitter function in the brain. In the present article increased cytokine secretion is implicated as a mechanism whereby stress can induce depression.

Animals↗
PubMed1998

Forced swim test-induced endocrine and immune changes in the rat: effect of subacute desipramine treatment.

Previously it has been reported that forced swim test (FST) exposure activates the HPA-axis and produces alterations in both cellular and noncellular immunity in rats. Furthermore, there is evidence to suggest that pretreatment with antidepressants has a protective effect against FST-induced immune changes. The purpose of the present study was to examine the effect of subacute treatment with the tricyclic antidepressant desipramine (DMI, 5 and 10 mg/kg; I.P.) on immobility in the FST, and on FST-induced changes in endocrine and immune parameters in the rat. DMI treatment at a dose of 10 mg/kg produced a significant reduction in immobility time in the FST, while the 5 mg/kg dose was ineffective. FST exposure produced a significant increase in serum corticosterone and a decrease in adrenal ascorbic acid concentrations, neither of which were significantly attenuated by DMI pretreatment. There was a slight but nonsignificant suppression of PHA-induced lymphocyte proliferation 15 min post-FST exposure. However, DMI treatment produced a significant increase in lymphocyte proliferation at this time point. FST exposure caused a reduction in the percentage of lymphocytes and an increase in the percentage of neutrophils in the peripheral blood; DMI treatment failed to significantly alter these stress-induced changes. There was a profound reduction in relative spleen weight observed in DMI-treated animals 120 min post-FST exposure and this was accompanied by an increase in circulating RBC concentrations. In conclusion, although the FST-induced behavioral changes were normalized by DMI treatment the peripheral aberrations induced by FST exposure (with the exception of lymphocyte proliferation) were not. In addition, DMI pretreatment induced stress-like changes in corticosterone, adrenal ascorbic acid and leucocyte subpopulations in the control animals.

Adrenal Glands↗
PubMed1998

Acute 3,4-methylenedioxymethamphetamine(MDMA) administration produces a rapid and sustained suppression of immune function in the rat.

(+)-3,4-Methylenedioxymethamphetamine (MDMA;'Ecstasy') is a ring substituted phenylisopropylamine that is structurally related to both amphetamines and hallucinogens. The unique behavioural activating properties of MDMA have led to its widespread abuse. MDMA induces many neurochemical, behavioural and endocrine alterations which closely resemble those elicited by exposure to acute stress, suggesting that MDMA could be regarded as a 'chemical stressor'. In addition to the neurochemical, behavioural and endocrine effects of stressor exposure, it has been reported that stress produces alterations in immune function. However, to date the effects of MDMA on immune function have been restricted to in vitro investigations. In this study we report, for the first time, that acute in vivo administration of MDMA (20 mg/kg, i.p.) produced a rapid (within 30 min) suppression of Con A-induced lymphocyte proliferation and a profound reduction in the total leucocyte count in rats that persisted for at least 6 h following injection. These alterations in immune function were accompanied by a significant increase in plasma corticosterone concentrations 30 min post MDMA administration which had returned to baseline values within 6 h of drug administration. In addition, there was a significant depletion in cortical 5-HT concentrations both 30 min and 6 h after MDMA administration. The results of this study provide evidence that in addition to the well established toxic effects of MDMA on the central serotonergic system, a single administration of this widely abused drug induces a rapid and sustained suppression of immune function.

Animals↗
PubMed1998

Beta-amyloid(Phe(SO3H)24)25-35 in rat nucleus basalis induces behavioral dysfunctions, impairs learning and memory and disrupts cortical cholinergic innervation.

Long-term behavioral effects, changes in learning and memory functions and aberrations of cholinergic fibers projecting to the parietal cortex were investigated after bilateral injections of beta-amyloid(Phe(SO3H)24)25-35 peptide in rat nucleus basalis magnocellularis (nbm). The beta-amyloid peptide used in these experiments contained the original beta-amyloid 25-35 sequence which was coupled to a phenylalanine-sulphonate group at position 24. This additional residue serves as a protective cap on the molecule without influencing its neurotoxic properties and results in water-solubility, stability and low rates of peptide metabolism. In this paper, home cage, locomotor and open-field activities, passive shock-avoidance and 'Morris' water maze learning abilities were assessed throughout a 35-day survival period. Subsequently, acetylcholinesterase (AChE) histochemistry was used to visualize alterations of parietal cortical cholinergic innervation. In response to the neurotoxic action of beta-amyloid(Phe(SO3H)24)25-35, a progressive hyperactivity developed in the rats in their home cages which were maintained throughout the 5-week post-injection period. This was accompanied by a significant hypoactivity in the novel environment of a locomotor arena. Beta-amyloid(Phe(SO3H)24)25-35-treated animals showed greatly impaired cortical memory functions in the step-through passive shock-avoidance paradigm, while spatial learning processes remained unaffected. Moreover, beta-amyloid(Phe(SO3H)24)25-35 injections in the nucleus basalis suppressed explorative behavior in rats and inhibited conditioned stress responses 28 days after surgery. Reductions of cortical cholinergic (AChE-positive) projections provided anatomical substrate for the behavioral changes. This indicated extensive, long-lasting neurodegenerative processes as a result of beta-amyloid(Phe(SO3H)24)25-35 infusion.

Acetylcholinesterase↗
PubMed1998

An assessment of the effects of central interleukin-1beta, -2, -6, and tumor necrosis factor-alpha administration on some behavioural, neurochemical, endocrine and immune parameters in the rat.

Despite a vast amount of research into the actions of cytokines within the central nervous system, the pharmacological role and/or physiological function of the various cytokines within the central nervous system is still not fully understood. The present study evaluated the effects of intracerebroventricular administration of interleukin-1beta, -2, -6 (20 ng) and tumour necrosis factor-alpha (40 ng) on elevated plus maze behaviour, monoamine levels in the hypothalamus, hippocampus and amygdala, plasma corticosterone and catecholamine concentrations and Concanavalin A-induced splenic lymphocyte proliferation in the rat. Both interleukin-1beta and tumour necrosis factor-alpha induced "anxiogenic-like" effects on the elevated plus maze, whereas interleukin-2 and interleukin-6 did not. However only interleukin-1beta led to endocrine variations often associated with stress and anxiety. Cytokine specific alterations in monoamine levels were evident in the hypothalamus and hippocampus, while neurotransmitter concentrations in the amygdala were not significantly altered by cytokine treatment. In addition, interleukin-1beta reduced Concanavalin A-induced lymphocyte proliferation, whereas the other cytokine treatments failed to significantly alter this response. These results demonstrate that in some, but not all, respects interleukin-1beta administration produced "stress like" effects on behaviour, monoamine neurotransmitters, hypothalamic pituitary adrenal axis activity and immune function, while the other cytokines produced less consistent effects on these parameters. It is noteworthy that although interleukin-1beta and tumour necrosis factor-alpha provoked an anxiogenic response in the elevated plus maze test of anxiety, neither cytokine significantly altered amygdaloid noradrenergic or serotonergic activity, as many previous studies have implicated increased amygdaloid noradrenergic and/or serotonergic activity in the pathophysiology of anxiety.

Animals↗
PubMed1998

Beta-amyloid-induced cholinergic denervation correlates with enhanced nitric oxide synthase activity in rat cerebral cortex: reversal by NMDA receptor blockade.

Ample experimental evidence indicates that acute beta-amyloid infusion into the nucleus basalis of rats elicits abrupt degeneration of the magnocellular cholinergic neurons projecting to the cerebral cortex. In fact, involvement of a permanent Ca2+ overload, partially via N-methyl-D-aspartate (NMDA) receptors, was proposed as a pivotal mechanism in beta-amyloid-induced neurodegeneration. A definite measure of NMDA receptor-mediated processes and subsequent Ca2+ entry is the induction of Ca2+/calmodulin-activated neuronal nitric oxide synthase (nNOS) in nerve cells. In the present account we therefore assessed activation of nNOS in correlation with cholinergic decline after beta-amyloid(1-42) or beta-amyloid(25-35) infusion into the rat nucleus basalis. The results demonstrate the beta-amyloid conformation-dependent enhancement of cortical nitric oxide synthase (NOS) activity. Furthermore, chronic application of the polyamine site NMDA receptor blocker ifenprodil effectively attenuated beta-amyloid neurotoxicity. We propose that nNOS activation reflects the degree of beta-amyloid-induced excitotoxic injury in a proportional manner. Moreover, Ca2+-mediated processes via NMDA receptors, or direct binding of beta-amyloid to this receptor may be a critical step in the neurotoxic mechanisms in vivo.

Amyloid beta-Peptides↗