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Biomedical subjects

B E Leonard

Publications and source records attributed to B E Leonard.

At least 37 records · Page 2Linked to original sources
PubMed2000

Methylenedioxymethamphetamine (MDMA; Ecstasy) suppresses IL-1beta and TNF-alpha secretion following an in vivo lipopolysaccharide challenge.

In this study we examined the effects of methylenedioxymethamphetamine (MDMA) administration on responsiveness to an in vivo immune challenge with lipopolysaccharide (LPS; 100 microg/kg; i.p.). LPS produced an increase in circulating IL-1beta and TNF-alpha in control animals. MDMA (20 mg/kg; i.p.) significantly impaired LPS-induced IL-1beta and TNF-alpha secretion. The suppressive effect of MDMA on IL-1beta secretion was transient and returned to control levels within 3 hours of administration. In contrast, the MDMA-induced suppression of TNF-alpha secretion was evident for up to 12 hours following administration. In a second study we examined the effect of co-administration of MDMA (5, 10 and 20 mg/kg; i.p.) on LPS-induced IL-1beta and TNF-alpha secretion, and demonstrated that all three doses potently suppressed LPS-induced TNF-alpha secretion, but only MDMA 10 and 20 mg/kg suppressed LPS-induced IL-1beta secretion. In addition, serum MDMA concentrations displayed a dose-dependent increase, with the concentrations achieved following administration of 5 and 10 mg/kg being in the range reported in human MDMA abusers. In order to examine the possibility that the suppressive effect of MDMA on IL-1beta and TNF-alpha could be due to a direct effect of the drug on immune cells, the effect of in vitro exposure to MDMA on IL-1beta and TNF-alpha production in LPS-stimulated diluted whole blood was evaluated. However IL-1beta or TNF-alpha production were not altered by in vitro exposure to MDMA. In conclusion, these data demonstrate that acute MDMA administration impairs IL-1beta and TNF-alpha secretion following an in vivo LPS challenge, and that TNF-alpha is more sensitive to the suppressive effects of MDMA than is IL-1beta. However the suppressive effect of MDMA on IL-1beta and TNF-alpha could not be attributed to a direct effect on immune cells. The relevance of these findings to MDMA-induced immunomodulation is discussed.

Animals↗
PubMed2000

Prolonged c-Jun expression in the basolateral amygdala following bulbectomy: possible implications for antidepressant activity and time of onset.

Olfactory bulbectomy is a well established animal model of depression. Neurochemical and behavioral alterations observed following olfactory bulbectomy, are due, in part, to the neurodegeneration of specific brain structures. Amygdaloid dysfunction in particular, is known to play a substantial role in the syndrome of the olfactory bulbectomized rat. The present study examined both short- and long-term alterations in immediate early gene expression, tyrosine hydroxylase and serotonin immunoreactivity, and classical silver staining, following olfactory bulbectomy in the basolateral amygdala. The results indicated no consistent change in Fos expression observed over the experimental period. Following bulbectomy, long term (up to 64 days post-lesion) Jun expression, not coincident with silver staining, was observed in the basolateral nucleus. The basolateral nucleus was also intensely immunoreactive for serotonin at this timepoint post-bulbectomy. Thus, following bulbectomy long term alterations in Jun expression occurs in the serotonin rich basolateral amygdala. As a site of action for antidepressant compounds, alterations at the immediate early gene level in this region may have implications both for the model, and antidepressant drug action therein.

Amygdala↗
PubMed2000

Characterization of D-fenfluramine-induced hypothermia: evidence for multiple sites of action.

The effects of D-fenfluramine on core body temperature has been largely investigated under conditions of either high or low ambient temperature, whereas little research has focused on this response under normal environmental conditions. Moreover, there has been neglect in research on the mechanisms underlying changes in body temperature. In this study, we demonstrate that D-fenfluramine (5 and 10 mg/kg) induces a sustained decrease in body temperature in the rat under normal ambient temperatures. Pre-treatment with the selective serotonin reuptake inhibitor sertraline (5 mg/kg), the full 5-HT(1A) receptor antagonist 4-fluoro-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-pyridinyl benzamide], WAY 100635 (0.15 mg/kg) and the 5-HT(2C) receptor antagonist benzofuran-2-carboxamidine, RO 43-0440 (2.5 mg/kg) blocked D-fenfluramine-induced hypothermia. Depletion of 5-hydroxytryptamine (5-HT) stores following treatment with the serotonergic neurotoxin parachlorophenylalanine reversed the initial hypothermic effects of D-fenfluramine but not the later effects, as D120 min post-challenge) in animals pre-treated with parachlorophenylalanine. Such findings are consistent with a requirement for D-fenfluramine uptake into 5-HT neurons followed by release of 5-HT from intracellular stores and stimulation of post-synaptic 5-HT receptors to reduce body temperature. The hypothermic response to D-fenfluramine was potentiated by ketanserin pre-treatment 30 min post-challenge but then antagonized at later time intervals. Pre-treatment with the dopamine, D(2) antagonist, haloperidol (1 mg/kg) and sulpiride (30 mg/kg) had a similar effect in blocking the hypothermia as WAY 100635, suggesting a role for dopamine D(2) receptors in the response. Pre-treatment with the alpha(2)-adrenoceptor antagonist yohimbine failed to block the hypothermic response. These results suggest multiple sites of action mediating D-fenfluramine-induced hypothermia and may be the result of a combined effect of D-fenfluramine and its active metabolite norfenfluramine affecting not only the release of 5-HT but also stimulation of post-synaptic receptors.

Adrenergic alpha-Antagonists↗
PubMed2000

Lipopolysaccharide administration produces time-dependent and region-specific alterations in tryptophan and tyrosine hydroxylase activities in rat brain.

The present study examined the effect of systemic administration of lipopolysaccharide (LPS; 100 and 250 microg/kg, i.p.) on tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities in frontal cortex, striatum and midbrain of the rat. Enzyme activities were determined by measuring accumulation of the transient intermediates 5-hydroxytrptophan (5-HTP) and L-dihydroxyphenylalanine (L-DOPA) following in vivo administration of the decarboxylase inhibitor, NSD 1015. TPH activity was increased 2 hours after administration of LPS (100 and 250 microg/kg) in both frontal cortex and midbrain, and a secondary increase was seen in the midbrain 12 hours after challenge. LPS provoked an increase in TH activity in the midbrain only, and this was evident for up to 24 hours after LPS administration. Thus in addition to previous studies demonstrating that LPS increases in vivo NA, DA and 5-HT release, this study shows that LPS increases the activity of the rate-limiting enzymes responsible for their synthesis.

5-Hydroxytryptophan↗
PubMed2000

Effects of reboxetine and sertraline treatments alone and in combination on the binding properties of cortical NMDA and beta1-adrenergic receptors in an animal model of depression.

Changes to the binding properties of cortical N-methyl-D-aspartic acid (NMDA) and beta-adrenergic receptors have both been reported as potential indicators of antidepressant activity. In the present investigation we examined the effects of the noradrenaline reuptake inhibitor, reboxetine, the serotonin reuptake inhibitor, sertraline, alone and in combination on the binding properties of cortical NMDA receptors and cortical beta1-adrenoceptors following 14 days of treatment in the olfactory bulbectomized rat model of depression. A decrease in the potency of glycine to displace the strychnine insensitive glycine antagonist [3H] 5,7 dichlorokynurenic acid (5,7 DCKA) was observed in cortical homogenates of OB rats when compared to sham-operated controls. Similarly, treatment with the combination of reboxetine and sertraline for 14 days produced a decrease in the potency of glycine when compared to vehicle treated controls. By contrast neither olfactory bulbectomy or drug treatment significantly altered basal or glycine enhanced binding of the non-competitive NMDA antagonist [3H] MK-801 in cortical homogenates. Reboxetine alone, and in combination with sertraline, down-regulated [3H]-CGP 12177 (a selective beta-adrenoceptor antagonist) binding in both OB and sham-operated animals. The lack of a bulbectomy effect in the [3H] CGP-12177 binding assay, and the fact that olfactory bulbectomy and antidepressant treatments produce a similar change to the potency of glycine at the NMDA receptor, suggests that these tests do not provide a neurochemical marker for either the behavioral hyperactivity deficit or antidepressant response in the model.

Adrenergic Uptake Inhibitors↗
PubMed2000

Effect of subchronic antidepressant treatments on behavioral, neurochemical, and endocrine changes in the forced-swim test.

The purpose of the present study was to examine the effect of subchronic treatment (24 days) with antidepressants displaying differential effects on noradrenaline and serotonin reuptake, on behavior, neurochemistry, and hypothalamic-pituitary-adrenal (HPA) axis activity following FST exposure in the rat. Desipramine (7.5 mg/kg, IP) significantly decreased immobility in the FST, whilst paroxetine (7.5 mg/kg IP) and venlafaxine (10 mg/kg, IP) were without effect. Nonetheless, treatment with all three antidepressants significantly attenuated stress-related increases in amygdaloid and cortical serotonin turnover. Of the three antidepressants examined, only desipramine attenuated the stress-associated elevation in serum corticosterone. In conclusion, although FST-induced increases in serotonin turnover in the frontal cortex and amygdala were attenuated following treatment with all three antidepressants, FST-induced behavioral changes and increased HPA axis activity were normalized only following desipramine treatment. In addition, these results suggest that neurochemical mechanisms independent of increased serotonergic activity subserve the normalization of behavior and HPA axis responses in the FST. These data also add to our understanding of the interactions between antidepressants and stress-induced behavioral, neurochemical, and endocrine alterations, and illustrates important differences between classes of antidepressants.

Amygdala↗
PubMed2000

Test conditions influence the response to a drug challenge in rodents.

These studies were conducted to examine the differential response to a drug challenge under varied experimental test conditions routinely employed to study drug-induced behavioral and neurophysiological responses in rodents. Apomorphine, a nonselective dopamine agonist, was selected due to its biphasic behavioral effects, its ability to induce hypothermia, and to produce distinct changes to dopamine turnover in the rodent brain. From such experiments there is evidence that characterization and detection of apomorphine-induced activity in rodents critically depends upon the test conditions employed. In rats, detection of apomorphine-induced hyperactivity was facilitated by a period of acclimatization to the test conditions. Moreover, test conditions can impact upon other physiological responses to apomorphine such as drug-induced hypothermia. In mice, apomorphine produced qualitatively different responses under novel conditions when compared to those behaviors elicited in the home test cage. Drug-induced gross activity counts were increased in the novel exploratory box only, while measures of stereotypic behavior were similar in both. By contrast, apomorphine-induced locomotion was more prominent in the novel exploratory box. Dopamine turnover ratios (DOPAC:DA and HVA:DA) were found to be lower in those animals exposed to the exploratory box when compared to their home cage counterparts. However, apomorphine-induced reductions in striatal dopamine turnover were detected in both novel and home cage environments. The implications of these findings are discussed with particular emphasis upon conducting psychopharmacological challenge tests in rodents.

Analysis of Variance↗
PubMed2000

An assessment of the acute effects of the serotonin releasers methylenedioxymethamphetamine, methylenedioxyamphetamine and fenfluramine on immunity in rats.

The purpose of the present study was to examine the effect of the serotonin releasing amphetamine derivatives methylenedioxymethamphetamine (MDMA), methylenedioxyamphetamine (MDA) and fenfluramine (FEN) on immunity in rats. Similar to MDA and MDMA, FEN reduced the number of circulating lymphocytes, provoked a suppression of Con A-stimulated lymphocyte proliferation and total IFN-gamma and IL-10 production in diluted whole blood cultures. Thus the non-psychostimulant amphetamine derivative FEN, shares the ability of the psychostimulant methylenedioxy-substituted amphetamine derivatives to alter these indices of immune function in the rat. However, when Con A-stimulated cytokine production was normalised for the number of lymphocytes in culture in order to examine cytokine production at a cellular level, the effect of the amphetamine derivatives begins to diverge. FEN shares with MDMA and MDA the ability to suppress production of the Th2 type cytokine IL-10. However the effect of these drugs on Th1 type cytokine secretion was much more complex. While the methylendioxy-substituted amphetamines increases the secretion of the Th1 type cytokine IL-2 without altering the related Th1 type cytokine IFN-gamma, FEN did not alter IL-2 secretion, but suppressed IFN-gamma secretion. In addition to these effects on T-cell responses, all three drugs inhibited LPS-induced TNF-alpha secretion from diluted whole blood cultures suggesting that macrophage activity is impaired following treatment. In all, these data extend our previous findings concerning the effects of MDMA on the immune system and demonstrate that the related serotonin releasers MDA and FEN also provoke immunological changes in rats.

3,4-Methylenedioxyamphetamine↗
PubMed2000

A double-blind, placebo-controlled, efficacy, safety, and pharmacokinetic study of INN 00835, a novel antidepressant peptide, in the treatment of major depression.

BACKGROUND: INN 00835 is a synthetic pentapeptide with a potential for rapid onset of action as an antidepressant. Its efficacy was investigated in a pilot study in patients diagnosed with major depression. METHODS: Fifty two patients received either active drug - INN 00835 (26 patients) - or placebo (26 patients), subcutaneously at 0.2 mg/kg for 5 consecutive days. The patients were evaluated for an additional 4 weeks after treatment. Efficacy was evaluated by the following psychiatric rating scales: HAMD, MADRS, CSRS, CGI, and VAS. The effect of treatment was also evaluated by using a biochemical marker: changes in blood platelet serotonin (5HT) uptake rates in drug-treated patients compared to those in the placebo group. Plasma concentrations of INN 00835 were measured by LC/MS. RESULTS: Statistical analysis indicated a strong pharmacodynamic correlation between plasma drug concentrations at 1 h after dosing and the reduction in the severity of depression as measured by the psychiatric rating scales. A minimum effective plasma concentration (MEC) of INN 00835 was 5 ng/ml. Statistically significant differences in response to treatment (P<0.05) were found between patients with plasma concentrations above MEC and those in the placebo group, as well as between subjects with plasma concentrations above and below the MEC. The peak effect was observed after the 5-day treatment and the response to treatment persisted during the 4-week follow-up period. The change of 5HT uptake rates after treatment was significantly larger in the drug-treated group than in the placebo group. LIMITATIONS: This was a pilot study conducted in a relatively small population (52 patients) and the limited number of blood sampling times did not allow a comprehensive pharmacokinetic analysis. There was a relatively large placebo response. The results have to be confirmed in future, large scale studies. CONCLUSIONS: INN 00835 appears to be a promising drug for the treatment of major depression.

Adult↗
PubMed2000

Olfactory bulbectomy provokes a suppression of interleukin-1beta and tumour necrosis factor-alpha production in response to an in vivo challenge with lipopolysaccharide: effect of chronic desipramine treatment.

The olfactory bulbectomized (OB) rat has been developed as an animal model of depression and exhibits several behavioural and neurochemical characteristics that are qualitatively similar to those found in clinically depressed patients. In addition to the behavioural and neurochemical abnormalities seen in OB rats, it has been reported that these animals have alterations in a number ex vivo measures of immune function many of which are reversed following chronic antidepressant treatment. In the present study we sought to examine the effects of olfactory bulbectomy on responsiveness to an in vivo immune challenge with bacterial lipopolysaccharide (LPS; 100 microg/kg, i.p.). In addition, the effect of chronic treatment with the tricyclic antidepressant desipramine (7.5 mg/kg, i.p.) on bulbectomy related behavioural changes, hypothalamic-pituitary-adrenal axis activity and immune responsiveness was evaluated. To our knowledge this is the first time that in vivo immunological responsiveness has been examined in the OB rat model of depression. OB rats exhibited a characteristic hyperactive response in a novel 'open field' environment, which was attenuated following chronic desipramine treatment. LPS provoked a large increase in circulating interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha in vehicle treated sham operated animals. Vehicle treated OB rats displayed a significant impairment in LPS-induced IL-1beta (54%) and TNF-alpha (70%) secretion compared to their sham operated controls, an effect that was potentiated following chronic desipramine treatment. Furthermore, sham animals that were chronically treated with desipramine displayed decreases in LPS-provoked IL-1beta (51%) and TNF-alpha (49%) secretion compared to vehicle treated counterparts. In addition, LPS-induced alterations in corticosterone and adrenal ascorbic acid concentrations were also attenuated by bulbectomy, an effect that was further enhanced following chronic desipramine treatment. In conclusion, these data provide evidence that olfactory bulbectomy in the rat impairs the ability of macrophages to produce the proinflammatory cytokines IL-1beta and TNF-alpha following an in vivo challenge with bacterial LPS. Whilst chronic treatment with desipramine normalized the behavioural hyperactivity observed in OB rats, such treatment further impaired LPS-induced IL-1beta and TNF-alpha secretion in bulbectomized rats.

Adrenal Cortex↗
PubMed2000

Evidence for a biochemical lesion in depression.

The monoamine hypothesis of depression predicts an impairment in central monoaminergic function. The lesion may comprise deficiencies in the absolute concentrations of norepinephrine and/or serotonin (5-HT). Depletion studies have shown a correlation between such deficiencies and depressive symptoms. Measurement of the concentrations of the neurotransmitters and their metabolites in cerebrospinal fluid, urine, and plasma of patients with depression has yielded equivocal results regarding the possibility of altered metabolism of these neurotransmitters. Other studies have investigated the possibility of altered numbers and/or affinities of the serotonin and norepinephrine receptors and uptake sites. For example, there is evidence for a reduction in the activity of the serotonin reuptake transporter in patients with depression and an increase in the density of 5-HT2 receptors in the brains of suicide victims. Similarly, in the noradrenergic system, up-regulation of beta-adrenoceptors is consistently observed. Most recently, attention has focused on the possibility that a lesion may occur in the postreceptor, subcellular components of the monoamine systems, such as the second messenger processes. Also, experimental evidence has shown "cross-talk" between the noradrenergic and serotonergic systems. There is therefore substantial clinical and experimental evidence that lesions in the serotonergic and noradrenergic systems are responsible for depression and that antidepressant treatment can reverse these alterations.

Antidepressive Agents↗
PubMed1999

Reboxetine attenuates forced swim test-induced behavioural and neurochemical alterations in the rat.

The forced swim test is a behavioural paradigm that is predicative of antidepressant activity in rodents. Until recently, research has focused on the ability of antidepressant drugs to decrease immobility in the forced swim test paradigm, but the neurochemical sequelae induced by swim stress, or the neurochemical basis of antidepressant-induced behavioural changes have received little attention. In this regard, we have recently demonstrated that forced swim test exposure increases serotonergic activity in the amygdala, frontal cortex and hippocampus and dopamine turnover in the striatum. In addition, forced swim test-exposure activates the hypothalamic pituitary adrenal axis. The purpose of the present study was to examine the effect of treatment with the selective noradrenaline reuptake inhibitor reboxetine (3, 10 and 30 mg/kg; i.p.) on immobility and defaecation scores in the forced swim test, and on forced swim test-induced neurochemical and hypothalamic pituitary adrenal axis changes in the rat. Reboxetine treatment (10 and 30 mg/kg) significantly decreased immobility and defaecation in the forced swim test in dose dependent manner. Furthermore, reboxetine produced a dose dependent attenuation of forced swim test-induced increases in serotonin turnover in the amygdala and frontal cortex and dopamine turnover in the striatum. Reboxetine (30 mg/kg) produced a modest, but non-significant, attenuation of forced swim test-induced increases in serum corticosterone concentrations. These data demonstrate that, in addition to the behavioural activity of reboxetine in the rat forced swim test paradigm, a dose-dependent attenuation of swim stress-induced increases in serotonergic and dopaminergic activity occurred in a region specific manner. These are the first data to demonstrate that treatment with the selective noradrenaline reuptake inhibitor, reboxetine can impact on the activity of other neurotransmitter systems in response to stress. Moreover, these data further demonstrate that this paradigm is a valuable tool in studying the effect of antidepressants, on both behaviour and swim stress-related alterations in central neurotransmitter function and hypothalamic pituitary adrenal axis activity in the rat.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Stressor-induced alterations in serotonergic activity in an animal model of depression.

The present study examined the effect of two neurogenic stressors (air puff and restraint) and a metabolic stressor (lipopolysaccharide; LPS 100 microg/kg, i.p.) on accumbal serotonergic neurotransmission in the olfactory bulbectomized (OB) rat model of depression. Both air puff and restraint stress caused greater increases in accumbal 5-HIAA in OB than in sham-operated rats. In contrast, bulbectomy resulted in a blunted serotonergic response to a challenge with LPS (a metabolic stressor). In addition, OB rats displayed significantly lower basal levels of 5-HIAA than sham-operated counterparts, a finding consistent with previous reports of the OB rat being a model of hyposerotonergic depression. The relevance of these findings to stressor-provoked depressive-like behaviors in the OB rat are discussed.

Air↗
PubMed1999

Activity and onset of action of reboxetine and effect of combination with sertraline in an animal model of depression.

The limitations of antidepressant drugs to treat depression has warranted ongoing research to identify pharmacological agents and strategies which offer a faster onset of action and greater therapeutic efficacy. Noradrenaline and serotonin are widely reported to be involved in the mechanism of action of antidepressants and the recent development of selective reuptake inhibitors of these transmitters has provided the opportunity to determine the effects of targeting these transmitter systems, alone and in combination, in an antidepressant response. The present study investigated the effects of reboxetine, a new antidepressant that selectively inhibits noradrenaline reuptake, sertraline, a selective serotonin reuptake inhibitor and a combination treatment composed of the two drugs in the olfactory bulbectomized (OB) rat model of depression. Sub-acute (2 days) administration of reboxetine (2.5, 5, and 10 mg/kg, i.p.) to sham-operated and OB rats reduced the immobility time in the forced swim test. Repeated (14 days) reboxetine (10 mg/kg) treatment attenuated the OB-related behavioural hyperactivity in the 'open-field' test. Examination of the onset of the antidepressant effect in the 'open-field' test demonstrated that reboxetine (10 mg/kg), sertraline (5 mg/kg) and the combination reduced the behavioural hyperactivity after 14 days but not before this following 3, 7 or 10 days of treatment. Reduced 5-hydroxyindoleacetic acid (5-HIAA) concentrations in amygdaloid cortex of both sham and OB rats following sertraline and combination treatments are likely to be related to acute pharmacological effects on the reuptake of 5-hydroxytryptamine (5-HT). Attenuation of the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.05 mg/kg s.c.) and clonidine (0.1 mg/kg s.c.) occurred in the reboxetine and sertraline combination treated groups following both 7 and 14 days administration indicating changes to 5-HT1A receptor and alpha2-adrenoceptor sensitivity. The results indicate that changes to 8-OH-DPAT and clonidine-induced responses occur quicker with the combination treatment than with either reboxetine or sertraline treatments alone.

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

Metyrapone displays antidepressant-like properties in preclinical paradigms.

A possible involvement of glucocorticoids in the aetiology of depression is suggested by commonly reported hypothalamo-pituitary-adrenocortical (HPA) axis abnormalities in depressed patients, the modulation of the HPA axis by antidepressant drugs and clinical reports of antidepressant efficacy with antiglucocorticoid agents. The effects of treatment with metyrapone, a glucocorticoid synthesis inhibitor, and the tricyclic antidepressant, desipramine, in two rodent models of depression, namely the forced swim test and olfactory bulbectomized (OB) rat, were investigated. In addition, the effect of chronic metyrapone and desipramine treatments on the hypothermic response to a challenge with the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was assessed. There is experimental evidence to suggest that attenuation of the hypothermic response to this agonist occurs following chronic antidepressant treatment. In the forced swim test, metyrapone (50 mg/kg) and desipramine (10 mg/kg) significantly reduced the immobility time. In the olfactory bulbectomized rat model of depression, chronic administration (14 days) of metyrapone (50 mg/kg b.i.d.) and desipramine (5 mg/kg b.i.d.) attenuated the OB-related hyperactivity in a novel stressful environment. Chronic metyrapone treatment (50 mg/kg b.i.d.) attenuated the hypothermic response to an acute challenge with 8-OH-DPAT (0.05 mg/kg s.c.), indicating a change to the sensitivity of 5-HT1A receptors. These preclinical tests demonstrate an antidepressant-like profile for metyrapone. Further exploration of the therapeutic potential and possible mechanism of action of glucocorticoid antagonism in depression is warranted.

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

Differential effect of chronic antidepressant treatments on lipopolysaccharide-induced depressive-like behavioural symptoms in the rat.

In the present study we observed that lipopolysaccharide (LPS) administration provoked a characteristic reduction in body weight gain, food consumption, saccharin (but not water) consumption and nocturnal locomotor activity. It has been previously suggested that the ability of LPS to suppress the consumption of, and preference for, a palatable solution such as saccharin without altering water consumption, may represent an anhedonic response. The results of the present study demonstrate that chronic treatment with the tricyclic antidepressant (TCA) desipramine (7.5 mg/kg; i.p.) prevented LPS-induced anorexia, loss of body weight, the antidipsogenic effect and hypoactivity. In contrast, chronic treatment with the antidepressants paroxetine (7.5 mg/kg; i.p.) and venlafaxine (10 mg/kg; i.p.) failed to alter any of the LPS-induced behavioural responses. Furthermore, chronic treatment with desipramine (and to a lesser extent paroxetine) reduced the consumption of, and preference for, saccharin suggesting that these antidepressant treatments induce an "anhedonic" response in their own right. In conclusion, chronic desipramine treatment attenuated LPS-induced depressive-like behavioural symptoms in the rat. However, chronic treatment with paroxetine and venlafaxine did not significantly alter LPS-induced behavioural responses. The results of the present study support the hypothesis that TCA's may exert part of their anti-depressive efficacy through their effects on the immune system. However, this property does not appear to be shared by newer antidepressants which possess a better side effect profile than the TCA's. The suppressive effect of TCA's on proinflammatory cytokine secretion is discussed as a mechanism by which these agents alter LPS-induced behavioural responses.

Adrenergic Uptake Inhibitors↗
PubMed1999

The determination of the optimal dose of milnacipran in the olfactory bulbectomized rat model of depression.

Olfactory bulbectomy (OB) is associated with a variety of behavioral abnormalities such as hyperactivity in the "open-field" test. Previous studies have shown that chronic administration of antidepressants can reverse this behavioral deficit. The activity of milnacipran (20, 30, and 40 mg/kg, PO bid) administered in two equally divided doses twice daily was assessed in the olfactory bulbectomized rat model of depression. It was found that chronic treatment with milnacipran at the doses of 30 and 40 mg/kg, but not 20 mg/kg, attenuated the lesion-induced hyperactivity of the OB rat in the "open-field" test following 14 days of treatment. In the step-through passive avoidance test, administration of milnacipran at doses of 20, 30, and 40 mg/kg had no effect on the performance deficit associated with olfactory bulbectomy. Olfactory bulbectomy reduced the concentration of noradrenaline (NA) in the frontal cortex. However, chronic milnacipran treatment did not significantly alter this deficit. It is concluded that milnacipran, when administered chronically at doses of 30 and 40 mg/kg, are effective at reversing the "open-field" deficit associated with olfactory bulbectomy, and that a dose of 30 mg/kg is an optimal dose.

Animals↗