Biomedical subjects

T J Connor

Publications and source records attributed to T J Connor.

At least 19 recordsLinked to original sources

PubMed2006

Chicken anaemia virus inoculated by the oral route causes lymphocyte depletion in the thymus in 3-week-old and 6-week-old chickens.

There have been many reports of the severe clinical disease and pathology seen in young chicks that have been vertically infected with chicken anaemia virus (CAV). The disease is characterized by anaemia, and atrophy of the thymus and bone marrow. However, while it has been suggested that horizontally acquired infections of older birds are common, to date there has been no description in the literature of the pathology of this type of infection. In the present study, 3-week-old and 6-week-old chickens were infected by the oral route, as is likely to occur naturally, and a wide range of tissues were examined immunocytochemically for the presence of CAV antigen. Histological examination was carried out on the thymus, spleen and bone marrow of all birds, and on all other tissue samples in which CAV antigen was found. CAV antigen and associated pathological change were detected in the thymus of both 3-week-old and 6-week-old birds. However, CAV antigen was rarely found in other tissues, which is in contrast to what is found in birds infected when 1-day-old. In particular, very few infected cells were found in the bone marrow. Anaemia and bone marrow atrophy, which are typically found in chicks infected vertically or when 1-day-old, did not develop in the 3-week-old or 6-week-old birds. The findings of this study show that CAV is capable of infecting thymocytes of older birds, in contrast to previous belief, and that it is associated with lymphocyte depletion. There was only limited evidence of viral replication in the other tissues examined.

Administration, Oral↗

PubMed2004

Retrospective characterization of Newcastle Disease Virus Antrim '73 in relation to other epidemics, past and present.

In November 1973 Newcastle disease suddenly appeared in Northern Ireland, where the viscerotropic disease had not been seen in 3 1/2 years and the two Irelands had been regarded as largely disease free for 30 years. It was successfully controlled with only 36 confirmed affected layer flocks, plus 10 more slaughtered as 'dangerous contacts'. Contemporary investigations failed to reveal the source of the Irish epidemic. Using archival virus samples from most of the affected flocks, RT PCR was conducted with primers selected for all six NDV genes. Phylogenetic analyses of three genes, HN, M and F, confirmed vaccine as the cause of one of the outbreaks. The other six samples were identical and closely related to previous outbreaks in the United States and western Europe initiated by infected imported Latin American parrots. The probable cause of the epidemic followed from the importation from The Netherlands of bulk feed grains contaminated with infected pigeon faeces.

HN Protein↗

PubMed2003

Serotonergic mediation of the antidepressant-like effects of nitric oxide synthase inhibitors.

Recent studies indicate that nitric oxide (NO) synthase inhibitors have antidepressant-like potential in various animal models. In the present study the behavioural activity of the NO synthase inhibitors, N(G)-nitro-L-arginine (L-NA) and 7-nitroindazole (7-NI), were assessed in a modified rat forced swimming test (FST). Both L-NA and 7-NI, dose dependently reduced immobility and increased swimming behaviour in the rat FST. This behavioural profile parallels the one previously shown with selective serotonin re-uptake inhibitors and serotonergic agonists. Thus, we examined the role of serotonin mediating the behavioural effects of L-NA and 7-NI in the rat FST. Depletion of endogenous serotonin using para-chlorophenylalanine (pCPA; 3 x 150 mg/kg, i.p.) completely blocked L-NA (20 mg/kg, i.p.) and 7-NI (20 mg/kg, i.p.)-induced reductions in immobility and increases in swimming behaviour during the FST. In conclusion these observations suggest that NO synthase inhibitors elicit their antidepressant-like activity in the modified swimming test through a serotonin dependent mechanism.

Animals↗

PubMed2001

Methylenedioxymethamphetamine (MDMA; 'Ecstasy') suppresses antigen specific IgG2a and IFN-gamma production.

Methylenedioxymethiamphetamine (MDMA; "Ecstasy") is a widely abused amphetamine derivative. In the present study, we examined the effect of acute MDMA administration on an antigen specific immune response. Responsiveness to an in vivo challenge with the soluble protein antigen keyhole limpet haemocyanin (KLH) was examined in rats following MDMA administration (2.5, 5 or 10 mg/kg; i.p.). KLH-specific serum IgM concentrations were measured 7 days following challenge, and serum IgG concentrations were measured 14 days following the KLH challenge. In addition, antigen-specific IFN-gamma and IL-6 production was measured in KLH-stimulated splenocytes. MDMA did not alter the KLH-specific IgM response. In contrast, MDMA (5 and 10 mg/kg) provoked a significant suppression of KLH-specific IgG production. Thus, MDMA administration did not alter the initial generation of the antibody response but rather inhibited antibody class switching from IgM to IgG. Two pathways for the genetic switch from IgM to IgG production were investigated. One pathway requires the Th(1) type cytokine IFN-gamma to stimulate IgM-secreting cells to switch to IgG(2a)-secreting cells. Another pathway requires the Th(2) type cytokines IL-4 and IL-6 to stimulate IgM-secreting cells to switch to IgG(1)-secreting cells. IgG(1) and IgG(2a) levels were measured to determine if these two pathways were differentially affected. The results indicate that only IgG(2a) levels were decreased following MDMA administration. Furthermore, this decrease in IgG(2a) was accompanied by decreased KLH-specific IFN-gamma production 14 days post KLH administration. In conclusion, these data indicate that MDMA alters the ability to switch from IgM to IgG(2a) production, possibly by reducing IFN-gamma. Potential health consequences for MDMA users are discussed.

Animals↗

PubMed2001

Methylenedioxymethamphetamine-induced suppression of interleukin-1beta and tumour necrosis factor-alpha is not mediated by serotonin.

The purpose of the present study was to examine the role of serotonin release in methylenedioxymethamphetamine (MDMA)-induced immunosuppression in rats. We examined the effect of pretreatment with the selective serotonin reuptake inhibitor paroxetine, and the tryptophan hydroxylase inhibitor para-chlorophenylalanine on MDMA-induced suppression of interleukin-1beta and tumour necrosis factor (TNF)-alpha secretion following an in vivo lipopolysaccharide challenge. Although paroxetine blocked MDMA-induced serotonin depletion in the cortex and hypothalamus, it failed to alter the suppressive effect of MDMA on lipopolysaccharide-induced TNF-alpha secretion. Similarly, although para-chlorophenylalanine caused a 90% depletion in cortical and hypothalamic serotonin content, it failed to alter the suppressive effect of MDMA on lipopolysaccharide-induced interleukin-1beta or TNF-alpha secretion. In conclusion, although MDMA is a potent releaser of serotonin, the suppressive effects of MDMA on lipopolysaccharide-induced proinflammatory cytokine secretion cannot be attributed to its serotonin-releasing properties.

Animals↗

PubMed2001

Prior exposure to methylenedioxyamphetamine (MDA) induces serotonergic loss and changes in spontaneous exploratory and amphetamine-induced behaviors in rats.

The substituted amphetamine 3,4 methylenedioxyamphetamine (MDA) is a popular recreational drug of abuse. Administration of MDA to experimental animals has been shown to induce damage to serotonergic axons and nerve terminals. However, there is a lack of information on whether these treatments can produce any long-term changes in behavioural performance particularly under stressful conditions. In the present study, MDA (7.5 mg/kg; i.p.) was administered twice daily to adult male Sprague Dawley rats for four days. Four weeks following the last dose, spontaneous behaviors of these animals were tracked and scored in a novel "open field" environment using an automated video registration and computer interpretation system. Changes in behavior were observed in MDA treated animals including reductions in exploratory oriented behaviors (locomotion and rearing) and increases in grooming behavior when compared to vehicle treated controls. MDA-treated animals also displayed an enhanced locomotor and stereotyped response to d-amphetamine (12 mg/kg; i.p.). Significant reductions in 5-HT concentrations (20-30%) were observed in the frontal cortex, amygdala, striatum, and hypothalamus as a result of MDA treatment. In addition, [3H] paroxetine binding was reduced by (40%) in the cortex of MDA treated rats indicating that the decrease in 5-HT concentrations were accompanied by a reduction in intact presynaptic 5-HT nerve terminals. Changes in behavioural performance in a novel "open field" environment and following d-amphetamine challenge might be considered as a behavioural model of serotonergic deficit induced by MDA. The findings of this study also suggest that MDA use may increase both the abuse potential, and the propensity to develop psychosis as a result of abusing other psychostimulants such as d-amphetamine.

Animals↗

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

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

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

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 sequential study of experimental infection of pigs with porcine circovirus and porcine parvovirus: immunostaining of cryostat sections and virus isolation.

The sequential tissue distribution of virus was investigated using virus isolation and immunofluorescence tests in 1-day-old piglets inoculated with porcine circovirus 2 (PCV2) and/or porcine parvovirus (PPV). Enlarged mesenteric lymph nodes were seen in the pig inoculated with PCV2 alone and killed at 26 days post-inoculation (PI). One of the pigs inoculated with PCV2 and PPV and killed at 21 days PI had an enlarged liver. The pig killed at 26 days PI in this group had enlarged liver, kidneys and heart. Histopathological changes were seen in lymphoid tissues of the pigs inoculated with PCV2 alone and killed at 14 and 26 days PI. Similar, but more severe, lesions were observed in the pigs infected with PCV2 and PPV and killed from 10 days PI onwards. Histological lesions of nephritis, pneumonia and hepatitis were also apparent in these animals. Mild nephritis was also seen in the pigs infected with PPV alone and killed at 14 and 26 days PI. Moderate amounts of PPV antigen were detected in tissues from the pigs inoculated with PPV alone and killed at 14 days PI. Low levels of PCV antigen were detected, mainly in lymphoid tissues, in the pigs inoculated with PCV alone and killed at 14 days PI. Low to moderate amounts of PCV antigen were detected in a wider range of tissues in the pig in this group killed at 26 days PI. In the pigs inoculated with both viruses, PPV antigen was detected in tissues of pigs killed from 3 to 26 days PI with maximal amounts detected between 6 and 14 days PI. PCV2 antigen was detected in low to moderate amounts in the tissues of pigs killed at 14 days PI. Large amounts of PCV2 antigen were detected in most of the tissues from pigs in this group killed between 17 and 26 days PI. Virus isolation results for PCV2 generally correlated well with the results for immunofluorescent staining. PPV was isolated from almost all tissues from pigs inoculated with PCV2 and PPV, a much higher incidence of positive tissues than observed for immunofluorescent staining.

Animals↗

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↗

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

Antigenicity and pathogenicity characteristics of molecularly cloned chicken anaemia virus isolates obtained after multiple cell culture passages.

The Cux-1 isolate of chicken anaemia virus (CAV), which had received 310 (P310) cell culture passages, was substantially less pathogenic than virus that had been passaged 13 times (P13). Molecularly cloned virus isolates, selected from the P310 and P13 virus populations using recombinant DNA cloning and transfection procedures, reacted differently with 4 CAV-specific monoclonal antibodies (MAbs), which had been raised to low-passage Cux-1 virus. In contrast to the strong immunofluorescence (IF) reactivities exhibited by all P13 cloned isolates tested, 80% and 57% of the P310 cloned isolates reacted weakly with MAbs 2A9 and 4H4, which are directed against conformational epitopes on the capsid protein, VP1. Sequence analysis of the VP1 coding regions possessed by ten P310 and two P13 cloned isolates showed that 6 amino acid changes within VP1 had been selected by multiple-cell culture passage. One of these at position 89 in VP1 appeared to be crucial for determining reactivity with MAb 2A9. Of nine P310 cloned isolates evaluated, 8 were substantially attenuated compared to the low-passage Cux-1 virus pool. It is concluded that the individual virus variants comprising the P310 virus pool differ with regards to their antigenicity and pathogenicity.

Amino Acid Sequence↗

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

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↗