Effect of single intracerebroventricular injection of α-interferon on monoamine concentrations in the rat brain

Kamata, Mitsuhiro; Higuchi, Hisashi; Yoshimoto, M.; Yoshida, Keizo; Shimizu, Tetsuo

doi:10.1016/s0924-977x(99)00067-x

Cited by 109 publications

(71 citation statements)

References 18 publications

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“…A single icv injection of 200 or 2000 U of hIFNα to rats was reported to decrease the 5-HT contenαt of the frontal cortex, and both 5-HT and 5-HIAA were decreased in the midbrain and the striatum [107]. However, we observed no effects of ip human or mouse IFNα on 5-HT or 5-HIAA in mice at doses (400-16,000 U/mouse) that induced behavioral changes [104].…”

Section: 51contrasting

confidence: 65%

“…The interferon used was the same used in the studies of Crnic et al (supplied by Dr Crnic) which had been shown to decrease locomotor activity and feeding [105,106]. In contrast, a single icv injection of IFNα (200 or 2000 U of hIFNαA/D) in rats was reported to decrease frontal cortical NE [107]. However, in another study, 1000 U hIFNα injected icv into rats increased apparent DA turnover (DOPAC:DA ratio) in the hippocampus (primarily caused by a substantial decrease in the measured hippocampal DA), but no such effect was observed in the prefrontal cortex or striatum [108].…”

Section: 51mentioning

confidence: 99%

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Effects of cytokines and infections on brain neurochemistry

Dunn

2006

Clinical Neuroscience Research

285

169

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Administration of cytokines to animals can elicit many effects on the brain, particularly neuroendocrine and behavioral effects. Cytokine administration also alters neurotransmission, which may underlie these effects. The most well studied effect is the activation of the hypothalamopituitary-adrenocortical (HPA) axis, especially that by interleukin-1 (IL-1). Peripheral and central administration of IL-1 also induces norepinephrine (NE) release in the brain, most markedly in the hypothalamus. Small changes in brain dopamine (DA) are occasionally observed, but these effects are not regionally selective. IL-1 also increases brain concentrations of tryptophan, and the metabolism of serotonin (5-HT) throughout the brain in a regionally nonselective manner. Increases of tryptophan and 5-HT, but not NE, are also elicited by IL-6, which also activates the HPA axis, although it is much less potent in these respects than IL-1. IL-2 has modest effects on DA, NE and 5-HT. Like IL-6, tumor necrosis factor-α (TNFα) activates the HPA axis, but affects NE and tryptophan only at high doses. The interferons (IFN's) induce fever and HPA axis activation in man, but such effects are weak or absent in rodents. The reported effects of IFN's on brain catecholamines and serotonin have been very varied. However, interferon-γ, and to a lesser extent, interferon-α, have profound effects on the catabolism of tryptophan, effectively reducing its concentration in plasma, and may thus limit brain 5-HT synthesis.Administration of endotoxin (LPS) elicits responses similar to those of IL-1. Bacterial and viral infections induce HPA activation, and also increase brain NE and 5-HT metabolism and brain tryptophan. Typically, there is also behavioral depression. These effects are strikingly similar to those of IL-1, suggesting that IL-1 secretion, which accompanies many infections, may mediate these responses. Studies with IL-1 antagonists, support this possibility, although in most cases the antagonism is incomplete, suggesting the existence of multiple mechanisms. Because LPS is known to stimulate the secretion of IL-1, IL-6 and TNFα, it seems likely that these cytokines mediate at least some of the responses, but studies with antagonists indicate that there are multiple mechanisms. The neurochemical responses to cytokines are likely to underlie the endocrine and behavioral responses. The NE response to IL-1 appears to be instrumental in the HPA activation, but other mechanisms exist. Neither the noradrenergic nor the serotonergic systems appear to be involved in the major behavioral responses. The significance of the serotonin response is unknown.

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Section: 51contrasting

confidence: 65%

Section: 51mentioning

confidence: 99%

Effects of cytokines and infections on brain neurochemistry

Dunn

2006

Clinical Neuroscience Research

285

169

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“…18 More importantly, IFN-␣ administration reduced brain levels of serotonin and 5-HIAA in several regions of the rat brain. 20 In clinical studies, significant decreases in serum TRP concentrations have been noted in patients receiving IL-2 or IFN-␣. 21,22 In another type of investigation, associations between plasma TRP concentrations and immune variables have been observed in psychiatric patients with major depression.…”

Section: Cytokines and Neurotransmitter Functionsmentioning

confidence: 99%

Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy

et al. 2002

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Cytokine therapy for cancer or viral diseases is accompanied by the development of depressive symptoms in a significant proportion of patients. Despite the increasing number of studies on the neurotoxic effects of cytokines, the mechanisms by which cytokines induce depressive symptoms remain largely unknown. In view of the relationship between neurotransmitter precursors and mood, the present study aimed at assessing the relationship between serum concentrations of the amino acids tryptophan and tyrosine, major precursors of serotonin and norepinephrine respectively, and depressive symptoms in cancer patients undergoing cytokine therapy. Sixteen cancer patients eligible to receive immunotherapy with interleukin-2 and/or interferon-alpha participated in the study. At baseline and after one week and one month of therapy, depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), and blood samples were collected for the determination of the large neutral amino acids (LNAA) (tryptophan, tyrosine, valine, leucine, isoleucine, phenylalanine) which compete for transport across the blood-brain barrier. Serum concentrations of tryptophan as well as the tryptophan/LNAA ratio significantly decreased between baseline, one week and one month of therapy. The development and severity of depressive symptoms, especially anorexia, pessimistic thoughts, suicidal ideation and loss of concentration were positively correlated with the magnitude of the decreases in tryptophan concentrations during treatment. These findings indicate that the development of depressive symptoms in patients undergoing cytokine therapy could be mediated by a reduced availability of the serotonin relevant amino acid precursor, tryptophan.

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“…24 Kamata also investigated the effects of 10-day i.c.v. treatment, but found no consistent alterations of monoamine levels.…”

Section: Discussionmentioning

confidence: 99%

“…11,[22][23][24][25][26][27] Divergent results might be attributable to methodological differences. To the best of our knowledge, this report is the first to address both the dose-dependent and the temporal effects of peripherally administered IFN-α on various brain regions.…”

Section: Discussionmentioning

confidence: 99%

Chronic intraperitoneal injection of interferon‐α reduces serotonin levels in various regions of rat brain, but does not change levels of serotonin transporter mRNA, nitrite or nitrate

Sato¹,

Suzuki²,

Yokoyama³

et al. 2006

Psychiatry Clin Neurosci

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Interferon-α therapy is associated with a high rate of depression, but the pathophysiological mechanisms remain unclear. The purpose of the present study was to investigate the effects of i.p. administered interferon-α on monoaminergic neurotransmission in the brain. The levels of monoamines and associated metabolites were measured in various regions of the rat brain using a high-performance liquid chromatography-electrochemical detection system. The serotonin transporter mRNA levels were also measured using in situ hybridization. After 1 day, dopamine turnover was diminished in the cortex. Norepinephrine turnover was decreased in most regions tested after 4 days. However, these changes were transient. After 14 days, serotonin turnover was increased in the frontal cortex and hippocampus in rats given a dose of 20 000 IU/kg; in the frontal cortex, hippocampus, amygdala, thalamus, hypothalamus and brainstem in those on 200 000 IU/kg; and in the thalamus and hypothalamus in those on 2 000 000 IU/kg (all P < 0.05). However, 14-day treatment did not significantly change serotonin transporter mRNA levels. Next, the question of whether interferon-α affects monoamine levels via induction of nitric oxide (NO), was investigated. However, there were no changes in either NO 2 -or NO 3 -, as markers of NO production, in any brain regions after 14-day treatment. These results suggest that chronic peripheral administration of interferon-α induces metabolic changes in the central serotonin system. Further investigation is needed to determine exactly how this cytokine affects the central serotonin system and to assess whether a central serotonin abnormality is involved in interferon-induced depression.

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Effect of single intracerebroventricular injection of α-interferon on monoamine concentrations in the rat brain

Cited by 109 publications

References 18 publications

Effects of cytokines and infections on brain neurochemistry

Effects of cytokines and infections on brain neurochemistry

Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy

Chronic intraperitoneal injection of interferon‐α reduces serotonin levels in various regions of rat brain, but does not change levels of serotonin transporter mRNA, nitrite or nitrate

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