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

Abstract

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.

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

“…Some studies reported increases (Kumai et al, 2000;Sato et al, 2006), whereas others have reported decreases (Kamata et al, 2000;Kitagami et al, 2003;Shuto et al, 1997) in brain DA and/or metabolites following acute or subchronic IFN-α administration. These discrepancies were likely due to differences in dosing, length of exposure, and, most importantly, the fact that speciesspecific IFN-α was variably used and rodents do not respond to human IFN-α with activation of classic type I IFN receptor signaling (Loftis et al, 2006a;Loftis et al, 2006b;Wang et al, 2008).…”

“…Initial evidence that inflammation can affect brain DA originates from neurochemical and behavioral studies in rodents administered acute or subchronic IFN-α that measured DA and/or DA metabolites in concert with depressive behaviors and changes in locomotor activity (Kamata et al, 2000;Kitagami et al, 2003;Kumai et al, 2000;Sato et al, 2006;Shuto et al, 1997). Some studies reported increases (Kumai et al, 2000;Sato et al, 2006), whereas others have reported decreases (Kamata et al, 2000;Kitagami et al, 2003;Shuto et al, 1997) in brain DA and/or metabolites following acute or subchronic IFN-α administration.…”

Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications

“…Early evidence that IFN-alpha may affect DA neurotransmission comes from studies in rodents that reported both increases and decreases in brain dopamine and/or metabolites that either did or did not correspond to locomotor changes or depressive-like behavior following acute or sub-chronic IFN-alpha administration (Shuto et al, 1997, Kamata et al, 2000, Kumai et al, 2000, Kitagami et al, 2003, Sato et al, 2006). These mixed results are likely due to differences in dosing, length of cytokine exposure, and most importantly, the fact that species-specific cytokines were variably used and rodents do not respond to human IFN-alpha with activation of classic type I IFNR signaling (Loftis et al, 2006a, Loftis et al, 2006b, Wang et al, 2008) Rhesus monkeys that express functional IFNARs and activate relevant signal transduction pathways in response to human IFN-alpha (Felger et al, 2007), exhibit immune, neuroendocrine, and behavioral responses to IFN-alpha similar to humans, including decreases in psychomotor activity and increases in depressive-like huddling behavior (in ~50% of animals) (Felger et al, 2007, Felger and Miller, 2012).…”

Inflammatory cytokine-associated depression

“…For example, both IFN-α treatment and low- grade inflammation lead to decreased 5-HT availability (e.g., the amino acid precursor tryptophan is metabolized by increased levels of indoleamine-2,3-dioxygenase leading to less tryptophan available for 5-HT synthesis). 163164 There is a increase in neopterin levels during inflammation, 165 and tetrahydrobiopterin (BH4) is a critical co-factor for mono-amine synthesis, including 5-HT. Not only is there less 5-HT synthesized, but IL-6 may also increase 5-HT release and subsequent enzymatic metabolism to 5-hydroxyindoleacetic acid.…”