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It has been known for years that the brain interacts with the immune system and vice versa. Furthermore, it is known that this interaction has an impact on motivation, emotion and behaviour. It is suggested that cytokines, messengers of the immune system, can modulate motivated behaviour and are involved in psychiatric conditions such as anxiety and depression. Previous studies (Pawlak et al., 2003; Pawlak et al., 2005) showed that cytokine expression in specific brain tissues is correlated with anxiety-like behaviour (open arm time) in the elevated plus-maze (EPM) in male Wistar rats, and that this relationship is site- (striatum, frontal cortex) and cytokine-specific (Interleukin-2 mRNA). These studies also found evidence for a biphasic impact of a single striatal IL-2 (1; 10; 25 ng) injection on anxiety-like behaviour in the EPM (Pawlak &amp;amp;amp;amp; Schwarting, 2006a).
In the first of the present studies (article 1), rats were tested for anxiety-like effects, acutely and 24 h later (drug free), after a single striatal interleukin-2 injection (0; 0.1 and 1 ng) followed by 45 min open field test. During the acute testing we observed a non-significant increase in anxiety-like behaviour in the group treated with the lowest dose (0.1 ng). On the second test day (24h later), animals treated with the lowest dose showed an increase in anxiety-like behaviour (i.e. reduced centre time) compared to the 1 ng and the control group. Therefore, in a subsequent study we tested for proactive drug mechanisms. Rats were tested in an open field 24 and 48 hours after interleukin-2 (0, 0.01, 0.1 ng) injection. The analyses showed no significant effects for the first (24 h after IL-2 infusion) or for the second exposure (48 h later). Therefore, it was suggested that emotion-related behaviour could be modulated by striatal IL-2 (in the used dosages) over a period of at least 24 h. However, such IL-2 effects can only be observed, if environmental challenges (e.g. open field) immediately follow infusion. In conclusion, proactive drug effects can be excluded for striatal IL-2 effects on emotion-related behaviour. IL-2 is assumed to be one factor which may mediate the behavioural and neurochemical (e.g. serotonergic, dopaminergic) features of depression and anxiety in the brain. The second study (article 2) investigated the impact of systemically injected IL-2 (2.5 μg/kg, i.p.) on serotonergic (5-HT, 5-Hydroxytryptophane) and dopaminergic (DA) neurotransmission in various cortical areas by in-vivo microdialysis in anaesthetised rats (Exp.1). Based on the serotonergic time profile obtained from Exp.1, two further experiments were conducted to test for acute (Exp.2a) and delayed (2 hours post injection, Exp.2b) behavioural effects of systemic IL-2 (0; 1; 2.5; 5.0 μg/kg) on depressive-related behaviour in the Forced Swim Test (FST). Because of the data found in our previous studies and the well known involvement of serotonin in anxiety disorders and anxiety-like behaviour, the effects of systemic IL-2 (0; 1; 2.5; 5.0 μg/kg) were tested in the EPM, 2 hours post injection (Exp.3).
The neurochemical results revealed that systemic IL-2 lastingly reduced extracellular 5-HT levels in the medial prefrontal (-75%), occipital (-70%), and temporal (-45%) cortices. The first effects were observed 40 minutes after injection, reached their maximum after circa 120 minutes and remained stable for rest of the experiment, at least 3 hours after IL-2 treatment. In contrast, dopamine was only moderately reduced in the medial prefrontal cortex. The functional relevance of these specific neurochemical changes was supported by subsequent behavioural evaluation since IL-2 had dose-dependent effects on depressive-related behaviour in the FST after delayed testing, with a significant increase in immobility with the lower dose (1 μg/kg). No such effects were observed acutely after injection. Despite the fact that a) the EPM is one of most frequently used tests to measure anxiety-like behaviour (article 3) and b) that anxiety and anxiety-like behaviour are in some way related to serotonin, we found no delayed effects of IL-2 on anxiety-like behaviour in the EPM.
In summary, these data show the potency of IL-2 to kinetically influence neurochemical processes and support the hypothesis that IL-2 dose-dependently affects depressive-related and partly anxiety-like behaviour, which may be related to its serotonergic effects in the brain.