Short- and Long-Term Effects of Interleukin-2 Treatment on the Sensitivity of Periadolescent Female Mice to Interleukin-2 and Dopamine Uptake Inhibitor

Abstract

Interleukin (IL)-2, a T-helper 1 (Th1) cell-derived cytokine, which potently modulates dopamine activity and neuronal excitability in mesolimbic structures, is linked with pathological outcomes (e.g., schizophrenia, depression, etc.) that at least partly reflect alterations in central dopaminergic processes. It has been suggested that dopamine neurons undergo pruning during adolescence and abnormalities in pruning predispose individuals to behavioral disorders. Since IL-2 is known as a neurodevelopmental factor affecting associated behavioral processes, the present study tested whether IL-2 can modulate stereotypic behaviors in both the periadolescent and adult periods. This study determined whether IL-2 treatment would produce long-lasting changes in sensitivity to a later challenge with IL-2 or GBR 12909, a highly selective dopamine uptake inhibitor. Four experiments were conducted. Firstly, a decrease in novelty-induced stereotypic behavior was observed in BALB/c periadolescent mice (38 days of age) following IL-2 administration (0.4 µg/2 ml) relative to vehicle control. In the second experiment, an initial dose of IL-2 was given in the periadolescent period, but did not affect rearing responses. A second dose of IL-2 given to the animals 30 days later as adults, resulted in a significant increase in rearing behaviors relative to control animals. In the third experiment, separate groups of experimental and control mice were administered GBR 12909, a highly selective dopamine reuptake inhibitor, 30 days following treatment with either IL-2 or vehicle. It was noted that this experimental group, which initially received IL-2, exhibited stereotypy, as evidenced by increased sniffing behavior. A fourth experiment revealed that IL-2 administered in periadolesecence and adulthood had no effect on other motor responses, indicating that IL-2 selectively modulates selective stereotypic behaviors. The results provide evidence, for the first time, that long-term changes in stereotypy in periadolescent mice are linked to an IL-2 mechanism, possibly utilizing dopamine.

Interleukin 18 activates MAPKs and STAT3 but not NF-κB in hippocampal HT-22 cells

“…For example, because HT-22 cells possess functional cholinergic properties (Liu et al, 2009), this cellular model may represent an useful in vitro tool to unravel IL-18 mediated molecular events in some of the cognitive deficits observed in Alzheimer’s disease, also considering the ability of IL-18 to activate STAT-3 in these cells. Moreover, similarly to what happens with other cytokines (Rankin et al, 2013; Zalcman et al, 1994), IL-18 may act as modulator of the activity of neurotransmitters including acetylcholine.…”

Altered IL-2, IL-6 and IL-8 serum levels in schizophrenia patients with tardive dyskinesia

“…In fact, a number of cytokine receptors are expressed in neurons and glial cells, suggesting that cytokine dysfunction may directly affect neurons and brain function (Merrill, 1992;Sawada et al, 1993;Petitto et al, 2012b). Moreover, certain cytokines and/or overloaded oxidative stress could induce the activation of immune system, and subsequently influence neurotransmitter metabolism, like dopaminergic system (De Simoni and Imeri, 1998;Larouche et al, 2008;Rankin et al, 2013). All these suggested that there may be inter-relationships among immune system dysfunction, the neurotransmitter metabolism imbalance, and oxidative stress, all of which are involved in the pathophysiology of TD.…”

“…IL-2 plays a crucial role in the regulation of neurotransmitter metabolism, including dopamine metabolism (Kim et al, 2000;Zalcman, 2002;Meyer et al, 2006;Potvin et al, 2008;Rankin et al, 2013). Since dopamine supersensitivity is one of the most important hypotheses to elucidate the pathogenesis of TD, some investigators have proposed possible relationships between IL-2, clinical symptoms, and the dyskinetic severity in schizophrenia patients with TD.…”

Fatty liver‐induced changes in stereotypic behavior in rats and effects of glucagon‐like peptide‐1 analog on stereotypy

“…Accordingly, in 2013, Rankin et al. [26] demonstrated that mice treated with GBR 1209—a selective dopamine reuptake inhibitor—30 days after an initial IL‐2 administration showed increased stereotypical behavior, suggesting an IL‐2 mechanism utilizing dopamine. Likewise, in our study, apomorphine provoked stereotypical behavior in mice with fatty liver possibly by dopaminergic pathways.…”