Sex-specific effects of sucrose withdrawal on anxiety-like behavior and neuroimmune response

Sugar bingeing induces maladaptive neuroadaptations to decrease dietary control and promote withdrawal symptoms. This study investigated sex differences in sucrose bingeing, sucrose withdrawal-induced negative mood effects and underlying neuroimmune response in the prefrontal cortex (PFC) and nucleus accumbens (NAc) of C57BL/6J male and female mice. Two-bottle sucrose choice paradigm was used to develop sucrose dependence in mice. Female mice consumed more sucrose than male mice when given free access to water and 10% sucrose for four weeks. A significant increase in the mRNA expression of neuroinflammatory markers ( Il1 beta , Tnf alpha ) was found in the PFC of males exposed to sucrose withdrawal. Sucrose bingeing and subsequent sucrose withdrawal showed elevated protein levels of pro-inflammatory cytokines/chemokines/growth factors in the PFC (IL1 beta , IL-6, TNF alpha, IFN- gamma , IL-10, CCL5, VEGF) and NAc (IL-1 beta , IL-6, IL-10, VEGF) of male mice as compared to their water controls. These effects were concurrent with reduced mRNA expression of neuronal activation marker ( cFos ) in the PFC of sucrose withdrawal males. One week of sucrose withdrawal after prolonged sucrose consumption showed anxiety-like behavior in male mice, not in females. In conclusion, this study demonstrates that repeated access to sucrose induces anxiety-like behavior when the sugar is no longer available in the diet and these effects are male-specific. Elevated neuroinflammation in reward neurocircuitry may underlie these sexspecific effects.