Stress and sleep disruption promote inflammation and metabolic adaptations, with important disease-modifying implications for psychiatric disorders. Using a novel chronic unpredictable sleep disruption (CUSD) paradigm, we characterised the impact of disrupted sleep and/or stress hormone exposure on locomotor behaviour and central markers of inflammation in the nucleus accumbens (NAc), a region implicated in regulation of mood, motivation and locomotor activity. Forty-eight Wistar rats (24 male; 24 female) were separated into groups exposed to combinations of CUSD/non-CUSD and corticosterone (200µg/ml in drinking water, dissolved in ethanol)/vehicle. CUSD treatment consisted of unpredictable exposure to light and sound (65-80dB) over five weeks. Locomotor activity was quantified in an open field arena across the final two weeks (10 days). Weight was also monitored daily. IL1B, TNFA, NFKB, MAPK, AMPK, and INSR gene expression were measured in the NAc using RT-PCR. Male CUSD animals gained significantly more weight (p=0.0028) over the five-week period than male non-CUSD animals; this effect was reversed in females (p=0.0246). A significant increase in risk-taking behaviour (time in centre; p=0.0094) was observed on day 1 for CUSD animals relative to non-CUSD animals, with reduced locomotion observed in these animals on days 9 (p=0.028) and 10 (p=0.0349). Significantly increased expression of IL1B (p=0.000206), TNFA (p=0.00245), and INSR (p=0.000658) were also present in the NAc of CUSD animals, but only in vehicle-treated animals. Results suggest CUSD promotes weight gain and risk-taking behaviour at three weeks; with progressive reductions in activity observed with ongoing exposure, concurrent with promotion of inflammation in the NAc.