Lipopolysaccharide induces anhedonia-like reward deficits, reflected by long-term increases in brain stimulation reward thresholds

Anhedonia is one of the core symptoms of major depressive disorder (MDD) and is characterized by the inability to experience pleasure. The role of inflammatory processes in MDD, and more specifically anhedonia, has been extensively reviewed. The endotoxin lipopolysaccharide (LPS) induces sickness behaviour 6 h after injection, while depressive-like behaviour as measured by a decreased preference for sucrose is expressed 24 h after administration. To better investigate the time-course in which anhedonia symptoms emerge, the sucrose preference test might not be of best choice, because of the possible interfering appetite-suppressing effects of LPS, at least at time points at which sickness behaviour is still apparent. Therefore, the aim of the current study was to determine the onset of reward-related disturbances of LPS on intracranial self stimulation (ICSS) thresholds. Bipolar stimulating electrodes were implanted into the lateral hypothalamus of male Wistar rats, and animals were trained in a discrete-trial currentthreshold ICSS procedure. After stable ICSS thresholdswere established, eight animalswere treatedwith LPS (250 μg/kg, i.p.); nine animals were treated with vehicle (0.9% NaCl) as control. Animals were tested in the ICSS paradigm 1 h, 4 h, 24 h and up to 14 days after administration. Our study showed significant elevations of ICSS thresholds up to 72 h after LPS administration, reflecting a decreased activity of brain reward circuitry and desensitization of the rewarding effects of ICSS and suggest an anhedonic state of the animal. The present study showed, to our knowledge for the first time, that LPS induces an anhedonic state up to 72 h after injection with a maximum at time point 4 h. The fact that response latencieswere not affected suggested that the used dose of LPS did not inducemotor deficits in the animals.Morework is clearly needed to further unravel the complex interaction of inflammatory processes in sickness behaviour and anhedonia.