Behavioral sensitization to cocaine after a brief social defeat stress: c-fos expression in the PAG

The experiments explored the nature and time course of changes in behavior and Fos expression in the periaqueductal grey area (PAG) in response to an injection of cocaine that was given following a single episode of social de feat stress. Social defeat stress was defined as an intruder mouse's respon se to an aggressive resident mouse. First, the intruder was briefly attacke d, and secondly, it was threatened while protected by a perforated cage for 20 min. plasma corticosterone levels rose after the beginning of the confr ontation and remained elevated during the protected phase. In a first exper iment, separate groups of intruder and control mice were challenged once wi th cocaine (20, 30, or 40 mg/kg) or saline. During tests for motor activity , behavioral measurements were obtained via (1) photobeam interruptions, (2 ) tracking of movements via image analysis, and (3) quantitative ethologica l analysis of postures and acts via video-records. Several indices of ambul atory or horizontal forward locomotion confirmed the stimulant effects of c ocaine. In a further experiment, separate groups of mice were challenged wi th 40 mg/kg cocaine at one time point, either during the social stress or 3 , 5, 7 or 9 days thereafter. A cocaine challenge significantly increased lo comotion 5 and 7 days after a brief social defeat stress, in excess of the level that is seen in nonstressed animals. Further experiments used immunoh istochemical assays of sections through the caudal ventrolateral FAG and sh owed a significant increase in Fos-like immunoreactivity (Fos-LI) 1 h after the social stress experience or after cocaine. Importantly, concurrent adm inistration of cocaine with social defeat stress produced inhibition of Fos expression throughout the FAG. A partial to complete recovery of cocaine-i nduced Fos expression was observed 5-7 days after social defeat stress. The results suggest that a single social stress episode is sufficient to engen der a delayed sensitization of stimulant hyperactivity. The initial inhibit ion of Fos expression by concurrent social stress and cocaine may point to a relevant initiating event in the process of sensitization to stimulants.