Persistent increase of I.V. cocaine self-administration in a subgroup of C57BL/6J male mice after social defeat stress

Abstract

Rationale: Stressful life experiences can persistently increase the motivation for, and consumption of, intensely rewarding stimuli, like cocaine, over time. In rodents, intermittent versus continuous exposure to social stress engenders opposing changes to reward-related behavior, as measured by consumption of sucrose and cocaine.

Objective: The present study examines if the effects of intermittent versus continuous social stress on cocaine self-administration in mice parallel those seen in rats.

Methods: Both forms of social stress involve a brief daily physical confrontation with an aggressive resident for 10 consecutive days. Continuous social stress involves constant visual and olfactory exposure to an aggressive resident via habitation in a protected portion of the resident's home cage, while exposure to an aggressive resident during intermittent social stress is limited to a single, physical encounter per day. Implementing a femoral vein catheterization method for the first time in mice, we determined divergent changes to intravenous cocaine self-administration.

Results: Modestly increased cocaine self-administration after intermittent social stress was confirmed. In a subset of animals, continuous social stress in mice substantially increased cocaine self-administration and sucrose intake. By stark contrast, another subpopulation had substantial attenuation of cocaine self-administration and sucrose intake after continuous social stress.

Conclusions: Bimodal divergence in responding for rewarding stimuli including cocaine after social stress experience likely reflects two opposing forms of coping to continuous social stress that promote either a sensitization or attenuation of reward-seeking.

Keywords: C57BL/6J mice; Cocaine; Intermittent versus chronic stress; Self-administration; Social defeat stress; Social interaction; Sucrose preference.

Fig 1:

Experimental Timeline.

Fig 2:

Longevity of either jugular (n=17) or femoral (n=11) vein catheterization in non-stressed controls. Data are expressed as percent of catheter survival over time.

Fig 3:

Three chamber compartment testing with an unfamiliar, stimulus resident male mouse 10 days after social defeat. Data are expressed as mean; **p<0.01 vs. controls.

Fig 4:

Twenty-four-hour consumption and preference for 1.0% sucrose solution versus water in a 2- bottle preference test by intermittently stressed mice (I; n=36), continuously stressed mice placed into the high responders group (HC; n=7), continuously stressed mice placed into the low responders group (LC; n=6), and controls (C; n=38). All values are mean ± SEM. *= p<0.05, ***=p<0.001 compared to the relevant control group.

Fig 5:

A. Acquisition of cocaine self-administration (0.3 mg/kg/inf) after intermittent SDS (n=14, filled squares) and contemporaneous controls (n=12, open circles) B. Responding for various doses of intravenous cocaine in mice with a history of intermittent social defeat (n=6) and contemporaneous controls (n = 9). Individual data were averaged over 2 sessions. Data are expressed as mean; * p < 0.05 vs. controls.

Fig 6:

A. Acquisition of cocaine self-administration (0.3 mg/kg/inf) after continuous social defeat (n=13, black squares) and contemporaneous controls (n=9, open circles). B. Acquisition of cocaine self-administration (0.3 mg/kg/inf) after continuous social defeat (high responders: n= 7, dark grey squares; low responders: n= 6, light grey triangles) and contemporaneous controls (n=9, open circles) C. Responding for various doses of intravenous cocaine in mice with a history of continuous social defeat (n=9, black squares) and contemporaneous controls (n=6, open circles). D. Responding for various doses of intravenous cocaine in mice with a history continuous social defeat (high responders: n= 5, dark grey squares; low responders: n= 4, light grey triangles) and contemporaneous controls (n=6, open circles). Data from each dose on the dose-effect curves were averaged over 2 sessions. Data are expressed as mean ± SEM.

Fig 7:

A. In animals with a history of continuous SDS (high responders: n= 7, dark grey bars; low responders: n= 6, light grey bars), the maximum number of cocaine infusions/session taken by any member of the low responders between days 2–7 of acquisition never exceeded the minimum number of cocaine infusions taken by high responders on corresponding days. B. The number of cocaine infusions across days 2–7 of acquisition formed a continuous distribution in animals with no history of SDS (controls: n= 9), unlike the bimodal distribution produced after CSDS.

Fig 8:

Twenty-four-hour intake of 1% sucrose during a preference test is predictive of cocaine consumption during acquisition in mice with a history of continuous SDS [(n=17) (r= 0.34; p=0.014)]. Open circles denote nonstressed controls (n=4), light grey squares denote animals placed in the low responders group (n=6) and dark grey squares denote high responders (n=7).