Increased responsiveness to punishment of cocaine self-administration after experience with high punishment

Abstract

One behavioral feature of drug addiction is continued drug use despite awareness that this causes negative consequences. Attempts to model this feature in animals typically involve punishing drug self-administration with electrical footshock to identify individuals whose drug use is differently suppressed by punishment. Here we sought to further study individual responsiveness of drug use to punishment in rats self-administering intravenous cocaine. Rats were first trained during several weeks to self-administer cocaine under a fixed-ratio 3 schedule of reinforcement. Then, their self-administration behavior was punished with increasing intensity of footshock (i.e., from 0.1 mA to 0.9 mA, every 30 min). With increasing intensity of punishment, rats first continued to self-administer cocaine before eventually stopping near completely. When retested, however, drug use became more responsive to punishment and was suppressed by a low and initially ineffective footshock intensity (i.e., 0.1 mA). This increase in responsiveness to punishment was seen in all individuals tested, albeit with varying degrees, and was acquired after one single experience with an intensity of punishment that near completely suppressed drug self-administration. Mere passive, non-contingent exposure to the same intensity, however, had no such effect. Once acquired, increased responsiveness to punishment persisted during at least one month when rats were tested every week, but not every day. Finally, increased responsiveness to punishment was not observed after exposure to a non-painful form of punishment (i.e., histamine). Overall, this study reveals that initial responsiveness of drug use to punishment can change rapidly and persistently with experience. We discuss several possible mechanisms that may account for this change in punishment responsiveness and also draw some of the implications and future perspectives for research on animal models of compulsion-like behavior.

Fig. 1. Experimental designs and procedures.

A Measurement of responsiveness to footshock punishment in experiment 1. The first box represents baseline sessions with no footshock punishment of cocaine self-administration. The second box corresponds to footshock punishment sessions. These sessions were subdivided into 7 30-min periods, corresponding each to a different current intensity: 0–0.9 mA. B Procedure for experiments 2 and 4. The first box represents baseline sessions with no punishment. The second and third boxes represent punishment sessions with 0.1 and 0.7 mA, respectively. Note that no punishment was delivered during the first 2 30-min intervals of footshock sessions.

Fig. 2. Measurement of responsiveness to footshock punishment.

A Footshock punishment-induced suppression of cocaine self-administration (n = 6). Number of cocaine injections (mean ± s.e.m.) during baseline or footshock punishment sessions (footshock 1 and 2) as a function of increasing current intensity. **p < 0.01, different from baseline; ^#p < 0.01, different from footshock 1. B Current intensity (mean ± s.e.m.) that suppresses by 50% (IS50%) the rate of cocaine self-administration. Lowering of IS50% during repeated exposure to footshock punishment. **, different from footshock 1 (p < 0.01). Each individual is represented by two gray circles linked with a solid line. Darker gray indicates overlapping individuals. C Progressive recovery to baseline levels of cocaine self-administration (mean ± s.e.m.) during intermediate re-baselining sessions. **, different from last baseline session before footshock 1 (p < 0.01).

Fig. 3. Persistent increase in responsiveness to footshock punishment after experience with 0.7-mA footshock punishment.

A Number of cocaine injections (mean ± s.e.m.) during baseline sessions or footshock sessions with current intensity set to 0.1 or 0.7 mA (n = 6). The horizontal gray box indicates when cocaine self-administration was punished by footshock during footshock sessions. Note that no punishment was delivered during the first 30-min interval. **p < 0.01, different from baseline. B Effects of punishment with 0.1 mA on number of cocaine injections (mean ± s.e.m.) before and after exposure to one session with 0.7-mA footshock punishment. **p < 0.01, different from Pre 0.7 mA. Right panel: Average rate of cocaine injections per 30 min over the last 3 h of punishment for all individual rats, each represented by two gray circles linked with a solid line. Darker gray indicates overlapping individuals. C Persistent increase in responsiveness to footshock punishment over time. Number of cocaine injections (mean ± s.e.m.) during punishment with 0.1 mA (i.e., last 6 30-min intervals) remained below control levels (i.e., 0.0 mA corresponding to the 30-min interval preceding onset of punishment) during repeated testing sessions. Testing sessions were interspersed by 4 intermediate re-baselining sessions. **p < 0.01, different from 0.0 mA. D Effects of punishment with 0.1 mA on number of cocaine injections (mean ± s.e.m.) before and after exposure to one session with non-contingent 0.7-mA footshock (n = 12). Right panel: Average rate of cocaine injections per 30 min over the last 3 h of punishment for all individual rats, each represented by two gray circles linked with a solid line. Darker gray indicates overlapping individuals.

Fig. 4. Recovery of initial responsiveness to footshock punishment.

A Number of cocaine injections (mean ± s.e.m.) during baseline sessions or footshock sessions with current intensity set to 0.1 or 0.7 mA (n = 7). *p < 0.05, **p < 0.01, different from baseline. B Effects of 0.1-mA footshock punishment on number of cocaine injections (mean ± s.e.m.) before and after exposure to 0.7-mA footshock punishment. *p < 0.05, **p < 0.01, different from before exposure to 0.7 mA. Right panel: Average rate of cocaine injections per 30 min over the last 3 h of punishment for all individual rats, each represented by two gray circles linked with a solid line. Darker gray indicates overlapping individuals. C Recovery of initial responsiveness to footshock punishment. Number of cocaine injections (mean ± s.e.m.) during punishment with 0.1 mA (i.e., last 6 30-min intervals) compared to control levels (i.e., 0.0 mA corresponding to the 30-min interval preceding onset of punishment) during repeated testing with no intermediate re-baselining sessions. **p < 0.01, different from 0.0 mA. For additional information, see legend of Fig. 3.

Fig. 5. No change in responsiveness to histamine punishment.

A Number of cocaine injections (mean ± s.e.m.) during baseline sessions or during sessions punished with 0.5 or 6 mg of i.v. histamine (n = 7). The horizontal gray box indicates when cocaine self-administration was punished by histamine during corresponding punishment sessions. Note that no punishment was delivered during the first 30-min interval. *p < 0.05, **p < 0.01, different from baseline. B Effects of 0.5-mg histamine punishment on number of cocaine injections (mean ± s.e.m.) before and after exposure to one session with 6-mg histamine punishment. Right panel: Average rate of cocaine injections per 30 min over the last 3 h of punishment for all individual rats, each represented by two gray circles linked with a solid line. Darker gray indicates overlapping individuals.