Fig. 1: Extended METH self-administration (SA) and contingent footshocks result in compulsive METH taking in a subpopulation of rats.

A Experimental timeline showing long access METH SA sessions and contingent footshock sessions. Footshocks were administered randomly during 50% of pressing the active lever for METH. B During the first phase of the experiment, footshocks reduced lever pressing in shock-sensitive (SS, n = 14) but not in always shock-resistant (ASR, n = 12) or compulsive rats. Always shock-resistant (ASR) and shock-sensitive (SS) rats were separated as per our previous published study in which we classified animals as shock-sensitive if they reduced their intake by 60% [33]. C Resistant/compulsive rats showed greater incubation of METH craving than SS rats at withdrawal day 15 (WD15) during forced abstinence. D SS rats were separated post-facto during the second phase of METH SA training because a subset of the SS rats, now labeled ‘Delayed shock resistance (DSR)’, developed shock-resistance during the second phase of the behavioral experiments. We named the remaining SS rats ‘Always sensitive (AS)’ (see H). E Footshocks caused marked reduction in METH intake in the sensitive rats during the first phase of footshocks. The figure shows METH intake during the last 3 days of training without shocks (L 3 d) and the last 3 days of the first footshock phase (FS L 3 d). F ASR rats showed greater incubation of METH craving in comparison to AS rats but not DSR rats during tests of relapse during the first forced abstinence period. G Regression analysis shows a positive correlation between METH intake during first sets of footshock days and active lever responding during the relapse test on WD15 of the first phase of the behavioral experiments. H Footshocks reduced lever pressing for METH in the AS rats but not in the ASR and DSR rats. I Footshocks reduced METH intake in the AS but not in the ASR and DSR rats. J Persistently compulsive SR (ASR) rats continued to show incubation of METH craving in comparison to AS rats during the second set of relapse tests. K Regression analysis showed a positive correlation between METH intake during footshock days and active lever responding on the second WD15 relapse test. CT, saline; ASR, always shock-resistant; SS, shock-sensitive, DSR, delayed shock-resistant; and AS, always sensitive rats. Key to statistics: *p < 0.05, **p < 0.01, ***p < 0.001, comparisons between METH groups (ASR, DSR, AS) and controls; #p < 0.05, ##p < 0.01, ###p < 0.001, comparisons between ASR and AS or SS; ! p < 0.05, !!p < 0.01, !!!p < 0.001, comparison between ASR and DSR; $p < 0.05, $$p < 0.01, $$$p < 0.001, comparison between DSR and AS; &p < 0.05, &&p < 0.01, &&&p < 0.001, comparison between before vs after footshocks; @p < 0.05, @@p < 0.01, @@@p < 0.001, comparison between WD1 and WD15.