Single prolonged stress effects on sensitization to cocaine and cocaine self-administration in rats

Abstract

Posttraumatic stress disorder (PTSD) is often comorbid with substance use disorders (SUD). Single prolonged stress (SPS) is a well-validated rat model of PTSD that provides a framework to investigate drug-induced behaviors as a preclinical model of the comorbidity. We hypothesized that cocaine sensitization and self-administration would be increased following exposure to SPS. Male Sprague-Dawley rats were exposed to SPS or control treatment. After SPS, cocaine (0, 10 or 20 mg/kg, i.p.) was administered for 5 consecutive days and locomotor activity was measured. Another cohort was assessed for cocaine self-administration (0.1 or 0.32 mg/kg/i.v.) after SPS. Rats were tested for acquisition, extinction and cue-induced reinstatement behaviors. Control animals showed a dose-dependent increase in cocaine-induced locomotor activity after acute cocaine whereas SPS rats did not. Using a sub-threshold sensitization paradigm, control rats did not exhibit enhanced locomotor activity at Day 5 and therefore did not develop behavioral sensitization, as expected. However, compared to control rats on Day 5 the locomotor response to 20mg/kg repeated cocaine was greatly enhanced in SPS-treated rats, which exhibited enhanced cocaine locomotor sensitization. The effect of SPS on locomotor activity was unique in that SPS did not modify cocaine self-administration behaviors under a simple schedule of reinforcement. These data show that SPS differentially affects cocaine-mediated behaviors causing no effect to cocaine self-administration, under a simple schedule of reinforcement, but significantly augmenting cocaine locomotor sensitization. These results suggest that SPS shares common neurocircuitry with stimulant-induced plasticity, but dissociable from that underlying psychostimulant-induced reinforcement.

Keywords: Animal model; Cocaine; Posttraumatic stress disorder; Self-administration; Sensitization; Single prolonged stress.

Fig 1

Locomotor activity induced by repeated cocaine is enhanced after single prolonged stress (SPS). Rats were exposed to SPS or control treatment and, 1 week later, were administered cocaine (i.p.) at 0, 5, or 10mg/kg immediately prior to daily locomotor testing (5 days) using a sub-threshold sensitization paradigm. Loco-motor activity was measured by total beam breaks for 10min following acute cocaine (a; 1 d) and repeated cocaine injections (b; 5 d). (a) Acute cocaine dose-dependently increased locomotoractivity in controls, but not SPS rats. SPS decreased acute cocaine (20mg/kg only) -induced locomotoractivity, compared to controls. (b) Repeated cocaine dose-dependently increased locomotor activity in both control and SPS groups. Furthermore, repeated cocaine (20 mg/kg only) enhanced locomotor activity in SPS, but not control, rats compared to acute cocaine. (c) Sensitization (% increase in beam breaks from Day 1 to Day 5) to 20mg/kg cocaine-induced loco-motor activity was enhanced in SPS compared to controls. Data are expressed as mean±SEM. n = 10–11 rats/group; *p < 0.05, **p < 0.01, ***p < 0.001 for all comparisons.

Fig 2

Single prolonged stress (SPS) does not alter cocaine self-administration acquisition, extinction, or cue-induced reinstatement. Rats exposed to SPS or control were previously trained (days 1–15) to self-administer cocaine at 0.32 mg/kg/i.v.-infusion (a–c) or 0.1 mg/kg/infusion (d–f) on a FR1 schedule of reinforcement. Active and inactive nose-pokes (NP) recorded across 60min daily sessions are presented. Rats maintained a previously acquired cocaine self-administration, as shown on Day 16, by increasing their responses on the active NP, however no SPS-induced differences were observed (a, d). Following the test for acquisition (Day 16), all rats underwent extinction training for 5 consecutive days (days 17–21; b, e). Rats extinguished their responses across extinction training days, but no SPS-induced differences were observed. Extinction was followed by cue-induced reinstatement (Day 22; c,f). Rats reinstated active NP responses, but no differences between control and SPS rats were observed. Data are expressed as mean±SEM. n = 6–7 rats/group.