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 20mg/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, asexpected. However, compared to control ratson 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.

Anhedonia, Reduced Cocaine Reward, and Dopamine Dysfunction in a Rat Model of Posttraumatic Stress Disorder

“…Stressed rats demonstrated similar levels of cocaine consumption and latencies to acquire self-administration when compared to controls under limited-access conditions, a finding that is consistent with a previous report [57]. Additional analysis of escalated cocaine intake indicates a trend toward a greater percent increase in drug consumption over time in SPS-exposed rats than controls.…”

Single-Prolonged Stress: A Review of Two Decades of Progress in a Rodent Model of Post-traumatic Stress Disorder

“…Drug sensitization is altered following SPS, although findings vary by the substance investigated. For example, we have shown that SPS blunts ethanol-induced behavioral sensitization ( 215 ), but enhances behavioral sensitization to repeated cocaine ( 216 ) and methamphetamine ( 217 ). Another group reported that SPS produced noradrenergic-dependent cross-sensitization to acute amphetamine ( 218 ).…”

Effects of oxytocin on methamphetamine-seeking exacerbated by predator odor pre-exposure in rats

“…Recent studies have demonstrated that footshock-induced stress increased alcohol consumption (Meyer et al 2013) whereas maternal separation in early life increased METH self-administration (Lewis et al 2015). Another PTSD model, single prolonged stress, enhanced locomotor sensitization to cocaine but did not alter cocaine SA (Eagle et al 2015) and had mixed effects on METH- or amphetamine-induced behavioral sensitization (Eagle and Perrine 2013; Toledano et al 2013). Predator odors, such as 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), are ecologically relevant stressors that reliably induce hyperarousal, a long-lasting avoidance of trauma-related cues, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis (Fendt et al 2005; Thomas et al 2006).…”