Effect of rate of intravenous cocaine infusion on psychomotor sensitization and striatal AMPAR expression in female rats

Abstract

The speed at which addictive drugs reach the brain influences the magnitude of their effects and increases abuse liability. For example, in rats, fast rates of i.v. cocaine infusion (5 s) induce greater cocaine intake and self‐administration, and enhance psychomotor sensitization compared to slower infusion rates (90 s). Psychomotor sensitization is a behavioral manifestation of drug‐induced neural plasticity thought to underlie addiction. However, most rate of infusion (ROI) studies included only males and were limited to acute experimenter‐administered infusions. Furthermore, increases in cell‐surface expression of AMPA‐type glutamate receptors within the nucleus accumbens (NAc) are associated with psychomotor sensitization and enhanced cocaine‐seeking, but potential effects of ROI on NAc glutamate plasticity had not been examined. Therefore here, we examined psychomotor sensitization and glutamatergic plasticity in female Long‐Evans rats (N=22) given either fast (5 s, n=9) or slow (90 s, n=9) cocaine infusions (50 μl, 2.0 mg/kg i.v.) or saline infusions (5 s, n=2; 90 s, n=2). Rats were given one infusion per session, three sessions per week, for 8 total infusions. To examine effects on AMPAR expression, tissue from the NAc and dorsolateral striatal (DLS) will be collected after an additional 21 days of withdrawal. Briefly, tissue will be prepared using established BS3 crosslinking approaches, and surface expression of AMPAR subunits GluA1 and GluA2 will be examined. Psychomotor sensitization is typically quantified by measuring locomotion using automated beam break measures or by hand scoring behavior. However, beam break measures are inaccurate in small enclosures, and hand scoring is time‐consuming. Here, we developed a novel approach to measuring locomotion using DeepLabCut, a markerless pose estimation method. In pilot studies, tracking locomotion using this method provided reliable measures of locomotion that were comparable to hand‐scored videos. This approach also provided more detailed analysis of the entire time course (rather than using time sampling), and provided additional quantitative measures including velocity. In pilot studies, females in the fast infusion group showed locomotor sensitization, whereas rats in the slow infusion group did not. To our knowledge, this is the first demonstration that repeated slow infusions of cocaine do not produce sensitization, and suggests that although total drug exposure is identical, the speed of drug delivery strongly influences cocaine‐induced plasticity in females. Ongoing studies are being conducted to examine effects on glutamate plasticity. We predict that enhancements in AMPAR surface expression may occur selectively in the 5 s group, based on previous sensitization studies in males, but that this effect may be more pronounced in DLS than NAc. Together these data will reveal how varying pharmacokinetics influence cocaine‐induced neurobehavioral plasticity in females.