Cocaine exposure results in persisting impairment of hippocampal long-term potentiation and reduced performance in a spatial working memory task in C57BL/6J mice

We investigated the effects of two different cocaine i.p. dosing schedules as well as the associated stress of vehicle (saline) injections on conditioned place preference (CPP), locomotor sensitization (LMS), long-term potentiation (LTP) in the ventral hippocampus (vH), and spatial working memory in a radial arm maze (RAM) task. CPP and LMS were established in male C57BL/6J mice using a modified conditioning protocol similar to the one described by Itzhak and colleagues (2012) that involved cocaine-treated mice receiving either a single escalating-dose protocol (4,8,16,24 mg/kg; 4 consecutive days) or double escalating-dose protocol (4,8,16,24,16,24,32,32 mg/kg; 2×4 day series) on their least preferred side of a two-chambered CPP apparatus (Med Associates). Both single escalating and double escalating dosing schedules produced significant CPP and LMS compared to mice that received an equivalent saline vehicle. For the electrophysiology studies, a separate group of littermates were handled intermittently throughout, but not exposed to, the conditioning protocol to serve as “non-behavior/naïve” controls for baseline LTP responses. Slices were prepared from the vH and field EPSPs were recorded in the CA1 region either 1 or 4 weeks after the final injection day. We observed that saline conditioning results in significantly increased vH LTP (1.69 +/− 0.03) compared to behaviorally naïve mice (1.57 +/− 0.03), an effect that persists at least 4 weeks after the last injection day. A single pre-treatment with the kappa-opioid receptor antagonist, norBNI (10 mg/kg), blocks this stress effect associated with the conditioning protocol and results in vH LTP (1.60 +/− 0.03) that is not significantly different from the behaviorally naïve group. When norBNI is given prior to the double-escalating conditioning with cocaine, 4 weeks after the last injection day we observed significantly decreased vH LTP (1.51 +/− 0.03) compared to those that received the saline vehicle (p < .05). Interestingly, the Esc/NorBNI treated animals also exhibited a significant leftward shift in the stimulus-response curve of the baseline fEPSP measurements. Together, these findings are consistent with the hypothesis that a cocaine-induced enhancement of neurotransmission contributes to a partial occlusion of LTP in the vH of cocaine-exposed mice that persists 4 weeks after the final drug exposure. A separate group of norBNI/saline-treated mice showed significant improvement in a spatial working memory RAM task mice over 10 days (initial errors 1.50 +/− 0.16, final errors 0.83 +/− 0.14, p < 0.05) whereas norBNI/cocaine-treated mice did not show a significant improvement (initial errors 1.33 +/− 0.14, final errors 1.17 +/− 0.16). This suggests that alterations in synaptic transmission and LTP in the vH may be associated with persisting drug-induced impairments in learning and memory performance. Support or Funding Information National Institute of Drug Abuse (NIDA) University of Georgia Interdisciplinary Toxicology Program This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.