Cannabinoid agonist rescues learning and memory after a traumatic brain injury

Abstract

Traumatic brain injury can cause persistent challenges including problems with learning and memory. Previous studies suggest that the activation of the cannabinoid 1 receptor after a traumatic brain injury could be beneficial. We tested the hypothesis that posttraumatic brain injury administration of a cannabinoid 1 receptor agonist can rescue deficits in learning and memory. Young adult male rats were subjected to a moderately severe controlled cortical impact brain injury, with a subset given postinjury i.p. injections of a cannabinoid receptor agonist. Utilizing novel object recognition and the morris water task, we found that the brain-injured animals treated with the agonist showed a marked recovery.

Figure 1

Study design and time course. (A) Diagram of the treatment groups and number of animals within each group (n). (B) Time course of surgical treatments, injections, behavioral testing, and animal sacrifice. The time course of the study started on Day 0, at which the rats were 70–75 days old and progresses through the injection treatments completing on Day 6, followed by behavioral testing: open field (OF), elevated plus maze (EPM), novel object recognition (NOR), and morris water task (MWT). The study was concluded between Days 31–35 when the animals were sacrificed.

Figure 2

Administration of a CB1R agonist (ACEA) rescued learning and memory-associated behaviors. (A) NOR test at the short time interval (15 min) showed that the TBI + vehicle treatment group had a significantly lower discriminatory index compared to the other treatment groups. Notably, the TBI + drug group was indistinguishable from the sham and naïve groups. (B) There were no significant differences between the treatment groups for the NOR test at the long time interval (24 h). (C) During the acquisition phase of the MWT, the TBI + vehicle treatment group took significantly longer to find the escape platform over the course of 5 days. In contrast, the TBI + drug and other treatment groups did not differ from one another. (D) The single probe trial following the MWT acquisition phase showed that the TBI + vehicle group spent significantly less time in the target quadrant than the other treatment groups. CB1R, cannabinoid receptor 1; ACEA, arachidonyl-2′-chloroethylamide; NOR, novel object recognition; TBI, traumatic brain injury; MWT, morris water task.

Figure 3

Cannabinoid receptor agonist treatment did not affect the traumatic brain injury (TBI) lesion volume. (A) Representative cresyl violet-stained coronal brain sections showing brain tissue damage to the right hemisphere. (B) There was no significant difference in the lesion volume between TBI + drug and TBI + vehicle treatment groups.