Effects of Increasing Endocannabinoid 2-AG Tone on Sensorimotor Gating and Anxiety-like behavior

The cannabinoid system has been widely studied for its ability to modulate multiple behavioral functions, including addiction-like behaviors. Our study aimed to determine if increasing endocannabinoid availability would alter sensorimotor gating and anxiety-like behavior in rats. Both types of behavior are aberrant in psychiatric illnesses such as post-traumatic stress disorder (PTSD). Sensorimotor gating is a mechanism which protects the brain from being overloaded by sensory stimuli to allow for normal information processing. The functionality of sensorimotor gating can be assessed using the prepulse inhibition (PPI) of startle paradigm, in which a weak prestimulus prior to a startling stimulus inhibits the resultant startle response. We were particularly interested in pursuing an understudied approach, augmentation of endogenous endocannabinoid ‘tone’ via inhibition of monoacylglycerol lipase (MAGL), the breakdown enzyme for the endocannabinoid 2-AG. To inhibit MAGL, we administered the JZL184 to increase brain levels of 2-AG. JZL184 did not affect PPI on its own but did reverse the PPI deficit that was produced by the psychotomimetic, amphetamine. Because JZL184 reversed sensorimotor gating deficits, we wanted to further determine if JZL184 possesses anxiety-reducing effects. The elevated plus maze (EPM) assesses rats’ innate anxiety-like state by measuring relative time spent exploring novel (fear-inducing) spaces (the open arms of the EPM) versus remaining in spaces that feel ‘safe’ (the closed arms of the EPM, which are darker and enclosed by walls). While JZL184 (16 mg/kg) did not increase open arm entries or time, it did reduce time spent in the closed arms. Moreover, it increased center time (an intermediate space between the open and closed arms that is moderately fear-inducing) and stretch-attends (rats stretch their bodies so that their head can peer into the open arm while their hindpaws remain in a closed arm). Both of those measures are ethological indices of novel-environment exploration. Taken together, these findings indicate that JZL184 produces a subtle anxiety-reducing effect in the EPM. To our knowledge, we are the first to demonstrate this effect via ethological measures of EPM exploration. Similarly, our data are the first to show effects of JZL184 on PPI. These results raise the possibility that modulation of the endocannabinoid system, specifically 2-AG tone, could be a novel pharmacological mechanism to regulate cognitive and emotional processes related to psychiatric disorders like PTSD.