Seeing through the smoke: Human and animal studies of cannabis use and endocannabinoid signalling in corticolimbic networks

Abstract

Public opinion surrounding the recreational use and therapeutic potential of cannabis is shifting. This review describes new work examining the behavioural and neural effects of cannabis and the endocannabinoid system, highlighting key regions within corticolimbic brain circuits. First, we consider the role of human genetic factors and cannabis strain chemotypic differences in contributing to interindividual variation in the response to cannabinoids, such as THC, and review studies demonstrating that THC-induced impairments in decision-making processes are mediated by actions at prefrontal CB₁ receptors. We further describe evidence that signalling through prefrontal or ventral hippocampal CB₁ receptors modulates mesolimbic dopamine activity, aberrations of which may contribute to emotional processing deficits in schizophrenia. Lastly, we review studies suggesting that endocannabinoid tone in the amygdala is a critical regulator of anxiety, and report new data showing that FAAH activity is integral to this response. Together, these findings underscore the importance of cannabinoid signalling in the regulation of cognitive and affective behaviours, and encourage further research given their social, political, and therapeutic implications.

Keywords: AEA; Amygdala; Anxiety; CB(1) receptor; Cannabidiol; Cannabis; Corticolimbic circuits; Decision-making; Elevated plus maze; Emotional salience processing; Endocannabinoid system; FAAH; Hippocampus; Individual differences; Mesolimbic dopamine system; Phytocannabinoids; Prefrontal cortex; Psychiatric disorders; Social interaction; THC.

Figure 1

Elevated plus maze behaviour in male and female mice at different ages. ICR mice were purchased from Harlan, Madison, WI, and were divided in three age groups of each sex (5–7 mice/group) as shown. Prior to use, mice were group housed on a 12 h light/dark cycle with lights on at 6:00 AM. All studies were carried out in accordance with the Declaration of Helsinki and with the Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of the Medical College of Wisconsin. The EPM consists of four arms 30 cm long and 5 cm wide, two open without walls and two closed by 30 cm high walls; the apparatus is elevated 40 cm above the floor (San Diego Instruments). Experiments began by placing a single mouse on the central platform facing an open arm: behaviors were recorded for 5 min as they explored the maze. Data were analyzed using video-based EthoVision System data analysis software (EthoVision 3.1; Noldus Information Technology). A: Percent entries into the open arms were calculated as the number of open arm entries/(open + closed arm entries) ×100. B: Total entries into open and closed arms. C: Total time spent in the closed arms. * p<0.05; ** p<0.01 and *** p<0.005 compared to the 4–6 week old group.

Figure 2

Amygdalar FAAH activity in male and female mice at different ages. Twenty-four hours after EPM, mice were decapitated; brains were removed and frozen on dry-ice. The amygdala was dissected on dry-ice, weighed and membranes were harvested as described previously (Hillard et al., 1995). Membranes were incubated with 0.2 nM [³H]AEA for 10 min. FAAH activity was calculated as the ratio of dpm (disintegration per minute) in the aqueous phase and the total dpm (aqueous + organic). *p<0.05 compared to 4–6 week old group.

Figure 3

Correlational analyses were made using Spearmańs bivariate test between FAAH activity in the amygdala and the following EPM parameters in female mice of all three ages: (A) percent entries into the open arms, (B) total arm entries, and (C) time spent in the closed arms. The correlation between EPM parameters and age in female mice were: (D) time spent in the open arms, (E) percent entries into the open arms, (F) time spent in the closed arms and (G) percent entries into the closed arms.