Cannabis Use and Mental Illness: Understanding Circuit Dysfunction Through Preclinical Models


Review

. 2021 Feb 5;12:597725.


doi: 10.3389/fpsyt.2021.597725.


eCollection 2021.

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Review

Bryan W Jenkins et al.


Front Psychiatry.


2021.

Free PMC article

Abstract

Patients with a serious mental illness often use cannabis at higher rates than the general population and are also often diagnosed with cannabis use disorder. Clinical studies reveal a strong association between the psychoactive effects of cannabis and the symptoms of serious mental illnesses. Although some studies purport that cannabis may treat mental illnesses, others have highlighted the negative consequences of use for patients with a mental illness and for otherwise healthy users. As epidemiological and clinical studies are unable to directly infer causality or examine neurobiology through circuit manipulation, preclinical animal models remain a valuable resource for examining the causal effects of cannabis. This is especially true considering the diversity of constituents in the cannabis plant contributing to its effects. In this mini-review, we provide an updated perspective on the preclinical evidence of shared neurobiological mechanisms underpinning the dual diagnosis of cannabis use disorder and a serious mental illness. We present studies of cannabinoid exposure in otherwise healthy rodents, as well as rodent models of schizophrenia, depression, and bipolar disorder, and the resulting impact on electrophysiological indices of neural circuit activity. We propose a consolidated neural circuit-based understanding of the preclinical evidence to generate new hypotheses and identify novel therapeutic targets.


Keywords:

bipolar disorder; cannabis use disorder; electrophysiology; major depressive disorder; oscillations; schizophrenia.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1


Figure 1

Rodent models of schizophrenia exhibit neural circuit disruptions and eCB modulation enhances this activity. Graphical summary of preclinical investigations demonstrating neural circuit disruptions induced by cannabinoid exposure in rodents used to model schizophrenia. Rodents modeling schizophrenia exhibit reduced baseline PFC neuronal firing rates, reduced baseline PFC, BC, and HIP spectral power, and enhanced baseline BC neuronal firing rates. THC exposure increases neuronal firing rates in the VTA after infusion. URB597 exposure increases neuronal PFC and HIP firing rates and spectral power. BC, barrel cortex; DISC1, DISC1 KO genetic mouse model of schizophrenia; HIP, hippocampus; NRG1, NRG1 knock-down genetic mouse model of schizophrenia; NVHL, NVHL rat model of schizophrenia; PCP, Phencyclidine rat model of schizophrenia; PFC, prefrontal cortex/prelimbic cortex; VTA, ventral tegmental area. Green: Increase; Red: Decrease.

Figure 2


Figure 2

Rodent models of major depressive disorder exhibit region- and frequency-specific neural circuit disruptions. Graphical summary of preclinical investigations demonstrating neural circuit disruptions induced by cannabinoid exposure in rodents used to model major depressive disorder. Rodents modeling major depressive disorder exhibit reduced baseline PFC, NAc, and STN spectral power in the lower frequency bands and enhanced baseline STN and HIP spectral power in the higher frequency bands. FSL, Flinders Sensitive Line rat model of major depressive disorder; HIP, hippocampus; NAc, nucleus accumbens; PFC, prefrontal cortex/prelimbic cortex; STN, subthalamic nucleus. Green: Increase; Red: Decrease.

Figure 3


Figure 3

Rodent models of bipolar disorder exhibit reduced baseline neural circuit spectral power and coherence. Graphical summary of preclinical investigations demonstrating neural circuit disruptions induced by cannabinoid exposure in rodents used to model bipolar disorder. Rodents modeling bipolar disorder exhibit reduced baseline PFC and HIP spectral power, and reduced baseline NAc coherence. CLOCKΔ19, CLOCKΔ19 genetic mouse model of bipolar disorder; DAT-KO, DAT-KO genetic mouse model of bipolar disorder; HIP, hippocampus; NAc, nucleus accumbens; PFC, prefrontal cortex/prelimbic cortex. Green: Increase; Red: Decrease.

Figure 4


Figure 4

Cannabinoid exposure disrupts neural circuit activity differently depending on administration route and dose, as well as the chosen cannabinoid. Graphical summary of preclinical investigations demonstrating neural circuit disruptions induced by cannabinoid exposure in healthy rodents. THC exposure increases neuronal firing rates in the PFC, HIP and VTA after i.p. injection or infusion, enhances spectral power after i.p. injection and suppresses spectral power after i.v. injection or vapor exposure, and suppresses PFC and HIP coherence after vapor exposure. WIN-55 exposure suppresses HIP and EC coherence after i.v. exposure. Studies showing no effect of cannabinoid exposure were not included. CP-55, CP-55940; EC, entorhinal cortex; HIP, hippocampus; PFC, prefrontal cortex/prelimbic cortex; VTA, ventral tegmental area. Green: Increase; Red: Decrease.

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