Cannabis Vapor Exposure Alters Neural Circuit Oscillatory Activity in a Neurodevelopmental Model of Schizophrenia: Exploring the Differential Impact of Cannabis Constituents

Abstract

Cannabis use is highly prevalent in patients with schizophrenia and worsens the course of the disorder. To understand how exposure to cannabis changes schizophrenia-related oscillatory disruptions, we investigated the impact of administering cannabis vapor containing either Δ9-tetrahydrocannabinol (THC) or balanced THC/cannabidiol (CBD) on oscillatory activity in the neonatal ventral hippocampal lesion (NVHL) rat model of schizophrenia. Male Sprague Dawley rats underwent lesion or sham surgeries on postnatal day 7. In adulthood, electrodes were implanted targeting the cingulate cortex (Cg), the prelimbic cortex (PrLC), the hippocampus (HIP), and the nucleus accumbens (NAc). Local field potential recordings were obtained after rats were administered either the "THC-only" cannabis vapor (8-18% THC/0% CBD) or the "Balanced THC:CBD" cannabis vapor (4-11% THC/8.5-15.5% CBD) in a cross-over design with a 2-week wash-out period between exposures. Compared to controls, NVHL rats had reduced baseline gamma power in the Cg, HIP, and NAc, and reduced HIP-Cg high-gamma coherence. THC-only vapor exposure broadly suppressed oscillatory power and coherence, even beyond the baseline reductions observed in NHVL rats. Balanced THC:CBD vapor, however, did not suppress oscillatory power and coherence, and in some instances enhanced power. For NVHL rats, THC-only vapor normalized the baseline HIP-Cg high-gamma coherence deficits. NHVL rats demonstrated a 20 ms delay in HIP theta to high-gamma phase coupling, which was not apparent in the PrLC and NAc after both exposures. In conclusion, cannabis vapor exposure has varying impacts on oscillatory activity in NVHL rats, and the relative composition of naturally occurring cannabinoids may contribute to this variability.

Keywords: cannabinoid; electomes; oscillations; oscillopathies; preclinical; psychosis.

Fig. 1.

Experimental design, lesion and electrode verification, and representative local field potential tracing. A) Cross-over design with a two-week wash-out period between exposures B) Electrode placements (top) and lesion (bottom) showing electrode termini (blue) in the PrLC (left), Cg + NAc (middle), and HIP (right), as well as lesion extent in all NVHL rats (purple represents size of smallest and pink represents size of largest lesions), compared to sham controls. C) Representative tracings from the Cg showing changes in theta and gamma frequencies at baseline and after cannabis vapor exposure for both sham and NVHL rats. Figures were made using the brain schematics available from Paxinos and Watson (2007).

Fig. 2.

NVHL rats exhibit reduced baseline spectral power compared to sham rats, and cannabis vapor differentially modulates this dysfunction. A) Spectral power tracing (left) and quantification (right) in the Cg showing baseline deficits in high-gamma power for NVHL rats (N = 5 rats, 10 recordings per region) compared to sham rats (N = 5 rats, 10 recordings per region); THC-only vapor reduced Cg beta and low-gamma power only in NVHL rats, an effect that was no longer apparent after Balanced THC:CBD vapor exposure; Balanced THC:CBD vapor exposure also attenuated the high-gamma baseline deficit in NVHL rats; both exposures enhanced delta, and reduced theta, power in the Cg of all rats; B) In NVHL rats, THC-only vapor exposure suppressed PrLC beta power while the THC:CBD-vapor exposure did not; for all rats, both exposures reduced theta power, and delta power to a lesser degree, while THC-only vapor exposure reduced both low- and high-gamma power; Balanced THC:CBD vapor exposure did not have any effect; C) In the HIP, NVHL rats showed baseline deficits in low- and high-gamma power, compared to sham rats whereas Balanced THC:CBD vapor exposure appeared to marginally improve baseline deficits; both exposures did not affect delta power and robustly suppressed theta power in NHVL and sham rats. D) In the NAc, NVHL rats showed baseline deficits in low-gamma power, compared to sham controls; THC-only vapor exposure reduced spectral power across all other frequencies in both NVHL and sham rats; THC:CBD exposure did not change from baseline measures any frequencies for NVHL rats, and selectively changed the gamma frequency band for sham rats. *P < .05; **P < .01 compared to sham control baseline; ^##P < .05 compared to NVHL rat baseline; ^φP < .05 compared THC-only treated rats to THC:CBD treated rats.

Fig. 3.

NVHL rats exhibit reduced baseline coherence within and between cortical and limbic regions, with variable impacts of cannabis vapor. A) Both vapor exposures enhanced HIP-Cg high-gamma coherence in the NVHL rats (N = 5 rats, 10 recordings per region) to levels that were no longer different from sham (N = 5 rats, 10 recordings per region) baseline coherence; B) THC-only vapor exposure reduced HIP-NAc high-gamma coherence in NVHL rats; C) Both types of cannabis-vapor exposures enhanced Cg-PrLC delta coherence in NVHL rats to levels above baseline coherence in sham rats; Cannabis vapor exposure did not alter D) HIP-PrLC, E) NAc-Cg, or F) NAc-PrLC coherence. *P < .05; **P < .01 compared to sham control baseline.

Fig. 4.

NVHL rats exhibit baseline deficits in phase coupling between HIP theta and Cg, PrLC, or NAc gamma, and cannabis vapor exposure selectively alters this delay. A–C) NVHL rats (N = 5 rats, 10 recordings per region) exhibited a 20 ms delay in coupling of HIP theta to high-gamma in the Cg, PrLC, and NAc; both vapor exposures reversed this delay in the B) PrLC and C) NAc, but not in the A) Cg; For all rats, the THC-only vapor exposure also enhanced the HIP theta–gamma coupling strength in all regions, an effect that was also observed to a lesser extent after Balanced THC:CBD vapor exposure; NVHL rats exhibited baseline theta–gamma coupling strength similar to sham rats (N = 5 rats, 10 recordings per region), for all pairwise comparisons. *P < .05; **P < .01 compared to sham control baseline. θ = theta frequency band; γ = gamma frequency band.

Fig. 5.

Graphical summary of power, coherence and phase coupling changes associated with NVHL lesions and cannabis vapor exposure. Cannabis vapor exposure produced constituent- and region-dependent disruptions in neural circuit oscillatory activity, often reducing theta, beta, and gamma power while enhancing delta power. Cannabis vapor exposure also enhanced coherence in cortical regions while reducing coherence and phase coupling between limbic regions. Cannabis vapor exposure further exacerbated baseline NAc, Cg, HIP gamma power deficits apparent in NVHL rats (N = 5 rats, 10 recordings per region), compared to sham controls (N = 5 rats, 10 recordings per region). PrLC = prelimbic cortex; NAc = nucleus accumbens; Cg = cingulate cortex; HIP = hippocampus. Δ = delta frequency band; θ = theta frequency band; β = beta frequency band; γ = gamma frequency band. Green = increase; red = decrease. Icons represent comparisons to sham baseline values and thus “N/A” is used for baseline sham findings. Figure was made using the brain schematics available from Swanson (2018).