Chronic exposure to inhaled vaporized cannabis high in Δ9-THC suppresses Adderall-induced brain activity

Abstract

Background: There are increasing reports of the misuse of prescription psychostimulants for cognitive enhancement together with recreational cannabis. This raises a concern that chronic use of cannabis high in Δ⁹-THC may alter the sensitivity to amphetamines. In this exploratory study we hypothesized chronic exposure to Δ⁹-THC through vaporized cannabis would diminish the central nervous system (CNS) activity of Adderall.

Methods: To address this issue we exposed male and female mice to inhaled vaporized cannabis (10.3% Δ9-THC) or placebo for 30 min each day for ten consecutive days. After 24 h, mice were imaged fully awake for changes in BOLD signal following an IP injection of Adderall (60 µg) during the scanning session. After a 2-week washout, without any cannabis or placebo exposure, mice were again imaged and challenged with Adderall during the scanning session. The data were registered to a mouse 3D MRI atlas with 134 brain regions providing site-specific increases and decreases in global brain activity.

Results: Mice exposed to cannabis when compared to placebo showed a decrease in brain activation to Adderall. The blunted Adderall response was characterized by a decrease in positive BOLD signal and increase in negative BOLD. The prefrontal cortex, accumbens, ventral pallidum, caudate/putamen, and thalamus were most affected. After a 2-week wash out there were no significant differences between the cannabis and placebo groups when challenged with Adderall.

Summary: This exploratory study shows that short, daily exposures to inhaled cannabis, something equivalent to recreational use, affects the sensitivity to the psychostimulant Adderall. The reduced Adderall effect on brain activity, particularly circuitry associated with dopaminergic signaling raises concerns about escalation in psychostimulant use.

Keywords: BOLD; accumbens; awake animal imaging; basal ganglia; functional MRI.

FIGURE 1

Statistical heat maps. Shown are 2D statistical heat maps for positive BOLD volume of activation (red) and negative BOLD volume of activation (blue). The areas shown were significantly different between mice exposed to placebo or cannabis and challenged with Adderall. The 3D color coded reconsrtuctions are a summary of the signficanlty affected areas from the 2D maps. ctx: cortex, n. nucleus.

FIGURE 2

Change in BOLD signal over time. Shown are time series of percentage change in BOLD signal over the 25 min scanning session (250 image acquisitions) for mice exposed to chronic placebo and challenged with Adderall before (black line) and after (blue line) the 2-week washout and mice exposed to chronic cannabis and challenged with Adderall before (gray line) and after (red line) washout. These time series were generated by averaging the BOLD signal at each image acquisition from the accumbens, caudate/putamen and ventral pallidum, areas comprising the basal ganglia. Adderall was injected (arrow) at 5 min (50 acquisitions). The 1% threshold is highlighted by the black line to account for the normal fluctuations in BOLD signal in the awake mouse brain.