Dose-dependent LSD effects on cortical/thalamic and cerebellar activity: brain oxygen level-dependent fMRI study in awake rats

Abstract

LSD (lysergic acid diethylamide) is a hallucinogen with complex neurobiological and behavioral effects. This is the first study to use MRI to follow functional changes in brain activity in response to different doses of LSD in fully awake, drug naive rats. We hypothesized that LSD would show a dose-dependent increase in activity in the prefrontal cortex and thalamus, while decreasing hippocampal activity. Female and male rats were given intraperitoneal injections of vehicle or LSD in doses of 10 µg/kg or 100 µg/kg while fully awake during the imaging session. Changes in blood oxygen level dependent (BOLD) signal were recorded over a 30 min window. Approximately 45 min post injection data for resting state functional connectivity were collected All data were registered to rat 3D MRI atlas with 173 brain regions providing site-specific increases and decreases in global brain activity and changes in functional connectivity. Treatment with LSD resulted in a significant dose-dependent increase in negative BOLD signal. The areas most affected were the primary olfactory system, prefrontal cortex, thalamus and hippocampus. This was observed in both the number of voxels affected in these brains regions and the changes in BOLD signal over time. However, there was a significant increases in functional connectivity between the thalamus and somatosensory cortex, and the cerebellar nuclei and the surrounding brainstem areas. Contrary to our hypothesis, there was an acute dose-dependent increase in negative BOLD which can be interpreted as a decrease in brain activity, a finding that agrees with much of the behavioral data from preclinical studies. The enhanced connectivity between thalamus and sensory motor cortices is consistent with the human literature looking at LSD treatments in healthy human volunteers. The unexpected finding that LSD enhances connectivity to the cerebellar nuclei raises an interesting question concerning the role of this brain region in the psychotomimetic effects of hallucinogens.