Classic and dissociative psychedelics induce similar hyper-synchronous states in the cognitive-limbic cortex-basal ganglia system

Abstract

The neurophysiological mechanisms behind the profound changes in perception and cognition induced by psychedelic drugs are not well understood. To identify neuronal activity specific to the psychedelic state, we here investigated the effects of classic psychedelics (LSD, DOI) and dissociative psychedelics (ketamine, PCP) on neuronal firing rates and local field potentials in several brain structures involved in cognitive processing in freely moving rats. The classic psychedelics had a net inhibitory effect on firing rates of putative interneurons and principal cells in all recorded regions. The dissociative psychedelics had a similar inhibitory effect on principal cells, but an opposite excitatory effect on interneurons in most regions. However, the inhibitory effect on principal cells was not specific to the psychedelic state, as similar inhibition occurred with a non-psychedelic psychotropic control (amphetamine). In contrast, both types of psychedelics dramatically increased the prevalence of high-frequency oscillations (HFOs) in local field potentials, while the non-psychedelic control did not. Further analysis revealed strong HFO phase locking between structures and very small phase differences corresponding to <1 ms delays. Such standing-wave behavior suggests local generation of HFOs in multiple regions and weak, fast coupling between structures. The observed HFO hypersynchrony is likely to have major effects on processes that rely on integration of information across neuronal systems, and it might be an important mechanism behind the changes in perception and cognition during psychedelic drug use. Potentially, similar mechanisms could induce hallucinations and delusions in psychotic disorders and would constitute promising targets for new antipsychotic treatments.