Effects of serotonin agonists LSD and 25CN-NBOH on conditioned place preference and on synaptic plasticity of VTA dopamine neurons in mice

Psychedelic compounds like LSD are often considered non-addictive, but some patterns of use and subjective effects raise questions about their rewarding potential. This study tested whether LSD and a selective 5-HT2A agonist (25CN-NBOH) produce rewarding effects in mice using conditioned place preference and measured changes in synaptic plasticity in dopamine neurons of the ventral tegmental area. No reliable place preference was found for either drug, supporting the idea that psychedelics have at most weak reinforcing effects. However, single doses, especially of LSD, induced synaptic plasticity in medial VTA dopamine neurons, suggesting the midbrain dopamine system may still play a role in their effects.

Study at a glance

Abstract

The current research on psychedelic compounds such as lysergic amide diethylamide (LSD) is leaning heavily on the notion that psychedelics are not addictive. While much of the literature supports this argument, some of the common use patterns and the descriptions of the subjective effects of these compounds in humans, together with rather lacking and mixed data from non-human animal studies leave room for questions of potentially rewarding or reinforcing stimulus effects. Initiated by a surprising finding in a control study, we investigated these potential rewarding effects of LSD and a selective 5-HT2A agonist 25CN-NBOH using both unbiased and biased designs of conditioned place preference as well as ex vivo patch-clamp electrophysiology measurements of glutamatergic synaptic plasticity on midbrain ventral tegmental area (VTA) dopamine neurons in C57Bl6/J mice. Our results showed no reliable formation of place preference with either compound, agreeing with previous claims of psychedelics having at most weak reinforcing effects. However, we did observe single doses of the drugs, especially LSD, inducing synaptic plasticity in the medially located VTA dopamine neurons, implicating a role for the midbrain dopamine system in the effects of psychedelic drugs.