Set and setting: the effects of psilocybin on nicotine self-administration in rats

PROJECT SUMMARY/ABSTRACT Recent studies in humans have suggested that psychedelic drugs have therapeutic potential for several mental health disorders, including substance use disorder and post-traumatic stress disorder. For example, psilocybin, a hallucinogenic compound present in several species of the genus Psilocybe, has been shown to reduce cigarette smoking in humans. Studies in animals using other psychedelic compounds, including those acting at the serotonin 5-HT2A receptor subtype, have demonstrated that these drugs can have similar effects on the motivational properties of drugs of abuse. However, no studies have examined the effects of psilocybin in an animal model of nicotine self-administration, which is a major goal of this study. Further, the subjective effects of psilocybin are variable, and influenced by both the internal state of the individual (“set”) and the environmental conditions in which the drug is administered (“setting”). For example, humans experiencing anxiety in an unknown environment are more likely to experience negative subjective effects which may be counterproductive from a therapeutic perspective. However, these issues of set and setting have never been investigated in any animal model of psychedelic effects. Thus, the overall hypothesis of this proposal is that the potential of psilocybin as a treatment for smoking can be modelled in animal models of nicotine reinforcement, and that this therapeutic potential depends on the subjects’ internal state and environmental conditions. We will first test the hypothesis that a single administration of psilocybin is sufficient to reduce nicotine motivation during nicotine self-administration in rats, and that this treatment will have an enduring effect on later tests of cue-induced reinstatement, which is an animal model of relapse. To manipulate the internal state of the individual (set), we will use a conditioned emotional response (CER) procedure to induce positive or negative emotional states before the psilocybin administration. To manipulate setting, rats will be administered psilocybin either in their homecages or in a mildly aversive, novel environment. When these experiments are complete, we will have established whether the therapeutic effects of psilocybin can be modelled in rats, which will enable future neurobiological studies. Further, if set and setting manipulations significantly alter the behavioral response to psilocybin, this will help identify the neurobiological correlates of these manipulations, which may enable the identification of pharmacological and/or non-pharmacological adjuncts to psychedelic psychotherapy.