UC San Diego

Classical hallucinogens are a class of psychoactive drugs that reliably alter perception, cognition, and behavior. Recently, a renewed focus on the mechanisms responsible for the effects of hallucinogens has emerged, as a renaissance of recreational availability and therapeutic interest has taken root. Identifying pharmacological substrates of hallucinogen effects allows us to predict potential dangers of novel hallucinogens, improve our understanding of psychotic disorders, and optimize the therapeutic value of hallucinogens while minimizing untoward side effects. The experiments herein use mouse models to address a broad array of questions regarding neural mechanisms of hallucinogen action. First, I used the head twitch response (HTR), a paroxysmal head rotation induced by hallucinogens in rodents, to probe the relationship between structural characteristics of putative hallucinogens and their potency in vivo. These experiments clarified structure-activity relationships of N-benzyl-5-methoxytryptamines and revealed that the in vivo potency of N,N-diallyltryptamines can be predicted by affinities at 5-HT2A and 5-HT1A receptors, with positive and negative contributions to potency, respectively. These are the first experiments to quantify the relative contributions of these receptors to the behavioral effects of a class of tryptamine hallucinogens. Next, I demonstrated that mice lacking mGlu5 receptors are hypersensitive to multiple behavioral effects of hallucinogens. This hypersensitivity persists when a 5-HT2A agonist functionally selective for PLC-mediated signaling is administered, indacating a role for the PLC signaling cascade in this phenomenon. These findings suggest that mGlu5 receptors may typically provide tonic inhibition in response to excessive neuronal excitation, mitigating hallucinogen effects. Finally, I used a discrete-trials interval timing task to explore pharmacological mechanisms responsible for hallucinogen effects on interval timing. These experiments first probed the effects of a tryptamine hallucinogen, psilocin, on timing in mice, and revealed effects to depend on activation of 5-HT2A but not 5-HT1A receptors. Then, studies identified a non-monotonic relationship between 5-HT2A activation and timing wherein either increases or decreases from baseline levels of 5-HT2A activation result in similar timing effects, and demonstrated the sufficiency of hallucinogen effects in prefrontal cortex to alter interval timing. These experiments reveal novel insights on the relationship between pharmacological characteristics of hallucinogenic drugs and their behavioral effects.