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.

Serious mental illnesses are debilitating and costly, and the development of effective treatments is imperative. Unfortunately, their heterogeneous and overlapping etiologies and symptomatologies present major obstacles to our understanding of these disorders. Carefully designed animal models and test paradigms with precise cross-species valid outcomes enable us to investigate the mutations, network disruptions, and environmental challenges that contribute to the development of neuropsychiatric symptoms and may be targeted for treatment. This dissertation presents two mouse models developed to study candidate risk genes associated with neuropsychiatric illnesses, including major depression, bipolar disorder, and schizophrenia. The studies presented herein provide insight into the development and potential treatments for these disorders.

Studies of humanized DISC1-Boymaw mice focus on the effects of a rare translocation associated with psychiatric illnesses in a large Scottish family. Our studies suggest that inhibition of protein synthesis and mitochondrial dysfunction resulting from the fusion of the DISC1 and Boymaw genes may contribute to the pathogenesis of illnesses in this family. The DISC1-Boymaw mice exhibit hypersensitivity to ketamine, a phenotype also observed in patients and in the other rare variant model presented here, the Sp4 hypomorphic (Hyp) mice, which have reduced expression of the transcription factor Sp4. Our investigation of Sp4 Hyp mice suggests that hypersensitivity to ketamine is mediated by inhibitory GABAergic neurons and not excitatory forebrain neurons.

Dysfunction of GABAergic neurons may be associated with cognitive and motivational deficits observed in the Sp4 Hyp mice and in patients. The cognitive deficits associated with psychiatric illnesses are predictive of vocational and social outcomes and should be prioritized in the development of treatments. Our studies suggest that a glycine type-1 transporter (GlyT-1) inhibitor may remediate attention deficits—but not impairments to motivation nor reward learning—in these mice and potentially in patients. It is the author’s hope that the findings presented in this dissertation and follow-up studies will contribute to the understanding and development of treatments for neuropsychiatric disorders.

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