Psilocybin as a lead candidate molecule in preclinical therapeutic studies of psychiatric disorders: A systematic review.

Psilocybin is the main psychoactive compound found in hallucinogenic/magic mushrooms and can bind to both serotonergic and tropomyosin receptor kinase b (TrkB) receptors. Psilocybin has begun to show efficacy for a range of neuropsychiatric conditions, including treatment-resistant depression and anxiety disorders; however, neurobiological mechanisms are still being elucidated. Clinical research has found that psilocybin can alter functional connectivity patterns in human brains, which is often associated with therapeutic outcomes. However, preclinical research affords the opportunity to assess the potential cellular mechanisms by which psilocybin may exert its therapeutic effects. Preclinical rodent models can also facilitate a more tightly controlled experimental context and minimise placebo effects. Furthermore, where there is a rationale, preclinical researchers can investigate psilocybin administration in neuropsychiatric conditions that have not yet been researched clinically. As a result, we have systematically reviewed the knowledge base, identifying 82 preclinical studies which were screened based on specific criteria. This resulted in the exclusion of 44 articles, with 34 articles being included in the main review and another 2 articles included as Supporting Information materials. We found that psilocybin shows promise as a lead candidate molecule for treating a variety of neuropsychiatric conditions, albeit showing the most efficacy for depression. We discuss the experimental findings, and identify possible mechanisms whereby psilocybin could invoke therapeutic changes. Furthermore, we critically evaluate the between-study heterogeneity and possible future research avenues. Our review suggests that preclinical rodent models can provide valid and translatable tools for researching novel psilocybin-induced molecular and cellular mechanisms, and therapeutic outcomes.

Acute administration of the NMDA receptor antagonists ketamine and MK-801 reveals dysregulation of glutamatergic signalling and sensorimotor gating in the Sapap3 knockout mouse model of compulsive-like behaviour.

Obsessive-compulsive disorder (OCD) is characterised by excessive intrusive thoughts that may cause an individual to engage in compulsive behaviours. Frontline pharmacological treatments (i.e., selective serotonin reuptake inhibitors (SSRIs)) leave approximately 40% of patients refractory to treatment. To investigate the possibility of novel pharmacological therapies for OCD, as well as the potential mechanisms underlying its pathology, we used the Sapap3 knockout (KO) mouse model of OCD, which exhibits increased anxiety and compulsive grooming behaviours. Firstly, we investigated whether administration of the NMDA receptor (NMDAR) antagonist ketamine (30 mg/kg), would reduce anxiety and grooming behaviour in Sapap3 KO mice. Anxiety-like behaviour was measured via time spent in the light component of the light-dark box test. Grooming behaviour was recorded and scored in freely moving mice. In line with previous works conducted in older animals (i.e. typically between 6 and 9 months of age), we confirmed here that Sapap3 KO mice exhibit an anxious, compulsive grooming, hypolocomotive and reduced body weight phenotype even at a younger age (i.e., 2-3 months of age). However, we found that acute administration of ketamine did not cause a reduction in anxiety or grooming behaviour. We then investigated in vivo glutamatergic function via the administration of a different NMDAR antagonist, MK-801 (0.25 mg/kg), prior to locomotion and prepulse inhibition assays. We found evidence of altered functional NMDAR activity, as well as sexually dimorphic prepulse inhibition, a measure of sensorimotor gating, in Sapap3 KO mice. These results are suggestive of in vivo glutamatergic dysfunction and their functional consequences, enabling future research to further investigate novel treatments for OCD.

Mechanisms of pathogenesis and environmental moderators in preclinical models of compulsive-like behaviours.

Obsessive-compulsive and related disorders (OCRD) is an emergent class of psychiatric illnesses that contributes substantially to the global mental health disease burden. In particular, the prototypical illness, obsessive-compulsive disorder (OCD), has a profoundly deleterious effect on the quality of life of those with lived experience. Both clinical and preclinical studies have investigated the genetic and environmental influences contributing to the pathogenesis of obsessive-compulsive and related disorders. Significant progress has been made in recent years in our understanding of the genetics of OCD, along with the critical role of common environmental triggers (e.g., stress). Some of this progress can be attributed to the sophistication of rodent models used in the field, particularly genetic mutant models, which demonstrate promising construct, face, and predictive validity. However, there is a paucity of studies investigating how these genetic and environmental influences interact to precipitate the behavioural, cellular, and molecular changes that occur in OCD. In this review, we assert that preclinical studies offer a unique opportunity to carefully manipulate environmental and genetic factors, and in turn to interrogate gene-environment interactions and relevant downstream sequelae. Such studies may serve to provide a mechanistic framework to build our understanding of the pathogenesis of complex neuropsychiatric disorders such as OCD. Furthermore, understanding gene-environment interactions and pathogenic mechanisms will facilitate precision medicine and other future approaches to enhance treatment, reduce side-effects of therapeutic interventions, and improve the lives of those suffering from these devastating disorders.

Default Mode Network Modulation by Psychedelics: A Systematic Review.

Psychedelics are a unique class of drug that commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of interconnected brain regions characterized by increased temporal coherence at rest have been termed the Default Mode Network (DMN). The DMN has been the focus of numerous studies assessing its role in self-referencing, mind wandering, and autobiographical memories. Altered connectivity in the DMN has been associated with a range of neuropsychiatric conditions such as depression, anxiety, post-traumatic stress disorder, attention deficit hyperactive disorder, schizophrenia, and obsessive-compulsive disorder. To date, several studies have investigated how psychedelics modulate this network, but no comprehensive review, to our knowledge, has critically evaluated how major classical psychedelic agents-lysergic acid diethylamide, psilocybin, and ayahuasca-modulate the DMN. Here we present a systematic review of the knowledge base. Across psychedelics there is consistent acute disruption in resting state connectivity within the DMN and increased functional connectivity between canonical resting-state networks. Various models have been proposed to explain the cognitive mechanisms of psychedelics, and in one model DMN modulation is a central axiom. Although the DMN is consistently implicated in psychedelic studies, it is unclear how central the DMN is to the therapeutic potential of classical psychedelic agents. This article aims to provide the field with a comprehensive overview that can propel future research in such a way as to elucidate the neurocognitive mechanisms of psychedelics.