Brianna Peacock

Introduction. Depression is a state of low mood with a lifetime prevalence of about 20% globally.¹ Potential etiologies include the monoamine hypothesis which describes a decrease in molecules like serotonin.^1,2 Loss or alteration of neuroplasticity may also play a role in pathogenesis, as suggested by the decreased BDNF observed in patients with major depression.^1,3 Excitatory receptor 5-HT_2A is thought to mediate neuroplasticity in the prefrontal cortex and has been observed as upregulated in unmedicated depressed patients and suicide victims.³ Current treatments include psychotherapy, such as cognitive behavioral therapy, and pharmacotherapy.¹ Pharmacotherapy includes first-line SSRIs,^1,3 tricyclic antidepressants, and monoamine oxidase inhibitors.¹ Patients with a suboptimal response to these treatments may be diagnosed with treatment-resistant depression, suggesting a need for new treatment options.⁴ Psilocybin, a tryptamine and prodrug for active component psilocin,⁵ is a potential treatment under research and is thought to mediate neuroplasticity through 5-HT_2A receptor agonism.³ Methods. 5-HT_2A receptor downregulation and synaptic vesicle protein 2A (SV2A) were measured in the prefrontal cortex of rats one- and seven-days following psilocybin injection.⁶ Pigs administered psilocybin were observed for behaviors associated with 5-HT_2A receptor agonism and brain tissue was assessed for psilocin occupancy of 5-HT_2A receptors.⁵ Psilocybin was administered to eighty rats in one of seven doses and changes in neuroplastic genes were observed in prefrontal cortical and hippocampal tissue.⁷ Rat cortical neurons were treated with various psychedelics and antagonists including ANA-12, rapamycin, and ketanserin to determine morphological effects and the roles of mTOR and TrkB.⁸ Rats treated with psilocybin were subjected to a forced swim test to examine behavioral and environmental effects of treatment.⁹ Results. Rat 5-HT_2A receptors were downregulated one day post-injection and SV2A was increased seven days post-injection.⁶ An increase in pig behaviors associated with 5-HT_2A receptor agonism was observed along with a psilocin occupancy of 67% of 5-HT_2A receptors, greater in the neocortex.⁵ Dose-dependent increases in neurogenic genes C-Fos, Arc, Egr2, and Ikb–a  were observed, particularly in the prefrontal cortex.⁷ Spinogenesis and neuritogenesis observed with psychedelics were blocked by antagonist co-administration.⁸ Rats administered psilocybin demonstrated increased swimming and climbing in forced swim test compared with control.⁹ Conclusions. Psilocybin acts as a 5-HT_2A agonist through pathways involving mTOR and TrkB to upregulate neuroplastic genes, particularly in the prefrontal cortex. Neuroplasticity alters behavioral flexibility to allow patients to develop better coping skills when faced with a stressful environment. These studies suggest that psilocybin is a potentially viable treatment for depression.

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