Major Depressive Disorder is a prevalent and debilitating mental illness. While heterogenous in pathogenesis, symptomatology, and neurobiology, it is marked by reduced mood, anhedonia and severely reduced quality of life. Standard treatments such as the commonly prescribed selective serotonin reuptake inhibitors (SSRIs) are effective in approximately 70% of patients and take weeks for response and remission to occur. Psilocybin exhibits rapid antidepressant actions in clinical trials and in rodent models of depression. Due to the pan-serotonergic agonist properties of psilocin, the active metabolite of psilocybin, I hypothesized that the antidepressant actions of psilocybin may be shared with SSRIs. Serotonin 1B receptor (5-HT1BR)-induced strengthening of stress sensitive synapses mediates therapeutic effects of SSRIs. Further evidence suggests that the therapeutic signaling of 5-HT1BR may include β-arrestin. I thus, sought to test if strengthening of stress-sensitive synapses induced by 5-HT1BR-β-arrestin signaling mediated the antidepressant effects of psilocybin. I demonstrated that psilocybin may acutely potentiate stress sensitive synapses in vivo and in hippocampal slices. I further show that psilocin-induced potentiation mimics that induced by 5-HT1BR activation. Comparing 5-HT1BR agonists, I find that β-arrestin recruitment down-stream from 5-HT1BR is associated with potentiating actions at stress-sensitive synapses in hippocampal and accumbal slices. However, in behavioral experiments, I found no antidepressant actions of psilocybin in a mouse model of stress-induced anhedonia. This suggests that psilocybin’s antidepressant actions may depend on extra-drug factors or that psilocybin is limited to restore certain stress-induced neurobiological and behavioral impairments. I further describe experiments exploring behavioral mechanisms and neurophysiological heterogeneity underlying rodent models of anhedonia. Using lickometry, I record detailed drinking behavior of mice and find evidence that loss of sucrose preference in stress-susceptible mice is mediated by impaired goal-oriented behaviors. Using electrophysiological recordings of D1- and D2 expressing medium spiny neurons, I show that anhedonic behavioral phenotypes induced by fentanyl abstinence is associated with neurophysiological changes in D1- medium spiny neurons that are overlapping but distinct from those seen following stress-induced anhedonia. Combined, these data show that psilocybin may strengthen stress-sensitive synapses via 5-HT1BR-β-arrestin signaling but that this may not be sufficient to rescue all types of stress-induced anhedonia.