Probing the antidepressant potential of psilocybin: integrating insight from human research and animal models towards an understanding of neural circuit mechanisms.

Interest in the therapeutic potential of serotonergic psychedelic compounds including psilocybin has surged in recent years. While human clinical research suggests psilocybin holds promise as a rapid and long-lasting antidepressant, little is known about how its acute mechanisms of action mediate enduring alterations in cognition and behavior. Human neuroimaging studies point to both acute and sustained modulation of functional connectivity in key cortically dependent brain networks. Emerging evidence in preclinical models highlights the importance of psilocybin-induced neuroplasticity and alterations in the prefrontal cortex (PFC). Overviewing research in both humans and preclinical models suggests avenues to increase crosstalk between fields. We review how acute modulation of PFC circuits may contribute to long-term structural and functional alterations to mediate antidepressant effects. We highlight the potential for preclinical circuit and behavioral neuroscience approaches to provide basic mechanistic insight into how psilocybin modulates cognitive and affective neural circuits to support further development of psilocybin as a promising new treatment for depression.

Amelioration of cognitive impairments induced by GABA hypofunction in the male rat prefrontal cortex by direct and indirect dopamine D1 agonists SKF-81297 and d-Govadine.

Deficits in prefrontal cortex (PFC) GABAergic neurotransmission are linked to cognitive impairments seen in schizophrenia and other disorders, and pharmacological reduction of PFC GABAA transmission disrupts processes including working and spatial memory. This provides an opportunity to examine whether compounds capable of neutralizing GABAergic dysfunction may ameliorate these cognitive deficits. PFC dopamine (DA) D1 receptor activation enhances GABA transmission, raising the possibly that direct or indirect agonists of DA D1 receptors would be effective in reversing working memory and other forms of cognitive deficits. To test this, male rats were pre-treated with two drugs that augment PFC D1 signalling before PFC infusion of the GABAA antagonist, bicuculline (50 ng) and assessment of spatial working and reference memory function. A moderate dose of the full D1 agonist SKF-81297 (0.1 mg/kg) completely reversed PFC GABA hypofunction-induced working memory deficits assessed in an delayed-response task, whereas lower and higher doses (0.05 and 0.3 mg/kg respectively) were associated with mild improvements or deleterious effects. Treatment with the tetrahydroprotoberberine d-govadine (0.5 or 1.0 mg/kg), a synthetic compound known to enhance DA release selectively in the PFC, also significantly improved delayed-response working memory function induced by PFC GABAA antagonism. Furthermore, administration of the optimal dose of both drugs led to a partial rescue of PFC GABA hypofunction-induced reference and short-term spatial memory impairments assessed on a radial maze task. These findings suggest that modulation of PFC DA signalling via actions on the DA D1 receptor represents a promising therapeutic strategy for working memory and other cognitive impairments observed in psychiatric disorders, including those with causes that extend beyond DA dysfunction.

Disinhibition of the prefrontal cortex leads to brain-wide increases in neuronal activation that are modified by spatial learning.

Deficient prefrontal cortex (PFC) GABA function is hypothesized to play a role in schizophrenia and other psychiatric disorders. In rodents, PFC GABAA receptor antagonism produces cognitive and behavioral changes relevant to these disorders, including impaired spatial memory assessed with the traditional working/reference memory radial maze task. This aspect of spatial memory does not depend on PFC, suggesting that deficient PFC GABAergic transmission may interfere with non-PFC-dependent cognitive functions via aberrant increases in PFC output. To test this, we assessed whether PFC GABAA antagonism (50 ng bicuculline methbromide) alters neuronal activation in PFC terminal regions, including the striatum, thalamus, hippocampus, amygdala, and cortical regions, of adult male rats using the immediate early gene, c-Fos, as an activity marker. A subset of these animals were also trained and/or tested on the working/reference memory radial maze task. These treatments caused widespread increases in neuronal activation in animals under baseline conditions, with notable exception of the hippocampus. Furthermore, PFC GABAA antagonism impaired task performance. In most instances, training and/or testing on the radial maze had no additional effects on neuronal activation. However, in both the hippocampus and rhomboid thalamic nucleus, PFC GABAA antagonism caused a selective increase in neuronal activation in animals trained on the maze. These results indicate that deficiencies in PFC GABAergic transmission may have widespread impacts on neuronal activity that may interfere with certain PFC-independent cognitive functions. Furthermore, these alterations in activity are modulated by plasticity induced by spatial learning in the hippocampus and rhomboid thalamic nucleus.

Regulation of sustained attention, false alarm responding and implementation of conditional rules by prefrontal GABAA transmission: comparison with NMDA transmission.

RATIONALE: Both prefrontal cortex (PFC) GABAA and NMDA transmission regulate attentional processes, yet how they may differentially regulate signal detection or other aspects of attention is unclear. OBJECTIVES: We examined PFC GABAA and NMDA receptor regulation of attention using a sustained attention task (SAT) permitting identification of distinct forms of impairments. As this task requires implementation of conditional rules, we also investigated how reducing PFC GABA transmission affected performance of visual and auditory conditional discriminations. METHODS: Male rats were well-trained on the SAT that required identifying whether a brief visual stimulus (500-50 ms) was present/absent by pressing one of two levers. They then received intra-PFC infusions of the GABAA antagonist bicuculline (12.5-50 ng), the NMDA antagonist MK-801 (6 µg), and i.p. injections of MK-801 (0.1-0.3 mg/kg) prior to testing. Separate groups were trained either on a similar task where the visual stimulus was presented for 2.5 s, or a task where presentation of one of two auditory cues required responding on a left or right lever. RESULTS: Both doses of bicuculline impaired vigilance, selectively increasing errors during nonsignal trials. Intra-PFC MK-801 induced subtle impairments at short signal durations. Systemic MK-801 impaired performance and increased response latencies. Visual and auditory conditional discrimination was impaired by 50 ng, but not 12.5 ng of bicuculline. CONCLUSIONS: These findings highlight a key role for PFC GABA transmission in reducing sensitivity to distractors during attentional performance. Furthermore, they reveal that disruption of GABA signaling can interfere with the ability to implement conditional rules.