Brain Sciences

Background: Our recent studies indicate that astrocytes in a key mesocorticolimbic region play an important role in nicotine reinforcement. Nicotine self-administration elevated the astrocyte marker glial fibrillary acidic protein (GFAP) in the nucleus accumbens (NAc) core. Metabolic inhibition of astrocytes in the NAc core with fluorocitrate attenuated nicotine self-administration and disrupted local extracellular glutamate and dopamine transmission. Cotinine is the major neuroactive metabolite of nicotine, demonstrating its own reinforcing effects and contributing to the development of nicotine reinforcement. Mechanisms underlying cotinine reinforcement remain underexplored. The objective of this study was to investigate the potential involvement of astrocytes in cotinine reinforcement. Methods: GFAP protein expression was measured in key mesocorticolimbic regions with a Western blot following chronic cotinine self-administration. The effects of fluorocitrate on cotinine self-administration and extracellular glutamate and dopamine levels were determined. Results: GFAP protein levels were higher in rats undergoing chronic cotinine self-administration than in those with saline self-administration within the ventral tegmental area (VTA) but not the nucleus accumbens or the medial prefrontal cortex. Intra-VTA microinjection of fluorocitrate inhibited the maintenance of cotinine self-administration. Perfusion of fluorocitrate in the VTA reduced local extracellular levels of glutamate and dopamine. Conclusions: These results indicate that cotinine self-administration augmented GFAP expression in the VTA and that metabolic inhibition of VTA astrocytes attenuated cotinine self-administration and impaired extracellular dopamine and glutamate transmission. Overall, these findings suggest that astrocytes in the VTA may play an important role in cotinine reinforcement, potentially through regulation of local extracellular glutamate and dopamine transmission.

Background/Objectives: Esketamine-related dissociation is a transient, pharmacologically induced altered state that differs from the trait-like pathological dissociation typically observed in trauma-related conditions. While most studies have quantified these effects using the Clinician-Administered Dissociative States Scale (CADSS), patients’ subjective phenomenology and meaning-making remain underexplored. This qualitative exploratory study investigated how patients narrate, interpret, and integrate dissociative experiences occurring during intranasal esketamine treatment for treatment-resistant depression (TRD). Methods: We conducted semi-structured interviews with 36 adults with TRD who were receiving intranasal esketamine in outpatient settings in Northern Italy (2022–2024). Interviews focused on the most salient dissociative experiences during treatment. Transcripts were anonymized and analyzed using inductive thematic analysis. Two researchers coded the data independently; discrepancies were resolved by consensus, and recruitment continued until thematic saturation was reached. Results: Four experiential domains emerged: sensory alteration and perceptual flow (10/36, 27.8%), time suspension and chronological drift (21/36, 58.3%), body and space alteration (20/36, 55.6%), and psychic distance from suffering (30/36, 83.3%). While a minority described transient distress or loss of control, most narratives framed dissociation as neutral or subjectively meaningful, often associated with a temporary reduction in ruminative self-focus and depressive distress. Conclusions: A narrative, phenomenological lens complements quantitative research by clarifying what esketamine-induced dissociation feels like to patients and how it is appraised in context. The findings do not imply a causal or mediating role in antidepressant efficacy. Rather, they suggest that dissociation functions as a transitional subjective state, the clinical relevance of which depends on anticipation, framing, monitoring, and integration. These results support the use of structured psychoeducation, in-session support, and post-session integration within real-world esketamine programs.

While phosphatidylserine (PS) is recognized for its neuroprotective properties, the effects of PS purity on human cortical neurons remain unexplored. This study investigates the effects of three different PS purities (15 µM of 50%, 70%, and 80%) on neuronal health using human-embryonic-stem-cell-derived cortical neurons. Our findings reveal that higher PS purity enhances the expression of key regulatory proteins Sirtuin 1 (SIRT1) and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), known for their roles in neuroprotection and mitochondrial function. Specifically, 80% PS purity significantly increases SIRT1 and PGC-1α levels, suggesting that PS purity strengthens neuroprotective pathways and improves mitochondrial quality control. Through SIRT1 knockdown experiments, we demonstrate that PS-induced upregulation of PGC-1α is SIRT1 dependent, highlighting a SIRT1-PGC-1α regulatory axis that enhances mitochondrial health. In an amyloid-beta 1–42 (Aβ₄₂)-induced Alzheimer’s disease (AD) model, PS treatment reduced cytotoxicity and countered the Aβ₄₂-induced downregulation of SIRT1 and PGC-1α, particularly at 70% and 80% PS purity, indicating PS’s role in preserving neuronal viability and combating AD-like pathology. These results suggest that the biological activity of PS preparations in vitro can depend on purity, motivating future studies to define compositional determinants and bioavailability relevant to translational applications.