Progress in Neuro-Psychopharmacology & Biological Psychiatry最新文献

Despite decades of research, antidepressant therapies are ineffective in many patients, and the rewiring of neuronal networks during depression has remained largely unexplored. Emerging evidence indicates that unbalanced inhibition/ excitation and dysregulations of ventral tegmental area (VTA) dopamine (DA) neuron activity are correlated with depression. Recently, caffeine and adenosine receptor antagonists were found to modulate VTA DA neuron activity, and investigations in both, humans and rodents, indicate that these receptors might serve as targets to treat depression. We employed a system-oriented approach and electrophysiology measurements to explore the impact of the adenosine A1 receptor antagonist DPCPX on the ventral hippocampus (vHPC)-VTA circuit and its ability to affect behavioral responses in forced swim and elevated plus maze tests. A single exposure to DPCPX reduced VTA DA neuron activity at doses known to elicit anxiety. With repeated exposure, a lower dose of DPCPX sufficed to stabilize DA neuron firing via vHPC and to prevent an influence of tetrahydrodeoxycorticosterone or forced swim task (FST), but not of elevated plus maze (EPM), on VTA DA neuron activity. Vice versa, repeated DPCPX enhanced active stress coping behavior in FST, but failed to exert an action in EPM. Our data indicate that repeated A1R antagonism in vHPC can rewire the vHPC - NAc - VTA circuitry to enhance stress resilience by orchestrating VTA DA neuron activity. As reinforced stress resilience may boost antidepressant therapy, A1 receptor antagonism may prove to be a promising strategy in the fight against major depressive disorder.

This study explores the long-term effects of embryonic ethanol exposure on cognitive functions and gene expression in zebrafish (Danio rerio). We hypothesized that ethanol exposure during a critical developmental stage would lead to deficits in executive functions, such as working memory and behavioral flexibility, as well as alterations in neurodevelopmental gene expression. Zebrafish embryos were exposed to ethanol for 2 h at 24 hpf, and behavior was assessed at the fry (15 days post-fertilization), juvenile (45 dpf), and adult (90 dpf) stages. The Y-FMP behavioral test revealed impairments in behavioral flexibility and working memory, indicated by increased repetitive strategy in the juvenile phase and reduced alternation strategy in adult individuals. Molecular analyses showed downregulation of genes responsible for neurodevelopment and also dopaminergic signaling, suggesting that ethanol exposure disrupts critical developmental pathways. Despite partial recovery of gene expression in the juvenile stage, cognitive deficits persisted, highlighting the long-term impact of embryonic ethanol exposure. This study underscores the need for early diagnostic and intervention strategies for individuals affected by Fetal Alcohol Spectrum Disorders (FASD) and calls for further research on biomarkers to distinguish FASD from other neurodevelopmental disorders. In conclusion, our findings demonstrate that embryonic ethanol exposure significantly impacts cognitive functions and gene expression pattern in zebrafish, mirroring the challenges faced by individuals with FASD. These results contribute to the understanding of the neurodevelopmental consequences of prenatal ethanol exposure and reinforce the importance of preventing ethanol consumption during pregnancy.

Post-traumatic stress disorders (PTSD) can lead to substance use disorders (SUD), and in particular opioid dependence. Although preclinical models of the literature focused on traumatic stress-induced potentiation of opioid dependence acquisition, none studied the effect of fear memories during opioid withdrawal. The goal of this study was thus to develop and describe a preclinical model of the PTSD/SUD comorbidity during this critical period in adult male mice. Classically, the traumatic-like memory was acquired by fear conditioning and was followed by morphine-conditioned place preference (CPP) to acquire the associative memory linked to the drug-reinforcing effect. Departing from this approach, we evaluated the effect of a stress on drug-induced CPP using regular re-exposures to a conditioned fear stimulus recall (FR), immediately followed by CPP tests, several days after the last morphine injection (from the 5th to the 21st day). Our data indicated that FR sessions induce a persistent morphine CPP, that is absent in morphine withdrawn mice not subjected to FR. This effect was prevented when antalarmin, a corticotropin-releasing factor receptor 1 antagonist, was administered during morphine withdrawal before each FR. Persistent morphine-induced CPP was concomitant with a FR-induced kappa opioid receptor mRNA upregulation in the prefrontal cortex, while mu opioid receptor mRNA expression was enhanced in control morphine withdrawn mice, an effect absent, however, in withdrawn mice subjected to FR. Surprisingly, in the amygdala, endogenous opioid-related mRNA expression changes in relation with the long-term persistence of drug-induced CPP were few, but next generation sequencing revealed differential expression of numerous microRNAs in that brain area between morphine-control vs morphine-FR mice. The present study thus proposes an innovative behavioral model of the PTSD/SUD-like comorbidity with biological modulations in both the prefrontal cortex and the amygdala, paving the way to develop adapted treatments for this comorbidity in clinics.