Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) frequently co-occur, leading to significant impairments in learning and memory. Despite the prevalence of these disorders, existing treatment strategies remain inadequate, necessitating novel approaches targeting underlying neural circuits. This study investigated whether optogenetic stimulation of medial prefrontal cortex subregions could rescue fear extinction deficits in a preclinical model of comorbid PTSD/AUD. We examined the differential roles of the infralimbic (IL) and prelimbic (PL) cortices in modulating extinction learning following combined stress and chronic alcohol exposure. Male and female Wistar rats underwent restraint stress (RS) and chronic intermittent ethanol exposure (CIE), followed by fear conditioning and extinction training. Animals received optogenetic stimulation (ChR2 or eYFP control) targeting either IL or PL cortex immediately prior to each extinction session. Extinction learning rates, days to criterion, and long-term memory retention (21-day spontaneous recovery) were assessed. Combined stress and alcohol exposure significantly impaired extinction learning compared to controls. IL-ChR2 stimulation recovered these extinction deficits in the RS + CIE group, accelerating extinction rates and reducing spontaneous recovery. Conversely, PL-ChR2 stimulation impaired extinction learning in control animals but produced no additional deficits in the already-impaired RS + CIE group, suggesting a ceiling effect. This study identifies the IL cortex as a critical regulator of fear extinction learning following stress and alcohol exposure, demonstrating that targeted circuit activation can overcome extinction deficits characteristic of comorbid PTSD and AUD. These region-specific effects provide important insights into the prefrontal mechanisms governing fear memory processes in pathological states.

Pairing casino-inspired audiovisual cues with reward delivery significantly increases risky decision-making in laboratory-based gambling tasks across rats and humans. The neurocognitive mechanisms underlying this effect are unclear. Data from the rat gambling task (rGT) suggests win-paired cues render choice insensitive to reinforcer devaluation, indicating habitual control of decision-making. Histone deacetylase enzymes (HDACs) negatively mediate gene expression. Inhibiting this process can facilitate the formation of long-term memories and accelerate habit formation. We therefore hypothesised that risky decision making in the cued rGT could be enhanced by administration of the non-specific class I HDAC inhibitor sodium butyrate (NaBut). Male Long Evans rats received NaBut after each cued rGT session during task acquisition. NaBut-treated rats developed a bias towards the risky options more rapidly during the first five training sessions. Immunohistochemical analysis indicated a relative increase in histone acetylation in the striatum and prelimbic frontal cortex after five days of NaBut treatment. Modeling the data using previously established reinforcement learning algorithms optimised for the rGT suggests that NaBut concurrently increased learning from rewards while also decreasing learning from punishments during this early learning period. However, once training was complete, NaBut-treated animals were just as sensitive as controls to the omission of reward, although behavioural changes were less apparent in risk-preferring rats. These findings suggest that development of a maladaptive, risky strategy while learning the cued rGT can be facilitated through HDAC inhibition, but fall short of conclusively demonstrating that such treatment results in greater habitual control over behaviour.

The ongoing global opioid crisis underscores the need to better understand the neurobiological mechanisms underlying opioid use disorder (OUD). Stress is a key risk factor for developing and maintaining OUD. While animal models report that the endocannabinoid system (ECS) plays a modulatory role in stress response, alterations of ECS stress reactivity in individuals with OUD have yet to be studied. Here, we aimed to study the response of the ECS to experimentally-induced mild psychosocial stress in individuals with non-medical prescription opioid use (NMPOU) without intravenous use. We compared plasma concentrations of the two main endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) along with structurally related N-acylethalonamines (NAEs) and arachidonic acid (AA) between individuals with chronic NMPOU (n = 21) and matched opioid-naïve healthy controls (n = 29) after social exclusion using the Cyberball task. Blood samples were collected before stress induction, and 10, 20, 30, and 60min after stress onset. We found a significant GROUP*TIME interaction for 2-AG, with controls showing increased 2-AG plasma levels after stress, contrasting with a blunted stress response in NMPOU. Both groups robustly differed in 2-AG levels at all time points after stress induction. No significant GROUP*TIME interactions were found for AEA, NAEs, and AA. Increased 2-AG levels were associated with greater feelings of social inclusion overall. Results suggest dysfunctional stress response at the level of the ECS in individuals with NMPOU. Specifically 2-AG might play a critical role in stress resilience and, thus, it might be a potential pharmacotherapeutic target in the treatment of OUD.

Ketamine and psilocybin have demonstrated therapeutic potential for mental disorders, including major depressive disorder, yet they engage distinct mechanisms of action. Ketamine, a dissociative hallucinogen, acts by blocking N-methyl-D-aspartate receptors (NMDAR), whereas psilocybin primarily targets serotonin receptors. These divergent mechanisms are reflected in their electrophysiological biomarkers. This study aimed to investigate the divergent effects of ketamine and psilocybin on different elements of the EEG frequency spectrum, focusing on aperiodic components as an indicator of excitation-inhibition balance in the neural circuitry. We re-analyzed a previously acquired EEG dataset from healthy volunteers using a placebo-controlled within-subject crossover design (Schmidt et al., Neuropsychopharmacology 37(4):865-875 2012). Participants received either placebo or S-ketamine (N=19) and placebo or psilocybin (N=16) during an auditory roving paradigm. Spectral parameters including periodic and aperiodic were extracted and partial least squares analysis was employed. Ketamine significantly altered the offset and slope of the EEG spectrum, suggesting a disruption in excitatory-inhibitory balance. While both drugs commonly reduced alpha power in similar regions, beta band activity was decreased exclusively under ketamine. These findings highlight ketamine's unique effects on aperiodic EEG components, reinforcing its role as a neurochemical model of prodromal psychosis. Psilocybin's effects appear distinct, emphasizing its targeted influence on oscillatory activity.

Depression is a common and serious mental disorder that has a significant impact on the quality of life of patients. Currently, the clinical drugs used to treat depression all have certain limitations in their efficacy and cannot fully satisfy the needs. Therefore, it is of great significance to search for new therapeutic targets and develop new antidepressant drugs. Ferroptosis is a newly discovered form of cell death in recent years and has been found to be closely related to the pathophysiological processes of many diseases. Notably, there is also an important connection between ferroptosis and depression. To better understand the intrinsic connection between the two area, we have summarized research results ranging from cell model studies, animal model studies to clinical observations. Meanwhile, we have analyzed and summarized the mechanism research of ferroptosis in the occurrence and development of depression from aspects such as iron metabolism disorders, lipid peroxidation imbalance, and abnormal functions of the antioxidant system. To explore the research on drug therapeutic targets targeting ferroptosis as a strategy, with the aim of seeking theoretical basis for the research and intervention treatment of depression.

PIWI-interacting RNAs (piRNAs), a class of small non-coding RNAs originally identified for their role in transposon silencing in germ cells, have recently been recognized as pivotal regulators of gene expression in the central nervous system. Beyond their canonical functions in genome defense, emerging evidence highlights piRNAs as key modulators of neuronal development, synaptic plasticity, axonal regeneration, and neuroimmune interactions-processes central to brain function and dysfunction. This review provides a comprehensive overview of piRNA biogenesis, molecular mechanisms, and regulatory pathways relevant to neurobiology. We focus on the growing body of evidence implicating piRNA dysregulation in major neurological and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, glioma, autism spectrum disorder, and schizophrenia. Importantly, we discuss the neuropharmacological implications of piRNA pathways as novel targets for therapeutic intervention and their potential utility as biomarkers for early diagnosis and treatment stratification. By integrating mechanistic insights with emerging translational evidence, this review highlights piRNAs as promising molecular targets in the development of next-generation neurotherapeutics aimed at modifying disease progression and improving brain health.

Cross-modal conflict control (CMCC) refers to the ability to prioritize information from one sensory modality while suppressing interference from another when presented with incongruent stimuli. Patients with substance use disorder (SUD) often exhibit CMCC deficits, but it has not been clarified whether this deficit occurs at the perception or response level. This study investigated whether CMCC deficits in patients with SUD originate at perception or response levels and examined the modulatory role of the left dorsolateral prefrontal cortex (DLPFC) using transcranial direct current stimulation (tDCS). 28 male patients with SUD completed a 2:1 mapping paradigm dissociating perception (PIC) and response level conflicts (RIC) under three tDCS conditions (anodal, cathodal, and sham). The paradigm required attending to visual or auditory stimuli while ignoring incongruent inputs from the other modality, with the left DLPFC as the stimulation target. At the perception level, patients with SUD exhibited no significant difference between the degree of visual interference with auditory and auditory interference with visual. At the response level, visual interference with auditory was greater than auditory interference with visual in patients with SUD. Furthermore, anodal tDCS applied to the left DLPFC reduced auditory interference with visual perception at the perception level and diminished audiovisual cross-modal interference intensity at the response level. Patients with SUD show dissociable CMCC deficits, with visual interference dominating at the response level but not at the perception level. Anodal stimulation of the left DLPFC enhanced perceptual-level attention and reduced response-level conflict, whereas cathodal stimulation had little effect. These results underscore the key role of the left DLPFC in such deficits and support the therapeutic potential of anodal tDCS for addiction.

Negative affective states, particularly those driven by stress, are known to trigger the development of opioid addiction and relapse. Previous preclinical research has identified sex differences in vulnerability to stress and resulting compulsion to consume drugs. To investigate sex differences in heroin self-administration, stress-induced reinstatement, and related affective state in rats. 22- and 50-kHz ultrasonic vocalizations (USVs), reflecting negative and positive affective state, respectively, were recorded during a heroin self-administration and footshock stress-induced reinstatement model in Sprague-Dawley rats. We hypothesized that females would display increased vulnerability towards heroin use disorder-like profiles. Females showed elevated acquisition of heroin self-administration, but behavioral patterns were not linked to gonadal hormone levels. During heroin acquisition, males emitted significantly more 50kHz calls compared to females, suggesting positive reinforcement-driven intake. We observed successful stress-induced reinstatement in both sexes, with males and females reaching similar overall numbers of active lever presses by the end of the reinstatement session. However, they appear to do so via different strategies, with females displaying "frontloading", rapidly lever pressing in the first 20min of the behavioral session, perhaps indicating differential stress vulnerability or differences in underlying neural encoding of stressor/reward value. Successful stress-induced reinstatement in both sexes is accompanied by a distinct pattern of USVs, whereby a high number of anticipatory 50kHz calls are emitted prior to the onset of reinstatement sessions, followed by 22kHz call production by males during reinstatement sessions, perhaps reflecting drug seeking to relieve negative affect or negative affective responses to drug unavailability. These findings indicate sex-specific vulnerabilities to development of heroin use disorders.

Opioid-related overdose deaths involving benzodiazepines have increased in recent years, and prior studies have reported that clinically used benzodiazepines can enhance the respiratory-depressant effects of mu opioid receptor (MOR) agonists. TPA023B is an α1-sparing GABAA positive allosteric modulator developed as a potential anxiolytic with fewer benzodiazepine-typical side effects. However, it is unknown if and to what degree TPA023B can affect MOR-agonist induced respiratory depression. The current study compared the effects of either TPA023B or midazolam, alone and combined with fentanyl, on respiratory depression in rats, using whole-body plethysmography. Male Sprague-Dawley rats were implanted with chronic indwelling intravenous (i.v.) catheters for drug infusions. Respiration (frequency, tidal volume, and minute volume) was measured using whole-body plethysmography. The tests consisted of a pretreatment (midazolam, 30mg/kg; i.v.; TPA023B, 1.0mg/kg; i.v; or vehicle) followed by a fentanyl injection (0.01, 0.03, 0.1mg/kg, i.v., or vehicle) and 60min of respiration assessment. Overall, fentanyl alone, but not TPA023B or midazolam alone, produced dose-dependent reductions in tidal volume and minute volume. When administered as pre-treatments, neither midazolam nor TPA023B increased the magnitude of fentanyl-induced respiratory depression, instead producing prolonged reductions in tidal volume and minute volume. Midazolam produced a more sustained reduction in these parameters than TPA023B. Benzodiazepines prolong fentanyl-induced respiratory depression, but this effect may be reduced by eliminating activity at α1GABAA receptor subtypes.

Stimulant drug users vary in their substance of choice and may, in some cases, switch up their preferred substance based on availability, cost or other factors. Poly-substance use is rarely assessed in rodent models of drug seeking. To determine if training drug alters the apparent reinforcing properties of methamphetamine (MA) and α-pyrrolidinopentiophenone (α-PVP). Female and male Wistar rats (N = 8 per group) were trained in the intravenous self-administration (IVSA) of α-PVP or MA. The impact of dose substitution (0.0125, 0.0250, 0.100, 0.300mg/kg/infusion) for each training drug was then assessed in all groups under FR and Progressive Ratio schedules of reinforcement. Male and female rats obtained similar numbers of infusions of MA (0.05mg/kg/infusion) and of α-PVP (0.05mg/kg/infusion) during acquisition, however more infusions of α-PVP than of MA were obtained by each sex. Mean lever discrimination ratios exceeded 80% on the drug-associated lever within 5 training sessions for α-PVP groups but were not consistently at this level for either MA group. Drug potency was similar across groups but was less effective in the MA-trained males. Interpretations of sex differences in the acquisition of drug IVSA require caution when dose is not varied across or within group. This study also further confirms that the apparent efficacy of a drug as a reinforcer depends at least partially on the behavioral antecedents, including the identity of the drug used for initial IVSA acquisition.