International Journal of Neuropsychopharmacology

Antidepressant drugs are the first-line treatment for chronic stress-related psychiatric disorders such as major depressive disorder, anxiety disorders, and post-traumatic stress disorder. However, their delayed-onset of therapeutic action, frequently occurring side effects, and incomplete clinical efficacy impose significant challenges for clinicians and patients adherence to treatment. Cannabidiol (CBD) is a major non-psychotomimetic phytocannabinoid with a wide range of potential clinical applications such as either a standalone drug or as an add-on treatment. In our study, we found that in chronically stressed male mice, CBD (30 mg/kg) rapidly induced behavioral improvement within 7 days, which was quicker than the high dose of escitalopram (ESC, 14 days). Additionally, repeated administration of a low and initially ineffective dose of CBD (7.5 mg/kg) potentiated the anti-stress effects of ESC (10 mg/kg) in mice subjected to 10 or 21 days of chronic unpredictable stress (CUS). Furthermore, our results suggested the involvement of N-acyl phosphatidylethanolamine phospholipase (NAPE-PLD) located in the prefrontal cortex (PFC) in the anti-stress effects of the 7-day treatment with ESC + CBD. This combination restored CUS-induced decreased expression of NAPE-PLD in the PFC. The behavioral effects of ESC + CBD were not observed in either constitutive NAPE-PLD knockout (KO) mice or mice with a CRISPR/Cas9-induced deletion of NAPE-PLD in the PFC. ESC + CBD treatment facilitated NAPE-PLD expression in parvalbumin (PV) interneurons in the PFC. As a conclusion, we suggest that CBD might be useful as an add-on therapy to optimize the action of (SSRI-)antidepressants, possibly by restoring the inhibitory/excitatory balance of the PFC via NAPE-PLD-mediated signaling. HighlightsO_LICBD (7.5 mg/kg) reduces the latency for anti-stress effects of escitalopram (ESC) C_LIO_LIESC + CBD increases neuroplasticity in the prefrontal cortex (PFC) C_LIO_LIESC + CBD reverses stress-induced loss of NAPE-PLD in PFC-Parvalbumin (PV)+ interneurons. C_LIO_LINAPE-PLD in the PFC participates in the anti-stress effects of ESC + CBD. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=151 HEIGHT=200 SRC="FIGDIR/small/441143v2_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@d61ef2org.highwire.dtl.DTLVardef@189e2ecorg.highwire.dtl.DTLVardef@1910213org.highwire.dtl.DTLVardef@11f6bbf_HPS_FORMAT_FIGEXP M_FIG Cannabidiol (CBD) enhances the antidepressant-like effects of escitalopram (ESC) in chronically stressed mice. While an effective dose of CBD (30mg/kg) alone rapidly improved stress-related behaviors when compared to a high dose of ESC (20mg/kg), ESC+CBD combination in sub-effective doses potentiated anti-stress responses and restored prefrontal cortex (PFC) function. These effects depended on N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) activity within PFC parvalbumin interneurons, highlighting NAPE-PLD-mediated signaling as a key mechanism by which CBD may optimize antidepressant efficacy and reestablish inhibitory/excitatory balance in the PFC. C_FIG Chemical compounds used in this articleCannabidiol (PubChem CID: 644019); Escitalopram oxalate (PubChem CID: 146571); URB597 (PubChem CID: 1383884); Ketamine hydrochloride (PubChem CID: 15851); xylazine hydrochloride (PubChem CID: 68554); 2,2,2-Tribromoethanol (PubChem CID: 6400); Flunixin meglumine (PubChem CID: 39212); Lidocaine hydrochloride (PubChem CID: 6314); Amoxicillin (PubChem CID: 33613).

Adolescent depression is a significant public health concern, yet treatment options remain limited, particularly due to age- and sex-related differences in antidepressant efficacy. This study explored the rapid and long-lasting antidepressant-like potential of psilocybin in adolescent Sprague-Dawley rats, examining acute and repeated oral dosing effects while incorporating sex as a biological variable. An acute administration of psilocybin produced rapid antidepressant-like effects 30 minutes post-treatment in both male and female rats, demonstrated by reduced immobility and increased escape-related behaviour in the forced swim test. However, repeated daily administrations over 7 days revealed notable sex differences. In males, the antidepressant-like effects were sustained, at least, for up to 15 days post-treatment at both tested doses. In contrast, in females, the effects were dose-dependent and less enduring, persisting only up to 8 days at the highest dose tested. To the best of our knowledge, these results are the first ones to underscore psilocybins potential as a fast-acting and long-lasting antidepressant during adolescence, a developmental stage marked by high vulnerability to depression and reduced response to conventional treatments, while also emphasizing the importance of tailoring therapeutic approaches to individual biological factors such as sex.

BackgroundRacemic ketamine and its enantiomer, esketamine, have emerged as fast-acting antidepressant options for individuals with treatment-resistant depression (TRD). Yet, despite growing clinical use, little is known about how sex assigned at birth shapes symptom-specific responses to these interventions, a critical gap in the move toward personalized psychiatry. MethodsWe conducted a pooled analysis of five randomized, double-blind, placebo-controlled trials in which adults with TRD received intranasal esketamine or placebo twice weekly for four weeks, alongside a newly initiated oral antidepressant. We evaluated the effects of sex assigned at birth on overall depression severity, measured via total Montgomery-[A]sberg Depression Rating Scale (MADRS) scores, and across four symptom factors: sadness, negative thoughts, detachment, and neurovegetative symptoms. Rates of clinical response and remission were also analyzed by sex assigned at birth. FindingsOverall, esketamine treatment improved total MADRS scores in both sexes; however, significant sex-specific patterns emerged. Females showed greater improvement in total MADRS scores than males towards the end of the trials, in both the placebo and esketamine arms. Females also showed more pronounced reductions in the sadness and detachment factors at the end of the trials, as well as in the neurovegetative factor on day 15, regardless of the treatment group. On the other hand, males showed a significant reduction in sadness symptoms after esketamine on day 2 of the treatment. Females had higher odds of responding, regardless of treatment arm, during later time points. InterpretationThese findings reveal that sex assigned at birth influences overall antidepressant response and shapes the trajectory and symptom profile of improvement. Our findings emphasize the critical importance of incorporating sex assigned at birth as a key variable, essential for optimizing TRD treatment strategies and advancing individualized mental healthcare. FundingCanadian Institutes for Health Research.

Patients characterized by stress-related disorders such as depression display elevated circulating concentrations of pro-inflammatory cytokines and a hyperactive HPA axis. Psychedelics are demonstrating promising results in treatment of such disorders, however the mechanisms of their therapeutic effects are still unknown. To date the evidence of acute and persisting effects of psychedelics on immune functioning, HPA axis activity in response to stress, and associated psychological outcomes is preliminary. To address this, we conducted a placebo-controlled, parallel group design comprising of 60 healthy participants who received either placebo (n=30) or 0.17 mg/kg psilocybin (n=30). Blood samples were taken to assess acute changes in immune status, and 7 days after drug administration. Seven days post-administration, participants in each treatment group were further subdivided: 15 underwent a stress induction protocol, and 15 underwent a control protocol. Ultra-high field magnetic resonance spectroscopy was used to assess whether acute changes in glutamate or glial activity were associated with changes in immune functioning. Finally, questionnaires assessed persisting self-report changes in mood and social behavior. Psilocybin immediately reduced concentrations of the pro-inflammatory cytokine tumor necrosis factor- (TNF-), while other inflammatory markers (interleukin (IL)-1, IL-1{beta}, IL-6, and C-reactive protein (CRP)) remained unchanged. Seven days later, TNF- concentrations returned to baseline, while IL-6 and CRP concentrations were persistently reduced in the psilocybin group. Changes in the immune profile were related to acute neurometabolic activity as acute reductions in TNF- were linked to lower concentrations of glutamate in the hippocampus. Additionally, the more of a reduction in IL-6 and CRP seven days after psilocybin, the more persisting positive mood and social effects participants reported. Regarding the stress response, after a psychosocial stressor, psilocybin blunted the cortisol response compared to placebo. Such acute and persisting changes may contribute to the psychological and therapeutic effects of psilocybin demonstrated in ongoing patient trials.

Nicotine intake by cigarettes is linked to the maintenance and development of anxiety disorders and impairs adaptive discrimination of threat and safety in humans. Yet, it is unclear if nicotine exerts a causal pharmacological effect on the affective and neural mechanisms that underlie aversive learning. We conducted a pre-registered, pseudo-randomly and double-blinded pharmacological fMRI study to investigate the effect of acute nicotine on Fear Acquisition and Extinction in non-smokers (n=88). Our results show that nicotine administration led to decreased discrimination between threat and safety in subjective fear. Nicotine furthermore decreased differential (threat vs. safety) activation in the hippocampus, which was functionally coupled with Nucleus Accumbens and amygdala, compared to placebo controls. Additionally, nicotine led to overactivation of the ventral tegmental area. This study provides mechanistic evidence that single doses of nicotine impair neural substrates of adaptive aversive learning in line with the risk for the development of pathological anxiety.

ObjectiveDespite many decades of experimental studies and clinical trials involving a variety of psychedelic agents, we still lack a comprehensive understanding of the effects of these substances on psychological experiences. As such, we designed and conducted a study to comprehensively characterise the effects of both psilocybin and 3,4-Methylenedioxymethamphetamine (MDMA) on a range of psychological outcomes in a substantive non-clinical population. MethodsThis study involved a single dose administration of psilocybin or MDMA in healthy individuals in a group setting (2-4 people per session). All participants underwent a single preparation session, a drug exposure session, and an integration session within 72 hours of dosing. Outcome assessments were conducted at a pre-dosing baseline, 1-3 days post dose (side effects only), one week post dose and at 3 month follow up (the later time point data is not included here). ResultsOf 48 participants, 25 initially received MDMA and 23 psilocybin. Ten cross-over participants received MDMA and then psilocybin and six participants received both in the reverse order: making a total of 31 MDMA and 33 psilocybin dosing sessions. In the week after dosing, we found significant changes in personality (a reduction in neuroticism and increase in extraversion), mindfulness, and connectedness following the administration of psilocybin but not MDMA. Psilocybin also produced significantly stronger mystical experiences compared to MDMA, and there was a significant correlation between the magnitude of these mystical experiences and changes in connectedness and mindfulness (but not changes in personality). Of note, participants seemed more comfortable with, and preferred, larger group sizes when being administered MDMA than psilocybin. DiscussionOur results identified a range of short-term psychological effects in non-clinical participants following a single dose of psilocybin, that were not reported following a single dose of MDMA. Notably, our results indicate that these effects following psilocybin may be moderated through its induction of mystical experiences, as has been previously hypothesised. Although preliminary, our results also suggest that larger group dosing sessions seem more feasible with MDMA than psilocybin.

RationaleDopamine D4 receptors (D4Rs) have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD), yet their precise role and therapeutic relevance remain underexplored. Highly selective D4R compounds may provide a valuable tool to elucidate D4R function and assess their potential as non-stimulant ADHD treatments. ObjectivesThis study examined the behavioral effects of two novel D4R drugs, namely, FMJ-01-38 (high-efficacy partial agonist) and FMJ-01-54 (full antagonist) in adolescent spontaneously hypertensive (SHR/NCrl) rats, a validated ADHD model, and Wistar controls. MethodsRats received intraperitoneal FMJ-01-38 or FMJ-01-54 (5-10 mg/kg) or vehicle prior to behavioral assays assessing locomotor activity (open field tests), recognition memory (novel object preference), attention and working memory (Y-maze test), and impulsivity (delay discounting task). ResultsFMJ-01-38 dose-dependently reduced locomotor hyperactivity and improved spontaneous alternation behavior in SHR/NCrl; at 5 mg/kg it enhanced novel-object preference and decreased impulsive choice and action, indicating attenuation of ADHD-like symptoms and cognitive enhancement. FMJ-01-54 produced similar improvements in Y-maze and novel-object performance without altering locomotor activity or impulsivity of SHR/NCrl, suggesting selective cognitive improvement. In Wistar rats, FMJ-01-38 increased novel-object preference only at the 5 mg/kg dose, while FMJ-01-54 treatment did not produce any significant behavioral effects. ConclusionsThese findings demonstrate that D4R modulation, through either partial agonism or antagonism, differentially ameliorates ADHD-related behaviors. Both FMJ-01-38 and FMJ-01-54 produced minimal effects in control animals, suggesting pathology-specific efficacy and highlighting D4R ligands as promising non-stimulant therapeutic candidates for ADHD.

Affective biases influence cognitive and emotional behaviour and play a significant role in major depressive disorder. We have shown that the NMDA antagonist and rapid-acting antidepressant, ketamine, selectively modulates affective biases, a neuropsychological effect which may underlie its efficacy. Clinical studies with different NMDA antagonists have found mixed effects but the reasons for these differences in efficacy are not understood. This study used a rat model of negative affective biases to investigate if different NMDA antagonists also differentially modulated affective biases. Dose-response experiments using the NMDA antagonists lanicemine, memantine, CP101,606, phencyclidine (PCP) and ephenidine, and ketamine metabolite, (2R,6R)-hydroxynorketamine (HNK), were performed to test their acute and sustained (24hrs) effects, and specificity of affective bias modulation. Our results showed that HNK, PCP, lanicemine, and ephenidine acutely attenuate negative biases. HNK, CP-101,606, and ephenidines effects were sustained at 24hrs post-treatment with a positive bias observed for HNK and a tendency towards a positive affective bias for CP101,606 and ephenidine. Lanicemines effects were sustained at 24hrs but only at the highest dose and PCP and memantine had no effects. Considering these findings in the context of clinical observations, we suggest that the ability to induce a sustained modulation of affective biases corresponds with therapeutic effects. The differences in efficacy observed with NMDA antagonists may be related to their ion trapping properties and those with very high and low ion trapping properties are less effective than those with more moderate ion trapping effects such as ketamine or ephenidine or the subunit selective antagonist, CP101,606.

Background and AimsPsilocybin is a psychedelic drug that may hold promise for a wide range of human health conditions, yet the identification of therapeutic processes and mechanisms of action remains exploratory. We conducted a scoping review on pre-clinical behavioural investigations of psilocybin in non-human animals to help determine the behavioural effects of psilocybin in non-human animals, to identify studies completed, behavioural tests employed, and what dosing modalities had been studied. MethodsA librarian-conducted literature search was performed using predefined key terms and search criteria and additional searching was conducted by reviewers, using electronic databases, grey literature sources, and reference lists of relevant articles or reviews. The final search updated occurred in October, 2021. Studies were reviewed, screened and selected against an a priori protocol using Covidence software by multiple reviewers with results plotted across the Research Domains Criteria construct. ResultsFrom 4124 records identified by database searching, 260 publications were subjected to full-text review with 77 studies included in this scoping review, published between 1962-2021. The preponderance of studies (n=64) investigated behavioural outcomes in rodents. Only 43 studies (55.8%) reported on housing conditions, and seventeen studies (22.1%) failed to report sample size. All studies reported behavioural outcomes following drug administration, with fifty-one studies (66.2%) using psilocybin, thirty studies (42.9%) psilocin, four studies (5.2%) administering whole mushroom extracts (WME), and a further eight studies investigating both psilocybin and psilocin and one study reporting the effects of both psilocin and WME. One hundred and thirty distinct behavioural investigations using fifty different behavioral paradigms were identified. Few adverse events were reported, and even exceedingly high doses were apparently well tolerated. ConclusionWith seventy-seven publications spanning close to sixty years, there is huge variation in study design and quality. Overall psilocybin presents a unique and strong safety profile with no evidence of biological toxicity, is characterized by unique time and dose-dependent effects, and its pattern of drug action is significantly context and training-sensitive. Data suggest putative effects of psilocybin include acute arousal, dose-dependent sedation, reductions in fear conditioning at low doses, reduced aggression, improved valence, acute disruption of working memory, the rescuing of deficits from chronic stress, and improved learning when combined with repeated environmental exposure after resolution of drug effect.

Background and PurposeWhile inflammation has been generally considered to exacerbate symptoms of schizophrenia, some clinical observations suggest that acute inflammation may alleviate positive symptoms. However, animal models often use excessive inflammatory stimuli, and the effects of acute inflammation--comparable to levels observed in patients--remain unknown. Experimental ApproachTo address this, we examined whether acute inflammation induced under relatively mild, clinically relevant conditions suppresses behavioural sensitization in methamphetamine (METH)-sensitized mice, a model of psychostimulant-induced psychosis with relevance to certain aspects of positive symptoms of schizophrenia. We used a repeated METH (1 mg/kg) sensitized model to evaluate the effects of acute inflammation on behavioural sensitization. Acute inflammation was induced via two methods using either lipopolysaccharides (LPS; 1 g/kg) to mimic peripheral immune activation or restraint stress (RS; single 2-h exposure) to model the neuroinflammation induced by psychological stress. LPS doses were adjusted with reference to the magnitude of peripheral cytokine elevation reported in patients, and RS was applied in short single sessions to avoid excessive inflammation. Key ResultsBoth LPS and RS significantly suppressed behavioural sensitization, without inducing other behavioural abnormalities. This suppression was dependent on toll-like receptor-4 activation. LPS-mediated suppression involved cyclooxygenase-2, whereas RS-mediated suppression was linked to the microglia-derived tumour necrosis factor-. LPS did not alter, whereas RS significantly reduced the striatal extracellular dopamine levels. Conclusion and ImplicationsThese findings suggest that acute inflammation suppresses behavioural sensitization through distinct mechanisms depending on the inflammatory trigger, providing a framework for understanding how inflammation may influence psychosis-related processes, with potential relevance to schizophrenia.

Depression remains a leading cause of disability worldwide, yet the predictive validity of many preclinical behavioral assays for antidepressant efficacy remains limited. The Differential Reinforcement of Low-Rate Behavior (DRL) task has classically been used in rodents to identify antidepressant-like effects, but its utility in non-human primates (NHPs) has not been established. Here, we adapted the DRL task for use in adult male cynomolgus macaques (Macaca fascicularis) and evaluated its pharmacological sensitivity and translational relevance across 19 compounds spanning multiple drug classes. Antidepressants, including SSRIs, SNRIs, NRIs, NDRIs, TCAs, MAOIs, and PDE4 inhibitors, generally shifted DRL performance in an antidepressant-like direction, increasing reinforcers earned and inter-response times while decreasing response output. In contrast, benzodiazepine and antipsychotic control compounds did not produce a consistent antidepressant-like profile, whereas stimulant effects were mixed, with nicotine and cocaine also producing overlapping antidepressant-like behavioral effects. Importantly, the primate DRL task identified antidepressant-like effects of PDE4 inhibitors while also capturing emesis, a dose-limiting side effect not observable in rodent models. These findings support the primate DRL task as a translationally relevant platform for screening antidepressant-like efficacy, while also highlighting important design considerations for interpreting pharmacological sensitivity in the NHP setting. By modeling behavioral processes implicated in depression, including response inhibition and temporal regulation, this assay offers a unique opportunity to bridge preclinical and clinical antidepressant development with improved sensitivity to both efficacy and tolerability.

Modification of mRNA by methylation is involved in post-transcriptional regulation of gene expression by affecting the splicing, transport, stability and translation of mRNA. Methylation of adenosine at N6 (m6A) is the most common and most important cellular modification occurring in the mRNA of eukaryotes. Evidence that m6A mRNA methylation is involved in regulation of stress response and that its dysregulation may contribute to the pathogenesis of neuropsychiatric disorders is accumulating. We have examined the acute and subchronic (up to 18 days once per day intraperitoneally) effect of the first METTL3/METTL14 activator compound CHMA1004 (methyl-piperazine-2-carboxylate) at two doses (1 and 5 mg/kg) in male and female rats. CHMA1004 had a profound locomotor activating and anxiolytic-like profile in open field and elevated zero-maze tests. In female rats sucrose consumption and swimming in Porsolts test were increased. Nevertheless, CHMA1004 did not exhibit strong psychostimulant-like properties: CHMA1004 had no effect on 50-kHz ultrasonic vocalizations except that it reduced the baseline difference between male and female animals, and acute drug treatment had no effect on extracellular dopamine levels in striatum. Subchronic CHMA1004 altered ex vivo catecholamine levels in several brain regions. RNA sequencing of female rat striata after subchronic CHMA1004 treatment revealed changes in the expression of a number of genes linked to dopamine neuron viability, neurodegeneration, depression, anxiety and stress response. Conclusively, the first-in-class METTL3/METTL14 activator compound CHMA1004 increased locomotor activity and elicited anxiolytic-like effects after systemic administration, demonstrating tha pharmacological activation of RNA m6A methylation has potential for neuropsychiatric drug development.

The medial prefrontal cortex (mPFC) belong to the neural circuitry responsible for the behavioral responses to antidepressants in humans or animals. In the forced swimming (FST), a predictive test for antidepressants in laboratory rodents, inhibition, or stimulation of mPFC may produce antidepressant-like, unlike or no behavioral effect at all. Controversial findings may result from the variety of subregions of mPFC controlling behaviour of rats in the FST. The aim in the present study was to estimate the contribution of subregions of the mPFC to the control of rat behavior in the FST. For an unbiased view and well-powered analysis of the mentioned effects, a systematic review at Medline (Pubmed) followed by a meta-analysis was performed. Compared to other subdivisions, inhibition of prelimbic or infralimbic mPFC caused a significant drop of immobility time in the FST, which is an antidepressant-like effect. Summarizing, prelimbic or infralimbic cortices seem more relevant than other subregions to the control of immobility in the FST underlying the effects of antidepressants on mood and behaviour.

Depressive disorders are one of the leading causes of non-fatal health loss in the last decade. Adding to the burden, the available treatments not always properly work for some individuals. There is, therefore, a constant effort from clinical and preclinical studies to bring forward a better understanding of the disease and look for novel alternative therapies. Two target systems very well explored are the serotonin and the brain-derived neurotrophic factor (BDNF) systems. Selective serotonin reuptake inhibitors (SSRIs), a commonly used class of antidepressants, target the serotonin transporter (SERT) and increase serotonin levels, which in turn also leads to an increase in BDNF. A rat model lacking SERT (SERT knockout) has been a useful tool to study the interplay between serotonin and BDNF. SERT-/- rats present increased extracellular levels of serotonin, yet BDNF levels are decreased, especially in the prefrontal cortex (PFC) and hippocampus. The animals further display anxiety- and depression-like behavior. Therefore, BDNF might mediate the phenotype expressed by the SERT-/- rats. In this study, we sought to investigate whether overexpression of BDNF in the brain of SERT-/- rats would rescue its anxious and depressive-like behavior. Through stereotaxic surgery, SERT-/- and wild-type (WT) rats received BDNF or GFP lentivirus microinfusions into the prelimbic cortex subregion of the mPFC and were submitted to the sucrose consumption, open field test, and forced swim tests. Additionally, we measured hypothalamus-pituitary-adrenal (HPA)-axis reactivity. The results revealed that SERT-/- rats presented decreased sucrose intake, decreased locomotor activity, and increased escape-oriented behavior in the forced swim test compared to WT rats. BDNF upregulation in WT rats caused alterations in the HPA-axis function, resulting in elevated basal plasma corticosterone levels and decreased plasma corticosterone upon stress. In conclusion, BDNF overexpression in the PrL, in general, did not rescue SERT-/- rats from its depression- and anxiety-like behavior, and in WT animals, it caused a malfunction in the HPA-axis.

Targeting reconsolidation with propranolol, a blocker of {beta}-adrenergic receptors ({beta}-ARs), emerged as a potential treatment for maladaptive memories such as those involved in posttraumatic stress disorder (PTSD). Reconsolidation targeting treatments for PTSD are becoming a common practice in the clinic and it is important to unveil any side effects upon non-targeted memories. While previous studies have focused on propranolols effects on the reconsolidation of emotional/distressful memories, the present study asked whether propranolol is involved in the reconsolidation of recognition memories - by assessing its effects on distinct memory components and the role of the hippocampus. Rats performed an object recognition (OR) task where they were exposed to different objects: A and B presented during the sample phase; A and C presented during the reactivation phase; and D in combination of either A, B, or C during a final test. Intra-hippocampal injections of propranolol (5 {micro}g or 10 {micro}g) were conducted immediately after the reactivation session. Propranolol infusions consistently impaired the addition of novel information to the previously consolidated memory trace regardless of dose, and the retention of familiar objects was not affected. Higher doses of propranolol also hindered memory of a familiar object that was not presented during the reactivation session, but was previously placed at the same location where novel information was presented during reactivation. The present results shed light on the role of {beta}-ARs on the reconsolidation of different memory components and argue for the need for further studies examining possible recognition memory deficits following propranolol treatment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=66 SRC="FIGDIR/small/492176v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@69c9f9org.highwire.dtl.DTLVardef@14afbaborg.highwire.dtl.DTLVardef@1d0d0a2org.highwire.dtl.DTLVardef@314e0c_HPS_FORMAT_FIGEXP M_FIG C_FIG Post-traumatic stress disorder is a chronic mental health condition, which may develop following direct or indirect exposure to a traumatic event. The administration of propranolol to individuals affected by this disorder before the reactivation of the trauma-related memory may diminish the symptoms of this mental condition. Here, we show that such treatment may have effects on non-targeted memories, other than the fear/distressful memory. In a series of experiments in rodents, we show that intra-hippocampal infusion of propranolol immediately after recalling and updating a recognition memory trace hampers the reconsolidation of the initial recognition memory trace during recall. This may lead to difficulties in recalling recent events related to declarative memories. In a high dose, propranolol treatment may also affect the conjunctive component (association between multiple elements) of the memory trace - in addition to the effect on the elemental component. This may lead, for example, to difficulties in locating a parked car in a non-usual location after the post-stress traumatic stress disorder therapy with propranolol. HighlightsO_LIWe established the role of the hippocampal {beta}-adrenergic system in the reconsolidation of recognition memories. C_LIO_LIPropranolol treatment may impair the updating of recognition memory traces. C_LIO_LIHigh doses of propranolol may disrupt both elemental and conjunctive components of memory. C_LIO_LIClinical treatment with high doses of propranolol for post-traumatic stress disorder may unintentionally affect non-pathological components of memories. C_LI

Stress is a prevalent mental health concern emerging predominantly in late adolescence or early adulthood. Since 2007, the Food and Drug Administration (FDA) has not approved any novel anxiolytic pharmaceuticals, fueling interest in nutritional supplements as alternative therapies for stress management. Building on prior zebrafish research, this study investigates the synergistic effects of Theanine (Th) and Walnut Peptide (WP) on stress mitigation and cognitive enhancement. Utilizing the human brain organoid stress (BO-stress) model, WP+ Th were observed to reduce stress and regulate expression of neurotransmitters, including Gamma-Aminobutyric Acid (GABA), serotonin (5-HT), dopamine (DA), and acetylcholine (Ach), as well as brain-derived neurotrophic factor (BDNF) and serotonin transporter (SERT). Subsequent in vivo study using C57BL/6J mouse-stress model demonstrated that the treatment (Th 85 mg/mL + WP 200 mg/mL), or administrated with vehicles, significantly improved their performance in stress and cognitive assessments, partially normalized neurotransmitter imbalances by modulating SERT and BDNF expression. These findings highlighted the potential of using WP + Th, particularly when delivered with vehicles (eg: powder/yogurt/milk), as a novel combined therapeutic approach for stress management and cognitive enhancement. We performed a correlation analysis between BO-stress model and mouse-stress model, revealing a alignement in the SERT levels.In addition, SERT was highly correlated with other markers in the mouse hippocampus and may represent a key target for modulating the balance between stress and cognition. Significance StatementThis study established an innovative human brain organoid-stress model and, in conjunction with mouse-stress model, elucidated the synergistic actions of Theanine and Walnut Peptide in mitigating stress and augmenting cognitive function. Their beneficial effects were mediated through the regulation of SERT and BDNF, presenting a promising non-pharmacological avenue for mental health care. In addition, species differences between humans and mice were also examined through correlation analysis of brain organoids and mouse models. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/640260v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@1a81886org.highwire.dtl.DTLVardef@e2281dorg.highwire.dtl.DTLVardef@1b7b167org.highwire.dtl.DTLVardef@dff9aa_HPS_FORMAT_FIGEXP M_FIG C_FIG

There is now evidence from multiple Phase II clinical trials that psychedelic drugs can exert long-lasting anxiolytic, anti-depressant, and anti-drug abuse (nicotine and ethanol) effects in patients. Despite these benefits, the hallucinogenic actions of these drugs at the serotonin 2A receptor (5-HT2AR) limit their clinical use in diverse settings. Activation of the 5-HT2AR can stimulate both G protein and {beta}-arrestin ({beta}Arr) -mediated signaling. Lisuride is a G protein biased agonist at the 5-HT2AR and, unlike the structurally-related LSD, the drug does not typically produce hallucinations in normal subjects at routine doses. Here, we examined behavioral responses to lisuride, in wild-type (WT), {beta}Arr1-KO, and {beta}Arr2-KO mice. In the open field, lisuride reduced locomotor and rearing activities, but produced a U-shaped function for stereotypies in both {beta}Arr lines of mice. Locomotion was decreased overall in {beta}Arr1-KOs and {beta}Arr2-KOs, relative to WT controls. Incidences of head twitches and retrograde walking to lisuride were low in all genotypes. Grooming was depressed in {beta}Arr1 mice, but was increased then decreased in {beta}Arr2 animals with lisuride. Prepulse inhibition (PPI) was unaffected in {beta}Arr2 mice, whereas 0.5 mg/kg lisuride disrupted PPI in {beta}Arr1 animals. The 5-HT2AR antagonist MDL100907 failed to restore PPI in {beta}Arr1 mice, whereas the dopamine D2/D3 antagonist raclopride normalized PPI in WTs but not in {beta}Arr1-KOs. Using vesicular monoamine transporter 2 mice, lisuride reduced immobility times in tail suspension and promoted a preference for sucrose that lasted up to 2 days. Together, it appears {beta}Arr1 and {beta}Arr2 play minor roles in lisurides actions on many behaviors, while this drug exerts anti-depressant drug-like responses without hallucinogenic-like activities.

ObjectiveThe purpose of this report was to analyze black market diversions of atomoxetine, a non-stimulant medication for ADHD, submitted to StreetRx. MethodData related to black market atomoxetine purchases entered on StreetRx between 2015 and 2019 were analyzed. Data included generic drug name, dosage, purchase price, and date and location in the United States. The mean price per milligram was determined and a heatmap generated. ResultsThe average price per milligram cost of 113 diverted atomoxetine submissions was $1.35 ({+/-} $2.76 SD) (Median = $0.05, Min = $0.01, Max = $20.00). The states with the most submissions included Michigan (11), Pennsylvania (9), Indiana (8), and Ohio (8). ConclusionFurture qualitative studies should investigate reasons why individuals are motivated to purchase atomoxetine, a non-stimulant medication, on the black market (recreational vs. nootropic vs. other clinical uses).

Nitric oxide (NO), mainly produced by neuronal nitric oxide synthase (nNOS) in the brain, has been implicated in stress responses and the pathophysiology of post-traumatic stress disorder (PTSD). Our group previously showed that inducible nitric oxide synthase (iNOS) knockout (KO) male mice exhibit compensatory changes in nNOS expression in the medial prefrontal cortex (mPFC) and impaired fear extinction, suggesting that this genetic model may be relevant for studying PTSD-related phenotypes. Given the frequent comorbidity of PTSD with anxiety and depression, and the marked underrepresentation of females in neuropsychopharmacology research, we performed a behavioral characterization of male and female iNOS KO mice, focusing on aversive memory, anxiety-, and depression-like behaviors. To our knowledge, this is the first systematic behavioral study of female iNOS KO mice, which is particularly relevant given that females are twice as likely to develop psychiatric disorders. We observed that female iNOS KO mice exhibited increased anxiety-like behavior in the elevated plus maze test (EPMT), whereas males showed antidepressant-like behavior in the forced swim test (FST). No general cognitive deficits were found in the Y-maze or object recognition (OR) tests in either sex. However, male iNOS KO mice exhibited deficits in fear extinction memory and extinction retrieval in both contextual and cued fear conditioning. These findings indicate that iNOS KO mice present sex-dependent behavioral phenotypes and may serve as a genetic model to investigate disorders related to fear memory, such as PTSD, and highlight the importance of considering sex as a biological variable in research.

BackgroundPsilocybin is a classic psychedelic that acutely alters brain functional connectivity. These changes are linked to therapeutic doses and subjective effects, with some evidence that changes persist beyond acute drug administration. However, the effects of lower doses on sustained connectivity changes remain unclear. MethodsTen healthy volunteers received three psilocybin doses (between 5 and 20 mg) in a randomized and blinded order, with at least one week between doses. Resting-state functional magnetic resonance imaging was completed at baseline and one week after a single dose. Functional connectivity changes were analyzed in relation to dose and altered conscious states at both the level of individual brain region connections (edges) and resting-state networks. ResultsDose-dependent changes in 77 edges (76 increases, 1 decrease, of 1275 possible) were observed, but none survived multiple-comparison correction. At the network level, we observed one dose-dependent between-network increase (of 21 possible), and one dose-dependent within-network increase (of seven possible); the latter surviving correction. Alterations in conscious state were positively associated with widespread connectivity changes (dose-adjusted), with many network-level associations surviving correction. These directional patterns showed that lower doses and smaller conscious state alterations were linked to decreased connectivity, whereas higher doses and greater conscious state alterations were linked to increased connectivity. ConclusionsDose level and acute subjective effects were positively associated with multiple functional connectivity changes one week after a low-to-moderate psilocybin dose. Further research is warranted to characterize these sustained effects and their therapeutic relevance to inform studies adopting similar dosing regimens in clinical cohorts. Trial RegistrationAustralian New Zealand Clinical Trials Registry: ACTRN12621000560897 Date registered: 12 May 2021 URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381526&isReview=true