International Journal of Neuropsychopharmacology

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

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.

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).

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.

1Copy number variations in the ARHGAP10 gene encoding Rho GTPase-activating protein 10 are significantly associated with schizophrenia. ARHGAP10 negatively regulates RhoA/Rho-kinase (ROCK) signaling. We previously demonstrated that fasudil, a non-selective ROCK inhibitor, exhibited antipsychotic-like effects in several mouse models of schizophrenia. ROCK has two subtypes, ROCK1 and ROCK2. ROCK1 is mainly expressed in the thymus and blood, while ROCK2 is predominantly expressed in the brain. Therefore, it is expected that like fasudil, selective ROCK2 inhibitors will exhibit antipsychotic-like effects, accompanied by a lower incidence of adverse effects due to ROCK1 inhibition. Here, we used genetic and pharmacological models of schizophrenia to investigate whether the selective ROCK2 inhibitor KD025 would show antipsychotic-like effects with a favorable adverse effect profile. Oral administration of KD025 suppressed the abnormal increase in the phosphorylation level of myosin phosphatase-targeting subunit 1, a substrate of ROCK, and ameliorated the decreased spine density of layer 2/3 pyramidal neurons in the medial prefrontal cortex of Arhgap10 S490P/NHEJ mice. Furthermore, KD025 mitigated the methamphetamine-induced impairment of visual discrimination (VD) in Arhgap10 S490P/NHEJ and wild-type mice. KD025 also reduced MK-801-induced impairments of VD, novel object recognition, and hyperlocomotion. Regarding side effects that are commonly seen with typical antipsychotics, KD025 did not affect systolic blood pressure and did not induce extrapyramidal symptoms, hyperprolactinemia, or hyperglycemia at the effective dosage in naive wild-type mice. Taken together, KD025 shows antipsychotic-like effects with a favorable adverse effect profile in genetic and pharmacological mouse models of schizophrenia.

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

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.

Alzheimers disease psychosis (ADP) is a common and serious condition with substantial unmet need for safe and effective treatments. Pimavanserin is approved in the US to treat Parkinsons disease hallucinations and delusions. This post-hoc analysis of randomized, double-blind, placebo-controlled, phase 2 trial of nursing-home-residents with ADP evaluated the efficacy of pimavanserin by improvements (least squares mean change) in the Neuropsychiatric Inventory-Nursing Home Version Psychosis Score (NPI-NH PS). The clinical significance of the primary endpoint was assessed using responder analyses ([≥] 30% and [≥] 50%); numbers needed to treat (NNT); cumulative response (0-100% improvement); All Patients and Severe Psychosis (NPI-NH PS [≥] 12) subgroups were evaluated; improvements in hallucinations and delusions by NPI-NH-PS frequency (3 or 4 points) and severity (2 or 3 points); and [≥] 50% responder analysis at earlier timepoints (weeks 2 and 4). Among 345 patients screened, 181 patients were randomized to pimavanserin (n = 90) and placebo (n = 91). Patients were elderly (mean age: 86 years) and frail (baseline mean NPI-NH PS scores of 9.5 and 10 for pimavanserin and placebo, respectively). Pimavanserin significantly improved NPI-NH PS relative to placebo (-3.76 versus -1.93, respectively; p = 0.0451). In responder analyses, pimavanserin demonstrated a significantly greater reduction in NPI-NH PS versus placebo at both the [≥] 30% (p = 0.0159) and [≥] 50% (p = 0.0240) thresholds with NNTs of 6 and 7, respectively. Furthermore, pimavanserin demonstrated significantly earlier reductions in NPI-NH PS compared with placebo for the [≥] 30% (p = 0.0336) and [≥] 50% (p = 0.0044) thresholds. The cumulative response analysis demonstrated significantly greater efficacy of pimavanserin for All Patients (p = 0.052) and Severe Psychosis (p = 0.004), and Severe Patients versus All Patients demonstrated a greater reduction in NPI-NH PS (p = 0.011; effect size = 0.73). Pimavanserin also demonstrated numerically greater improvements for the frequency and severity of delusions and hallucinations. Responder analyses at earlier timepoints demonstrated significantly greater response rates with pimavanserin versus placebo at week 2 (p = 0.016) but not 4 (p = 0.051). These findings support pimavanserin as safe and effective in a population of nursing-home-resident patients with ADP.

Cognitive impairment is a common but under-treated feature of Major Depressive Disorder (MDD). Preclinical and early human studies suggest that 5-HT4 receptor (5-HT4R) agonists rapidly improve learning and memory, consistent with this receptors role in hippocampal neuroplasticity. However, their effects in clinically depressed patients, remain unexplored. In this double-blind, randomised study, 52 right-handed, unmedicated individuals with MDD received 6-9 days of the 5-HT4R agonist PF-04995274 (15mg, once daily) or placebo. Participants subsequently underwent fMRI scanning during a memory encoding task and completed behavioural measures of auditory verbal learning and spatial working memory. Compared to placebo, PF-04995274 significantly increased activity in the hippocampus (ROI analysis) in response to novel versus familiar images, particularly in the left hemisphere. Whole brain analysis also revealed greater activation in the left inferior parietal lobule, a key region for memory processing. In contrast with previous studies using the 5-HT4R agonist prucalopride, PF-04995274 had limited effects on behavioural measures of memory. The results demonstrate that short term 5-HT4R agonism enhances hippocampal and parietal activity during memory encoding in patients with depression. This replicates and extends previous findings in healthy volunteers using prucalopride, and is consistent with preclinical evidence establishing a key role for 5-HT4Rs in hippocampal-dependent learning and memory. This translational evidence supports a role for 5-HT4R activation in modulating memory-related brain circuits in MDD and highlights its therapeutic potential for treating cognitive symptoms of depression.

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.

BackgroundNMDA receptor antagonists, such as ketamine, are widely used to model schizophrenia-related phenotypes in preclinical studies. While zebrafish have emerged as a promising model organism for neuropsychiatric research, few studies have characterized their behavioral responses to repeated ketamine exposure. MethodsThree independent experiments were conducted to evaluate the acute, repeated and sustained behavioral effects of ketamine in adult zebrafish. In Experiment I, fish were exposed to 10, 20, or 40 mg/L ketamine once daily for five days, and submitted to the social preference (SPT) and open tank (OTT) tests on days 1 and 5, and re-exposed and re-tested on day 7 after a 48-hour washout. Experiments II and III assessed whether behavioral changes persisted following 5- or 14-day exposure protocols, with testing conducted 48 hours after the final treatment. ResultsKetamine induced robust, concentration-dependent alterations in Experiment I: it reduced social interaction and increased locomotor activity in the SPT on all experimental days, while increased rotational behavior in the OTT on days 1 and 5. These effects did not intensify over repeated exposure and were not sustained after a 48-hour washout in either protocol (Experiments II and III). ConclusionsThe results support the utility of zebrafish for modeling acute behavioral responses to NMDA receptor antagonism, capturing features of schizophrenia-like phenotypes. However, no evidence of behavioral sensitization or lasting disruption was observed, diverging from rodent studies. Future studies should incorporate antipsychotic validation, neurochemical analyses, and alternative exposure strategies to further develop zebrafish as a translational model for psychiatric research.

Prenatal exposure to infection is a risk factor in the development of several neuropsychiatric disorders, including schizophrenia and depression, which often co-occur with alcohol misuse, exacerbating adverse outcomes. Despite these consequences, little is understood regarding the mechanisms by which early exposure to infection might increase the risk of alcohol misuse. We have previously demonstrated that maternal immune activation (MIA) combined with adolescent alcohol exposure (AA) increases home-cage drinking and disrupts neural circuit function in adulthood. The current project aims to determine whether these findings extend to the motivation to work for alcohol, and whether prenatal anti-oxidant treatment can prevent the effects of MIA on self-administration. Pregnant Sprague-Dawley rats were exposed to poly(I:C) (4mg/kg) or saline on gestational day 15, and the anti-oxidant n-acetylcysteine (NAC; 100 mg/kg) or saline 24 hours before and after MIA. Offspring were given 24-hour home cage access to 10% ethanol and water dur adolescence. In adulthood, offspring were trained to self-administer 10% ethanol and tested on escalating schedules of reinforcement: fixed ratio (FR)1, FR2, FR4, and progressive ratios (PR). MIA and NAC independently led to an increased willingness to work for alcohol in males, compared to saline-treated rats. NAC treatment suppressed the effect of MIA on self-administration behavior. These data support the hypothesis that oxidative stress caused by MIA negatively influences development, priming the brain to be more susceptible to the negative effects of AA, leading to an increased risk of alcohol misuse in adulthood, particularly in males.

Acute alcohol withdrawal encompasses somatic withdrawal signs and increased negative affect. In prolonged alcohol withdrawal the somatic withdrawal signs have resolved but the increased negative affect persists. We investigated acute and prolonged alcohol withdrawal after 9 daily injections of 2.5 g/kg alcohol plus 4-methypyrazole, an alcohol dehydrogenase inhibitor, in male and female C57BL/6J mice, and examined whether nicotinic acetylcholine receptor (nAChR) drugs could attenuate withdrawal-induced negative affect. Male mice showed changing somatic withdrawal signs over time and negative affect that persisted at least 21 days into withdrawal. Pre-treatment with mecamylamine, a non-specific nAChR antagonist, or varenicline, a nAChR partial agonist, reduced withdrawal-induced anxiety- and compulsive-like behavior in the marble-burying test during prolonged withdrawal. In contrast, female mice did not exhibit somatic withdrawal signs or anxiety- or compulsive-like behaviors. Instead, female mice showed a deficit in social interaction that was not attenuated by mecamylamine. Alcohol clearance and sedation were not different between sexes, indicating that differences in withdrawal signs and negative affect are not confounded by differences in alcohol metabolism. These findings suggest that cholinergic drugs may be a promising therapeutic for withdrawal-induced negative affect in male, but not female, mice.

Childhood Adversity (CA) is one of the strongest factors associated with the onset of Major Depressive Disorder (MDD), and both CA and MDD have been linked to altered hippocampal structure/function. The current study aimed to explore the relationships between retrospectively reported childhood emotional neglect (CEN), current wellbeing and depressive symptoms, and a range of hippocampal-dependent cognitive functions i.e., anterograde learning and memory, episodic memory recollection, and imagination (episodic future thinking and scene construction). In two-wave recruitment periods at undergraduate intake 2014-15 (Cohort 1) and 2016-17 (Cohort 2), a combined cohort of n=1485 university students completed online surveys, with n=64 further participating in experimental testing session. As anticipated, higher CEN ratings consistently correlated with poorer current wellbeing and higher depressive symptoms. However, whilst the anticipated relationships between CEN, current wellbeing, and subjectively reported estimates of hippocampal-dependent cognitions were observed in the data reported in the online survey, an unexpectedly circumscribed pattern was observed on formal in-person examination of these cognitive functions. More specifically, higher CEN related to less vivid and less detailed imagined future/scene constructions and with an attenuated sense of presence and emotional valence during these simulations. A similar pattern was not evidence when participants simulated experienced past events (i.e. episodic memories). Current depression scores did not consistently correlate with vividness, detail, or emotional valence. In addition, and contrary to expectation, no relationship between CEN, depressive symptoms, and the spatial coherence of imagined or recollected events was seen. Moreover, neither CEN nor depressive symptoms correlated with many key measures of anterograde memory. Hence, we observed a highly specific constellation of impairment related to CEN when explored on a simulation per simulation basis, that was not obviously linked to altered hippocampal function, indicating that the relationship between CEN, hippocampal function, and subsequent psychopathology may not readily explained by either spatial or mnemonic hippocampal- related deficits. We consider whether the observed experiential differences in the qualia of imagined simulations may represent an important therapeutic target to decrease a CEN-driven latent vulnerability to MDD.

While ketamine is already approved for treatment resistant depression in adult patients, its efficacy and safety profile for its use in adolescence still needs further investigations. Preclinical studies proved dose- and sex-dependent effects induced by ketamine during adolescence, but few studies have evaluated the short- and long-term safety profile of ketamine at the doses necessary to induce its antidepressant-like effects. The present study aimed at evaluating the antidepressant-like effects of ketamine (1, 5 or 10 mg/kg; vs. vehicle; 1 vs. 7 days) during adolescence in naive or early-life stressed (i.e., maternal deprivation) rats of both sexes in the forced-swim or novelty-suppressed feeding tests. Safety was evaluated by measuring the psychomotor- and reinforcing-like responses induced by adolescent ketamine. In addition, long-term safety was evaluated in adulthood at the level of cognitive performance, or addiction liability (induced by a challenge dose of ketamine in rats treated with adolescent ketamine). The main results reinforced the potential for ketamine as an antidepressant for adolescence, but at different dose ranges for each sex. However, some safety concerns emerged for adolescent female rats (i.e., signs of sensitization at the dose used as antidepressant) and adult male rats (i.e., addiction liability when re-exposed to ketamine in adulthood), suggesting the need for caution and further research before moving forward the use of ketamine as an antidepressant for adolescence.

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.

Acute alcohol intake decreases brain glucose metabolism and increases brain uptake of acetate, a metabolite of alcohol. This shift in energy utilization persists beyond acute intoxication in individuals with alcohol use disorder (AUD), and may contribute to alcohol craving. We recently found that ketone therapies decrease alcohol withdrawal and alcohol craving in AUD. Here, we studied the effects of a single-dose ketone ester (KE) supplement on brain energy metabolism and alcohol craving. Five AUD and five healthy control (HC) participants underwent two 18F-fluorodeoxyglucose positron emission tomography (PET) scans, after consumption of 395 mg/kg KE or without (baseline), in randomized order. In the AUD group, KE reduced alcohol craving scores compared to baseline. KE decreased blood glucose levels and elevated blood {beta}-hydroxybutyrate (BHB) levels compared to baseline in both groups. Whole-brain voxel-wise maps of the cerebral metabolic rate of glucose (CMRglc) decreased by 17% in both groups, with the largest KE-induced CMRglc reductions in the frontal, occipital, and cingulate cortices, hippocampus, amygdala, and insula. There were no group differences between AUD and HC in blood or FDG measures, and no correlations between reductions in craving with CMRglc. Cingulate BHB levels, as assessed with 1H-magnetic resonance spectroscopy in 5 participant with AUD, increased 3-fold with KE compared to baseleline. In sum, administration of a single dose of KE rapidly shifted brain energetics from glucose to ketone metabolism in HC and AUD. KE also reduced ratings of alcohol craving, demonstrating its potential clinical effectiveness for supporting brain health and alcohol craving in AUD.

The muscarinic acetylcholine receptor 1 (mAChR1, M1) has been identified as a primary target for Alzheimers disease (AD) and better understanding of the receptor biology, especially in regard to biased signalling of the receptor, will allow for the development of improved drugs targeting cholinergic dysfunction in AD. The aim of this study was to determine the contribution of phosphorylation of M1 to the learning and memory (LM) effects of M1 agonism. The contribution of M1 phosphorylation dependent signalling in LM was assessed using the mAChR1 positive allosteric modulator, VU0486846, in a scopolamine (1.5 mg/kg) induced LM deficit model in mice expressing HA-tagged M1 (M1-WT), phosphorylation deficient HA-tagged M1 (M1-PD), or mice deficient in M1 (M1-KO). LM was assessed using a fear conditioning (FC) testing paradigm where context and cued memory retrieval was measured 24 hrs after training and a higher level of freezing indicated intact memory. Results demonstrated that scopolamine induced a significant LM deficit in both context and cued retrieval in M1-WT mice which was partially rescued by VU0486846 confirming a contribution of M1 signalling in LM. The scopolamine induced deficit in contextual retrieval in M1-KO mice was not rescued by VU0486846, which is an M1 selective ligand, while scopolamine did not induce a deficit in cued retrieval in M1-KO mice. In M1-PD mice, scopolamine induced a LM deficit in contextual retrieval, however this was also not rescued by VU0486846 treatment. Similarly to M1-KO animals, M1-PD mice did not display a scopolamine induced deficit in cued retrieval. When freezing responses were compared across strains, M1-PD mice displayed a deficit compared to M1-WT and M1-KO mice in contextual retrieval, while both M1-PD and M1-KO mice displayed a deficit compared to M1-WT mice in cued retrieval. These results demonstrate that although M1 agonism can restore a LM deficit in both contextual and cued testing paradigms, only the cued retrieval response is dependent on the M1. Additionally, biased Gq M1 signalling is not sufficient to restore contextual memory and requires phosphorylation of the receptor. Furthermore, biased M1 signalling results in LM deficits not seen with KO of the receptor. Overall, these results reiterate the importance of considering the bias of ligands when developing M1 agonists for dementia in the future.

Background and aimsMethamphetamine (MA)-induced psychosis (MIP) is associated with increased oxidative toxicity (especially lipid peroxidation) and lowered antioxidant defenses. Advanced glycation end products (AGEs) cause oxidative stress upon ligand binding to AGE receptors (RAGE). There are no data on whether MA use may cause AGE-RAGE stress, and whether the latter is associated with MIP. MethodsThis case-control study recruited 60 patients with MA use disorder and 30 normal controls and measured serum levels of oxidative stress toxicity (OSTOX, lipid peroxidation), antioxidant defenses (ANTIOX), magnesium, copper, atherogenicity, and AGE, soluble RAGE (sRAGE), and computed a composite reflecting AGE-RAGE axis activity. FindingsMA dependence and use were accompanied by increased AGE, sRAGE, AGE-RAGE, OSTOX/ANTIOX, Castelli risk index 1 and atherogenic index of plasma, indicating that MA causes AGE-RAGE axis stress, oxidative damage, and atherogenicity. The severity of dependence and MA dose were strongly correlated with increased sRAGE concentrations. Increased AGE-RAGE stress was strongly associated with OSTOX, OSTOX/ANTIOX, and MA-induced intoxication symptoms, psychosis, hostility, excitation, and formal thought disorders. We found that 54.8% of the variance in MIP symptoms was explained by the regression on AGE-RAGE, the OSTOX/ANTIOX ratio, lowered magnesium, and increased copper, and that these biomarkers mediated the effects of increasing MA doses on MIP symptoms. We found that 36.0% of the variance in the atherogenicity indices was explained by OSTOX/ANTIOX, AGE-RAGE, and lowered magnesium. ConclusionsMA use causes intertwined increases in AGE-RAGE axis stress and oxidative damage, which together predict the severity of MIP symptoms and increased atherogenicity.

BACKGROUNDPost-traumatic stress disorder (PTSD) and co-morbid depression are frequently associated with severe symptoms, poor response to treatment and worse prognosis. Due to the absence of a suitable animal model, little is known about the biological basis of the comorbidity, severely limiting the discovery of new and more effective treatment options. The Flinders Sensitive Line rats (FSL) is a well-validated, selectively bred animal model of depression. However, several of its features, such as cognitive deficits and altered hypothalamic-pituitary-adrenal (HPA) axis response, also match symptomatic clusters of PTSD. In parallel, its resistant counterpart, the Flinders Resistant Line (FRL), is extensively used as a simple control. Still, little is known about its performance compared to the original strain, Sprague Dawley (SD), from which the FSL/FRL was originally derived. AIMSCharacterizing the behavioural performance and mechanisms involved in FSL, FRL and SD rats in fear-memory paradigms. METHODSFSL, SD and FRL animals were submitted to tests assessing hippocampal-dependent and fear-related memory. Subsequently, plasticity factors and endocrine responses to stress were analysed to elucidate the molecular basis for the observed behavioural alterations. RESULTSWe found that FRL animals presented intact recognition memory and innate fear responses but could not properly display conditioned responses in the Conditioned Fear Conditioning (CFC) paradigm. FSL animals, despite a poor performance in the Novel Object Recognition task (NOR), showed similar levels of conditioned responses compared to SD, but impairments in extinction learning, a feature highly related to PTSD. The behavioural alterations were accompanied by alterations in plasma corticosterone levels and hippocampal expression of the glucocorticoid receptor and FKBP51. CONCLUSIONFor the first time, we demonstrate an animal model of resilience and vulnerability to PTSD and co-morbid depression. The results suggest that the endophenotypes may be based on aberrant endocrine stress responses in the hippocampus.