INTRODUCTION:The ventral hippocampus (vHPC) itself or its input pathways can directly influence behaviors related to anxiety and depression. Cofilin 1, as a member of the actin-depolymerizing factor/cofilin (ADF/cofilin) family, participates in dendritic spine remodeling, thereby influencing depression-like behaviors. METHODS:To investigate the effects of Cofilin 1 on neural circuits related to depression, this study utilized Thy1-YFP-H transgenic mice to create an ovariectomized (OVX) + chronic restraint stress (CRS)-induced depression model. Recombinant virus AAV2/9 was bilaterally injected into the vHPC CA1 region using stereotactic surgery to knock down or overexpress Cofilin 1. The sucrose preference test (SPT), tail suspension test (TST), elevated plus maze test (EPM), and novel inhibition feeding test (NSFT) were used to assess depression-like behaviors. Meanwhile, ImageJ and Imaris software were employed to analyze the density and morphology of dendrites and dendritic spines of excitatory neurons in the HPC and related brain regions. RESULTS:The results showed that OVX + CRS induced depression-like behaviors in mice. Overexpression of vCA1 Cofilin 1 rescued a subset of depression-like behavioral phenotypes, increased dendritic density in the mPFC and vHPC, and upregulated dendritic spine density in the vHPC CA1 region. It also decreased dendritic density in the aBLA and nucleus accumbens core while increasing dendritic density in the pBLA and AcbSh. These findings suggest that overexpression of vHPC Cofilin 1 may influence depression-related neural structure by altering dendritic and dendritic spine density and connectivity, thereby improving depression-like behaviors. However, although knockdown of vCA1 Cofilin 1 did not significantly affect depression-like behaviors in mice, it reduced dendritic density and overall dendritic spine density in vHPC region, and increase negative changes in these brain regions including mPFC, BLA and NAc. CONCLUSION:Overexpression of Cofilin 1 in the vHPC CA1 subregion exerts antidepressant-like effects in mice, yet this intervention only ameliorates a subset of depression-related behavioral phenotypes. In contrast, knockdown of endogenous Cofilin 1 in vCA1 exacerbates OVX + CRS-induced dendritic and dendritic spine atrophy in the vCA1, and further aggravates adverse structural remodeling across downstream regions including the mPFC, BLA and NAc. Notably, these widespread neuronal morphological deficits triggered by vCA1 Cofilin 1 knockdown are insufficient to produce statistically significant worsening of depression-like behaviors in the model mice.
Interest in the therapeutic potential of cannabigerol (CBG), a non-psychotomimetic cannabinoid derived from Cannabis sativa, has increased recently. However, preclinical studies examining its effects on cognitive impairment, a core symptom domain of schizophrenia, remain limited. Based on the N-methyl-d-aspartate receptor (NMDA-R) hypofunction hypothesis of schizophrenia, MK-801, a potent NMDA-R antagonist, is widely used as a pharmacological model of schizophrenia that replicates the cognitive impairments observed in patients. This study investigated whether repeated systemic administration of CBG (10 mg/kg/i.p.) could reverse long-term recognition memory (LTM) impairment induced by a single dose of MK-801 (0.1 mg/kg/i.p.) in male rats, using the novel object recognition paradigm. Additionally, we evaluated whether these effects were associated with changes in BDNF/TrkB receptor (TrkB-R) signaling. ELISA and quantitative real-time PCR analyses were performed to evaluate BDNF protein levels and BDNF and TrkB-R mRNA expression in the hippocampus and medial prefrontal cortex (mPFC). MK-801 significantly impaired LTM compared with control group, whereas co-administration of CBG prevented this deficit. MK-801-induced memory impairment was associated with reduced hippocampal and cortical BDNF protein levels, without changes in BDNF or TrkB-R mRNA expression. CBG and MK-801 combined treatment did not restore BDNF mRNA expression and protein levels although it significantly increased TrkB-R mRNA expression in the mPFC. These results suggest that activation of TrkB-R signaling through a BDNF-independent mechanism may contribute to the preservation of LTM by CBG. Our results provide relevant evidence supporting the therapeutic potential of CBG for cognitive impairments associated with schizophrenia.
BACKGROUND:The anorectic peptide nesfatin-1 has been identified as a potential mood regulator. Abnormal nesfatin-1 expression has been observed in both depression animal models and clinical cohorts, but its exact role in depression pathogenesis remains unclear. AIM:This study aimed to detect peripheral and central nesfatin-1 alterations in rats with chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors, and explore their correlations with hypothalamic-pituitary-adrenal (HPA) axis activity and brainstem monoamine synthesis. METHODS:Rats were subjected to 5-week CUMS. Enzyme-linked immunosorbent assay (ELISA) quantified plasma mature nesfatin-1 peptide, and Western blot (WB) detected full-length nucleobindin 2 (NUCB2)/nesfatin-1 in the hypothalamus and brainstem. Spearman's rank correlation was performed solely within the CUMS group (n = 6); these exploratory correlational findings require cautious interpretation due to small sample size. RESULTS:CUMS significantly increased plasma nesfatin-1 as well as hypothalamic and brainstem NUCB2/nesfatin-1. In CUMS rats, plasma nesfatin-1 was positively correlated with corticosterone and forced swim test (FST) immobility time, and negatively correlated with sucrose preference index(SPT) and weight gain. Brainstem NUCB2/nesfatin-1 showed a positive correlation with tryptophan hydroxylase (TPH), while no significant correlation was found between hypothalamic NUCB2/nesfatin-1 and all measured parameters. CONCLUSION:Chronic stress-induced nesfatin-1 elevation accompanies peripheral HPA hyperactivation and aggravated depressive-like behaviors. Brainstem NUCB2/nesfatin-1 positively correlates with TPH, suggesting NUCB2/nesfatin-1 may link neuroendocrine activity and serotonergic plasticity with the brainstem as a core site. This study provides preliminary correlational evidence for coordinated NUCB2/nesfatin-1 changes across peripheral and central systems under stress-induced depression.
Aging affects multiple physiological functions including physical activity behavior, the sleep-wake cycle, and cognition, processes which are regulated in part by lateral hypothalamic orexin neurons. Loss of orexin peptides and neurons is associated with aging, as well as conditions such as type-1 narcolepsy, which are characterized by altered cognitive function. Direct brain administration of orexin-A improves cognitive function; however, the cognitive effects of orexin agonists delivered systemically have not been studied, in part due to the lack of small molecule agonists suitable for systemic administration. In this study, we developed a metabolically stable small molecule dual agonist ROXA-47 with low nanomolar potencies at both OX1R and OX2R. The effects on cognition of ROXA-47 and a previously reported OX2R agonist YNT-185 were measured by peripheral injections in 6 mo. and 12-mo. old mice using two-way active avoidance (TWAA) and/or the contextual object recognition task (CORT). To determine the individual receptor effect of ROXA-47 on TWAA and CORT memory, OX1R (SB-334867) or OX2R (JNJ-10397049) antagonists (5 mg/kg, i.p.) were injected prior to ROXA-47 (40 mg/kg, i.p.). ROXA-47 and YNT-185 decreased latency and increased total responses in the TWAA, while both ROXA-47 and YNT-185 enhanced discrimination index in the CORT, indicating improved cognition in 6 mo. old and 12-mo. old mice. ROXA-47-enhanced TWAA and CORT memory was attenuated by SB334867 but not JNJ-10397049, suggesting that ROXA-47 improves cognitive function in mice primarily via OX1R activation. These results suggest that small molecule orexin agonists may have therapeutic potential for age-related cognitive decline.
The treatment of advanced Parkinson's disease (PD) remains challenging, with few options to address motor fluctuations and dyskinesia simultaneously. Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors may be a therapeutic option that could alleviate both fluctuations and dyskinesia. mGlu4 receptors form hetero-dimers with metabotropic glutamate 2 (mGlu2) receptors, suggesting that additive anti-parkinsonian and antidyskinetic could be obtained upon dual mGlu2-mGlu4 positive allosteric modulation. Here, the mGlu2 positive allosteric modulator (PAM) LY-487,379 and the mGlu4 PAM ADX-88178 were administered, either alone or together, in combination with L-3,4-dihydroxyphenylalanine (L-DOPA), to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets, after which the severity of parkinsonism, dyskinesia and psychosis-like behaviours (PLBs) was assessed. We discovered that each of LY-487,379 and ADX-88178 enhanced the anti-parkinsonian action of L-DOPA and reduced dyskinesia severity when administered separately; when administered concurrently, the resulting anti-parkinsonian (P < 0.001) and anti-dyskinetic (P < 0.01) effects were greater than when both molecules were administered separately. LY-487,379, but not ADX-88178, alleviated L-DOPA-induced PLBs; when the two compounds were administered simultaneously, the resulting anti-psychotic benefit was greater than the effect achieved with LY-487,379 (P < 0.01). Our results indicate that dual mGlu2-mGlu4 positive allosteric modulation results in greater anti-parkinsonian and anti-dyskinetic effects than positive allosteric modulation of either target separately. In addition dual mGlu2-mGlu4 positive allosteric modulation enhances the anti-psychotic effect of selective mGlu2 positive allosteric modulation. Concurrent mGlu2-mGlu4 positive allosteric modulation represents a promising avenue for the treatment of complications in advanced PD.
Esketamine has been approved for the treatment of treatment-resistant depression. However, there is an unmet clinical need to extend the duration of esketamine's action to reduce the high recurrence rate after drug withdrawal and the potential side effects of repeated esketamine use. Here, we found that increasing extracellular signal-regulated kinase (ERK) activity by pharmacologically inhibiting dual-specificity phosphatases 6 (DUSP6) had no antidepressant-like effects. However, when combined with 10 mg/kg esketamine, it extended esketamine's antidepressant-like effects from 7 days to 10 days in naïve mice. Regrettably, inhibition of DUSP6 does not exert a dose-sparing effect or an early onset on the behavioral effects of esketamine. Moreover, inhibiting ERK activity by using SL327 prevents the rapid and sustained antidepressant-like effects of esketamine, and SL327 alone has no significant effects. These results suggest that ERK-related signaling is essential for the rapid and sustained antidepressant-like effects of esketamine, and enhancement of ERK activity has the potential to prolong the antidepressant-like effects of esketamine.
Stress is a major factor in alcohol drinking, but its effects may depend on sex and prior experience with ethanol's aversive consequences. This study examined whether yohimbine-induced pharmacological stress modifies ethanol-induced flavor aversion learning (FAL), voluntary ethanol intake, and plasma cortisol in male and female Wistar rats. Rats received vehicle or yohimbine, and a subset was first exposed to an ethanol-induced FAL procedure (intraperitoneal ethanol, 1.5 g/kg). Animals pre-exposed and not pre-exposed to FAL then underwent a 12-day two-bottle voluntary ethanol procedure with escalating concentrations (2%, 4%, 8%, 10%). Intake was analyzed across concentration phases and during an a priori high-concentration phase (8%-10%). Plasma cortisol was measured at the end of the experiment. FAL was acquired across groups, although its temporal expression varied with sex and yohimbine. During voluntary drinking, intake increased with concentration and was higher in females. Intake depended on the interaction among concentration, sex, prior FAL, and yohimbine. The clearest pattern emerged at high concentrations: under vehicle, females pre-exposed to FAL showed lower intake than non-pre-exposed females, a difference absent under yohimbine; within pre-exposed females, yohimbine increased intake. This pattern was not observed in males, although vehicle-treated pre-exposed males showed increased intake at 10%. Yohimbine increased plasma cortisol overall, and females showed higher cortisol than males, but cortisol did not fully parallel the intake pattern. Prior aversive ethanol experience and pharmacological stress interact in a sex-dependent manner to shape voluntary ethanol intake, with the clearest impact in females.
This study aimed to evaluate the anti-seizure potential of new selenobenzimidazole compounds and identify their potential molecular targets. The primary research question was whether these novel benzimidazolic derivatives could effectively control seizures and mitigate their severity. The research combined an in vivo animal model of neonatal epilepsy with in silico molecular target prediction. The anti-seizure effects of several selenobenzimidazole compounds were tested by administering them at different doses and measuring their impact on seizure latency and severity. Four of the evaluated compounds demonstrated a positive, dose-dependent increase in the latency to seizure onset. The compound with a chlorine substituent was particularly effective. Another compound, which contains a trifluoromethyl group, significantly reduced overall seizure severity. The in silico analysis predicted that the compounds likely interact with the GluN1 and GluN2B subunits of the NMDA receptor. The results indicate that the new selenobenzimidazoles represent a promising chemical class for developing anticonvulsant drugs. Their efficacy and predicted interaction with NMDA receptor targets, which are implicated in epileptic encephalopathies, support their potential for future anti-seizure drug development.
Psilocin (4-hydroxy-N, N-dimethyltryptamine) is a substituted tryptamine alkaloid and a nonselective serotonergic agonist acting predominantly at 5-HT2A/C receptors, with substantial binding to 5-HT1A and 5-HT2B receptors. Microdosing is the practice of taking a very small, sub-perceptual dose, typically 5% to 10% of a full recreational dose, to improve mood, creativity, and focus without hallucinogenic effects. However, rigorous preclinical evidence for its behavioral and neurobiological effects remains limited. We therefore examined whether chronic psilocin microdosing alters behavior and dentate gyrus (DG) cell proliferation in adult male Wistar rats. Psilocin was administered subcutaneously at 0.05 or 0.075 mg/kg. Animals received six doses of psilocin or saline on alternate days over 18 days prior to the first behavioral assessment, and microdosing on alternate days continued between behavioral tasks for five weeks. To minimize acute drug effects, all behavioral assessments were performed 48 h after the preceding dose. Animals were tested sequentially in the Elevated Plus Maze, Hole-Board, Open Field, Social Interaction, and modified Forced Swim Test, with six-day intervals between tests. DG cell proliferation was quantified by BrdU and Ki-67 immunohistochemistry. Across this regimen, psilocin microdosing did not measurably affect locomotor activity, depressive-like behavior, sociability, or novelty seeking, and it did not increase DG proliferation by either marker. A small anxiogenic effect was detected in the Elevated Plus Maze. These data indicate that, under the present dosing schedule and endpoints, chronic psilocin microdosing produces limited behavioral effects and does not enhance hippocampal progenitor proliferation in rats.
Disruptions in glutamatergic signaling within the prefrontal cortex (PFC) have been increasingly implicated in the pathophysiology of Attention-Deficit/Hyperactivity Disorder (ADHD). The Spontaneously Hypertensive Rat (SHR) is widely recognized as the standard animal model for ADHD, though it presents certain experimental limitations. To overcome these, we developed the congenic strain SHR.LEW-(D4Rat76-D4Mgh11) (SLA16). Here, we tested the hypothesis that SHR and SLA16 male rats differ in their PFC sensitivity to NMDA receptor (NMDAR) modulation by MK-801 (a non-selective NMDAR antagonist) and ifenprodil (a GluN2B-selective antagonist). Behavioral performance was evaluated using the open-field and object recognition tests following intra-PFC microinjections. Pharmacological manipulations revealed distinct strain-dependent responses, indicating differential NMDAR sensitivity. Although GluN2A and GluN2B protein levels in the PFC did not differ between strains, SLA16 rats exhibited reduced hippocampal GluN2A and GluN2B expression, accompanied by enhanced hyperactivity and impulsivity compared to SHR. These findings highlight the contribution of NMDAR-mediated glutamatergic mechanisms to ADHD-related behavioral phenotypes and support the SLA16 strain as a model for investigating the molecular and neural pathways underlying this disorder.
Negative affective signs are induced during withdrawal from acute opioid injection and increase in magnitude over repeated injections. Recent evidence indicates that opioid use also causes alterations in oligodendrocyte differentiation and myelination. To investigate these phenomena in mice, we examined spontaneous withdrawal following 10 days of oxycodone administration (30 mg/kg/day).Following a single injection, oxycodone increased exploratory locomotion and elevated thermal pain thresholds, consistent with the acute effect of opioid drugs. Twenty-four hours after oxycodone injection, mice interacted less in an open field, but did not differ from controls in the three-chamber social preference task. The following day (i.e., at the 48-h withdrawal point), oxycodone-withdrawn animals showed decreased marble burying. Tissue harvested from the medial prefrontal cortex (mPFC) after this test was analyzed for expression for 5 genes associated with regulation of oligodendrocyte cell lineage progression. RT-qPCR revealed decreased expression of Tcf7l2 and Klk6.These findings indicate behavioral and neurobiological alterations in response to oxycodone. The increased locomotion and antinociception seen following an acute oxycodone dose corroborates past rodent studies. Decreased marble burying during withdrawal represents a novel finding and may reflect anhedonia. The observed changes suggest that alterations in myelin-related gene expression accompany affective signs of acute withdrawal after repeated opioid exposure.
INTRODUCTION:Major Depressive Disorder (MDD) is a prevalent condition affecting 4% of the population, resulting in significant functional impairment from biopsychosocial factors. Cognitive Behavioral Therapy (CBT) is considered the first choice followed by pharmacotherapy. Probiotics have been investigated to treat symptoms of MDD. This quasi-experimental, open-label study aims to evaluate the effect of probiotic blend supplementation on depressive and anxiety symptoms and biomarkers in depressive patients undergoing pharmacotherapy and CBT. METHODS:Adult individuals diagnosed with MDD attending a primary healthcare unit received pharmacotherapy, CBT and probiotics supplementation. Patients who agreed were allocated to interventions and followed up for six months, with three assessments of clinical scales and biomarkers. Probiotics supplementation was introduced at time 1 (4.7 ± 0.3 months after CBT initiation) and maintained for 1.95 ± 0.2 months. RESULTS:Probiotics with CBT decreased anxiety and depressive symptoms, followed by an increase at the end of the study (P < 0.001). Serum BDNF levels increased across time (P < 0.001). This effect was not observed for lactate, hs-CRP, IL-6, IL-10, TNF-α, NO or NGF-β levels. Following the probiotic period (time 2), Spearman's correlation demonstrated a significant negative correlation between both anxiety and depression symptoms and IL-6 levels (P < 0.05). A negative association was observed between depression scores and BDNF (P < 0.01). CONCLUSION:Anxiety and depression symptoms were significantly reduced through continuous CBT combined with probiotic blend supplementation. However, this beneficial effect on symptoms did not persist in all patients after probiotic discontinuation. In contrast, the accompanied increase in serum BDNF levels remained elevated for all patients, even after cessation. The significance of this combined effect remains evident despite limitations such as the small sample size and the sequential design, supporting the microbiota-homeostasis hypothesis in MDD.
BACKGROUND:Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition often associated with severe behavioral disturbances and limited pharmacological treatment options. Cannabidiol (CBD) has emerged as a potential therapeutic option; however, evidence on its long-term effectiveness and safety in children with ASD is scarce. OBJECTIVE:To evaluate the long-term effectiveness and safety of purified CBD as add-on therapy in children with severe ASD and treatment-resistant behavioral symptoms. MATERIAL AND METHODS:We conducted a prospective observational before-and-after study in children and adolescents (3-18 years) with ASD severity levels 2 or 3 and intellectual disability treated with add-on CBD. The primary outcome was change in caregiver-identified symptoms, while secondary outcomes included standardized behavioral scales (Repetitive Behavior Scale-Revised [RBS-R], Vineland Adaptive Behavior Scales-II maladaptive behavior domain, Aberrant Behavior Checklist [ABC], Pediatric Sleep Clinical Global Impressions-Severity, Autism Family Experience Questionnaire, and Parental Stress Scale). Safety and tolerability were assessed through caregiver-reported adverse events. RESULTS:Twenty children were enrolled, of whom 13 completed the long-term follow-up (mean 27.6 ± 1.3 months). Of the caregiver-identified symptoms, improvements observed during the initial short-term study were maintained or further improved during follow-up. Standardized scales showed modest but sustained improvements, particularly in irritability, social withdrawal, and hyperactivity. Mild, transient adverse events, mainly irritability or decreased appetite, did not recur during long-term followup, and concomitant medications were reduced in 40% of patients. CONCLUSION:Long-term treatment with purified CBD in children with severe ASD was well tolerated and associated with sustained improvement in caregiver-reported outcomes and standardized scales.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized not only by the gradual loss of motor control but also by a wide range of non-motor symptoms, including anxiety and depression, which can precede motor dysfunction by years. These psychiatric manifestations are commonly managed with selective serotonin reuptake inhibitors (SSRI). However, their impact on motor function in the early stages of PD remains controversial. In this study, we investigated the effects of fluoxetine in a progressive model of parkinsonism induced by repeated low-dose reserpine in male Wistar rats. Animals received short- (four injections) or middle-term (ten injections) reserpine (0.1 mg/kg, one every 48 h) treatment combined or not with daily fluoxetine (10 mg/kg) administration, and were evaluated for catalepsy, oral movements, open field behavior, body weight, and immunoreactivity for tyrosine hydroxylase (TH) and serotonin (5-HT). Fluoxetine decreased anxiety-like behavior, assessed by reducing the time animals spend exploring the center of the apparatus; potentiated reserpine-induced motor deficits, leading to earlier onset of cataleptic immobility, enhanced oral dyskinesia, reduced exploratory activity and body weight loss. In addition, fluoxetine alone decreased TH immunoreactivity in the dorsal striatum while increasing 5-HT labeling in the dorsal raphe nucleus, suggesting serotonergic modulation of dopaminergic circuits. In conclusion, fluoxetine administration prevented anxiety-like behavior but anticipated and exacerbated the motor changes caused by reserpine. Furthermore, simultaneous treatment with fluoxetine and reserpine worsened motor and behavioral impairments irrespective of TH changes, indicating that functional disturbances may precede dopaminergic degeneration. These findings highlight that fluoxetine, while targeting mood alterations, may exacerbate motor alterations during prodromal and initial stages of parkinsonism.
Dextromethorphan (DM) is an FDA-approved treatment for major depressive disorder when combined with bupropion. DM functions as an inhibitor for 5-HT membrane transporters and antagonist for sigma-1 receptors (S1Rs) and NMDA receptors, which are pharmacological actions potentially therapeutically relevant for obsessive-compulsive disorder (OCD). The present study examined DM and compounds selective for these receptor mechanisms using the schedule-induced polydipsia (SIP) procedure, a preclinical model of compulsive behavior. Rats were food-restricted and given a fixed-time 60-s schedule of food pellet delivery during experimental sessions. After 20 sessions, rats were ranked by water consumption and divided into low (LD) and high (HD) drinkers. DM, the 5-HT2A/C receptor agonist DOI, the S1R agonist SA4503, and noncompetitive NMDA receptor antagonist racemic ketamine were tested. Additionally, dose-combination tests assessed whether the 5-HT2A receptor antagonist M100907, the NMDA receptor agonist NMDA, or the S1R antagonist BD1047 reversed DM's effects. DM dose-dependently reduced water consumption in both LD and HD rats, and ketamine selectively reduced water intake in only HD rats. Both SA4503 and DOI reduced water consumption in the LD and HD rats. None of the antagonists reversed DM's suppression of SIP. These findings demonstrate that DM acutely reduces compulsive-like drinking in a SIP paradigm, suggesting further investigations into DM as a treatment for OCD.
Depression is a complex mental disorder threatening global public health. Its pathophysiological mechanisms involve multidimensional dysfunctions including the emotional-cognitive circuit, Hypothalamic-Pituitary-Adrenal (HPA) axis, neurotransmitter systems and neuroplasticity. Current studies mostly analyze each system in isolation, lacking a unified integrated framework. This review proposes that the Brain-Derived Neurotrophic Factor/cAMP-responsive Element Binding Protein (BDNF/CREB) signaling pathway serves as the core hub mediating multisystem network dysfunction in depression. It systematically elucidates the multilevel molecular mechanisms of this pathway, such as genetic polymorphisms, stress-induced epigenetic modifications, and post-transcriptional regulation by microRNAs (miRNAs); clarifies its bidirectional regulatory effects on the plasticity of the prefrontolimbic emotional-cognitive circuit, neurotoxic effects of the HPA axis, and imbalance of monoaminergic/amino acid neurotransmitter systems; summarizes the targeted activation mechanisms of antidepressant interventions (e.g., ketamine, repetitive Transcranial Magnetic Stimulation (rTMS), Selective Serotonin Reuptake Inhibitors (SSRIs)) on this pathway, and verifies its value as a disease biomarker and therapeutic target combined with clinical evidence. This review points out the limitations of current research and prospects the precision research direction integrating multiomics and neuroimaging, reconceptualizing depression as a network disorder centered on the abnormality of the BDNF/CREB signaling hub, so as to provide theoretical support for elucidating the pathological mechanism of depression and developing precision diagnosis and treatment strategies.
Anxiety- and stress-related disorders are commonly treated using combinations of centrally acting drugs. However, the behavioral outcomes of interactions between GABAergic and glutamatergic systems remain incompletely characterized. The present study investigated the effects of flumazenil, ketamine and midazolam, and their combinations, on anxiety-like behavior in adult male rats using aversive 22-kHz ultrasonic vocalization (AUV) and the elevated plus maze (EPM). Systemic administration of flumazenil (0.1-10 mg/kg, i.p.) produced a significant, dose-dependent reduction of AUV in Sprague Dawley rats, indicating intrinsic anxiolytic-like effects. Sub-anesthetic ketamine (2.5 mg/kg, i.p.) reduced AUV when administered alone in Wistar rats; however, co-administration with flumazenil was associated with dose-related changes in this effect, with higher flumazenil doses producing significant increases in AUV related to ketamine alone. Midazolam (0.25 mg/kg, i.p.) markedly reduced AUV in Wistar rats, whereas its combination with ketamine partially attenuated this reduction. In the EPM, midazolam alone increased open-arm exploration in Wistar rats, while co-administration with ketamine increased closed-arm time and reduced locomotor activity. Together, these findings highlight the behavioral consequences of interactions between ketamine and midazolam and suggest flumazenil as a modulator of acute ketamine-induced effects on anxiety-related behavior, although this interaction requires further investigation.
Obesity and substance use disorders (SUDs) are chronic relapsing conditions that may co-occur through convergent pathophysiological mechanisms involving dysregulated reward circuitry. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) - originally developed for type 2 diabetes and obesity - act on both peripheral metabolic and central reward pathways, positioning them as potential candidates for repurposing in addiction medicine. In this narrative review, we sought to synthesize the shared neurobiology of obesity and SUDs and critically evaluate emerging translational evidence supporting GLP-1 RAs as adjunctive treatments in addictive disorders. We conducted comprehensive searches of PubMed/MEDLINE, Embase, PsycINFO, and Web of Science from January 2015 through December 2025, supplemented by manual reference screening. Eligible studies included preclinical investigations of GLP-1 signaling on substance-related behaviors and pilot clinical trials assessing GLP-1 RAs in SUDs. Preclinical data consistently demonstrated that GLP-1 RAs can reduce intake and seeking of alcohol, nicotine, opioids, and psychostimulants through modulation of mesolimbic dopamine signaling. In addition, early clinical trials revealed therapeutic potential for reducing alcohol use, supporting smoking cessation, and mitigating post-cessation weight gain. However, the current evidence base is limited by modest sample sizes and insufficient follow-up periods. In conclusion, GLP-1 RAs represent a promising adjunctive pharmacotherapy for SUDs and may be particularly suitable for patients with co-occurring obesity. However, critical gaps remain regarding optimal dosing, long-term safety and efficacy, and their therapeutic potential in opioid and psychostimulant use disorders.
Rationale These studies characterized the locomotor and discriminative stimulus effect of nicotine, mecamylamine, and varenicline in efforts to optimize detection of substitutes and antagonists of nicotine. Objectives We compared nicotine- and varenicline-induced locomotor activity (LMA) to confirm the assay's utility as a predictor of therapeutic potential, and determined how training dose and pretreatment interval affect the nicotine discriminative stimulus, and influence varenicline's ability to substitute. Methods Mice were assessed for LMA following injection of nicotine tartrate (NicT), varenicline, mecamylamine, or saline. A time-course study in rats was conducted to identify the minimum effective dose and shortest pretreatment time at which NicT exerts discriminative stimulus control. Cohorts were trained using (i) a standard 0.4 mg/kg, 15-min, (ii) a 0.1 mg/kg, 5-min, or (iii) a dose-fading (0.4 → 0.1 mg/kg), 5-min protocols. Substitution and antagonism tests were conducted with varenicline and mecamylamine. Results Nicotine and varenicline produced early depressant and delayed stimulant effects; mecamylamine was inactive. Nicotine's depressant effect had four-fold greater potency than varenicline. In discrimination, 0.1 mg/kg NicT fully substituted at a 5-min pretreatment interval. The low-dose and faded groups showed enhanced sensitivity. Varenicline fully substituted in the standard and faded groups but only partially in the low-dose group. Conclusions The matching biphasic profiles of nicotine and varenicline suggest that LMA studies may be useful in identifying compounds with therapeutic potential targeting the nicotinic acetylcholine receptor. Low-dose, short pre-treatment time discrimination procedures reveal varenicline's predicted α4β2 partial agonist profile, whereas high dose, long pre-treatment times may broaden the nicotine cue and mask partial substitution.
Recent data show a dramatic increase in stimulant use in the past five years. Amidst this rise, methamphetamine (METH) use is contributing to increases in stimulant overdose deaths. Understanding factors that contribute to stimulant use are critical to the current public health landscape. It is well known that age and sex modulate the acceptability of drugs. Research suggests the balance of appetitive and aversive characteristics of drugs can influence future and continued use. The present set of studies examined METH-induced conditioned taste avoidance (CTA) to assess how age and sex impact learning when the trace interval between the unconditioned and conditioned stimulus is extended up to several hours. In Experiment 1, adult rats underwent METH CTA with 0-to-6-h trace intervals across three days followed by a two-bottle saccharin preference test. In Experiment 2, adolescent rats were assigned to METH or lithium chloride CTA groups at intervals of up to 4 h. In Experiment 3, the trace interval was set at 4 h and METH doses varied (0-10 mg/kg). Results indicate adults' CTA learning is systematically weaker as trace intervals increase and females show weaker aversion learning than males. Moreover, adolescents display generally weak aversions to METH, particularly at longer trace intervals. The greatest sex differences are found at the 4-h trace interval. These data contribute to studies examining sex and age as factors in drug use vulnerability. The results indicate female adolescents are likely more vulnerable than other groups to METH.
