The sodium-glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin has been reported to exert significant neuroprotective effects on neurobehavioral deficits; however, its effects on chemotherapy-induced neuroplastic changes have not yet been investigated. The present study investigates the behavioral changes and hippocampal cellular responses through which empagliflozin exerts antidepressant effects against chemotherapy-induced pathological alterations. We employed a mouse model of depression induced by oral administration of the chemotherapeutic agent sorafenib for 28 days. Sorafenib-induced cardiotoxicity was assessed using immunohistochemistry. Behavioral changes were evaluated using the forced swim test (FST), tail suspension test (TST), sucrose preference test (SPT), female urine sniffing test (FUST), and open field test (OFT). Synaptic transmission and long-term potentiation (LTP) at hippocampal Schaffer collateral-CA1 synapses were measured using extracellular field recordings. Oral administration of sorafenib induced macrophage infiltration and apoptosis in mouse hearts, whereas co-treatment with empagliflozin prevented these effects. In addition to cardiotoxicity, sorafenib also elicited depression-like behaviors, as evidenced by increased immobility time in the FST and TST, reduced sucrose preference in the SPT, decreased sniffing time in the FUST, and reduced time spent in the central zone during the OFT. Moreover, these neurological impairments were accompanied by a reduced input-output curve and diminished magnitude of LTP at hippocampal Schaffer collateral-CA1 synapses. Co-treatment with empagliflozin effectively prevented these neurological and cellular changes. Inhibition of sodium-glucose cotransporter-2 prevents sorafenib-induced depression-like behaviors and suppresses the decline in synaptic transmission and LTP in the hippocampus, thereby contributing to the antidepressant effects of empagliflozin.

Neuropsychiatric symptoms can emerge early in Alzheimer's disease (AD), but whether innate fear is altered prior to amyloid plaque deposition remains unclear. This study aimed to examine innate fear responses in young adult male APP/PS1 mice and to evaluate whether D-cycloserine (DCS) rescues such deficits via GluN2B-containing NMDA receptors. Male APP/PS1 mice (2-3 months old) exhibited impaired innate fear responses in the looming disk test, while their motor function and contextual fear memory remained intact. Hippocampal Grin2b expression was reduced in the APP/PS1 mice. DCS restored normal fear responses, an effect blocked by GluN2B antagonists but unaffected by GluN2A inhibition. Our results demonstrate that innate fear deficits emerge early in male APP/PS1 mice and are rescued by DCS through activation of hippocampal GluN2B-containing NMDA receptor, highlighting a potential target for early AD-related neuropsychiatric symptoms.

Interleukin 1β (IL-1β) is a proinflammatory cytokine that binds to two receptors, IL-1R1 and IL-1R2. IL-1R1 activation initiates neuroinflammation, and IL-1R2 is a decoy receptor that reduces IL-1R1 signaling by sequestering IL-1β. Emerging evidence links IL-1β to substance use disorders. Methamphetamine and ethanol increase IL-1β levels in the brain, and antagonism of IL-1β signaling reduces negative affective behaviors caused by methamphetamine and ethanol. However, effects of chronic opioid exposure on the IL-1β system in the brain and blocking IL-1β signaling on rewarding effects of opioids are unknown. We determined if oxycodone self-administration (SA) causes brain-region specific changes in IL-1β, IL-1R1, and IL-1R2 levels (mRNA and protein) and if antagonizing IL-1β signaling affects oxycodone SA behaviors. Following 14 days of oxycodone SA (0.056 mg/kg/inf), IL-1R2 mRNA levels were increased in the basolateral amygdala (BLA) and IL-1R1 mRNA levels in the BLA were decreased. For IL-1β itself, oxycodone SA did not affect mRNA levels. Oxycodone SA also did not alter protein levels of IL-1R2, IL-1R1, pro-IL-1β, mature-IL-1β, or the relative expression ratios between pro- and mature-IL-1β. Systemic administration of anakinra, an IL-1R1 antagonist, did not block acquisition of oxycodone SA. Intracerebroventricular (ICV) administration of anakinra following oxycodone acquisition did not reduce oxycodone SA and infusions. Our results show that oxycodone SA induces notable changes in IL-1 receptor mRNA in the BLA but is not affected by pharmacological antagonism of IL-1β signaling.

Although methamphetamine addiction and fatality rates are on the rise in the United States, there are currently no FDA approved drugs to treat methamphetamine use disorder (MUD). To better understand factors contributing to addiction, researchers have used various rodent models of stress including footshock, social defeat and maternal separation, however, these models involve physical or early life stress exposure and thus are less translatable to model human psychological stress. The present study implemented predatory odors as a model of psychological stress and examined whether ten days of chronic exposure to coyote urine or 2-phenylethylamine (PEA) enhanced subsequent reward to a subthreshold dose of methamphetamine. Results from the current study suggest that coyote urine, but not PEA, can enhance vulnerability to drug reward/motivation in the conditioned place preference model, as shown by increased drug-seeking behavior in animals conditioned with a subthreshold dose of methamphetamine. Specifically, methamphetamine conditioned animals previously exposed to coyote urine acquired methamphetamine CPP and displayed persistent drug-seeking behavior during the extinction trials, effects not seen in stress controls or PEA exposed rats. In conclusion, coyote urine may serve as a mild psychological stressor to alter motivation for subthreshold doses of methamphetamine and potentially other drugs associated with addiction.

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.

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.

Prenatal exposure to cannabis and nicotine frequently co-occurs in humans, yet studies on the long-term cognitive consequences remain limited. This early-life exposure may alter the way the brain responds to stress during adolescence. This study examined whether prenatal vaporized THC and nicotine (COMBO) co-exposure alters adolescent cognitive performance as a function of chronic stress, sex, diet, and developmental stage. Pregnant dams were exposed to either Air or COMBO inhalation daily from GD 2 until labor. At weaning, offspring were assigned to either a normal (ND) or high-fat diet (HFD), and at PND 35, half were exposed to unpredictable chronic mild stress (UCMS) during adolescence. Cognitive performance was assessed in early and late adolescence using the Novel Object Recognition (NOR) test and Morris Water Maze (MWM) to evaluate memory, and the Object-Based Attention (OBA) task to assess attention. Prenatal THC and nicotine co-exposure produced selective context-dependent cognitive effects rather than broad impairments across behavioral domains. In the NOR task, significant differences were primarily sex-dependent, while stress exposure was associated with reduced exploration behavior in COMBO offspring. OBA performance showed few significant main effects, although diet-, sex-, and stress-related differences emerged in specific measures. In the MWM task, latency decreased across testing days, with a treatment-related difference observed only within the UCMS cohort. Overall, these findings suggest that cognitive outcomes following combined prenatal THC and nicotine exposure are influenced by stress exposure, diet, and sex to a greater extent than by prenatal exposure alone.

Rat elevated plus maze (EPM) pharmacology is often interpreted through endpoint lists, yet the construct assignment of individual variables is rarely tested against pharmacological calibration and reporting practice. This creates a contemporary reproducibility problem: secondary endpoints may be treated as anxiety indices without evidence that they belong to the same domain as proportional open-arm measures. We address this problem with a targeted critical framework synthesis combining a purposive calibration corpus (Corpus A, 14 foundational rat EPM studies, 1985-1998) and a structured sampled reporting audit (Corpus B, 57 post-2000 rat EPM pharmacology papers). The synthesis is explicitly not a systematic review and not a pooled meta-analysis; no figure digitization was used. The audit indicates a median of four EPM parameters reported per study and that 88% of studies present EPM data exclusively in figures without tabulated mean ± SEM values, which is consistent with the no-digitization rule rather than a justification for it. Primary proportional open-arm measures show complete terminological stability in the sampled corpus (Terminological Instability Index, TII = 0.00), whereas closed-arm entries, rearing, head dipping, and stretched-attend posture/risk assessment show high instability (TII ≥ 0.43). Pharmacological calibration across benzodiazepine, yohimbine, and FG-7142/PTZ anchor classes is consistent with a proportional open-arm core, a motor-control and mixed-variable layer, and a context-dependent ethological periphery. We propose that the rat acute EPM should be interpreted not as a retrospective catalogue of anxiety-like readouts, but as a domain-structured behavioral pharmacology assay in which primary claims should be anchored in the proportional open-arm core, checked against motor/mixed variables, and extended to ethological measures only under explicit calibration and design conditions.