Pharmacology Biochemistry and Behavior最新文献

The use of second-generation antipsychotic (SGA) medications in pediatric patients raises concerns about potential long-term adverse outcomes. The current study evaluated the long-term effects of treatment with risperidone or olanzapine on body weight, caloric intake, serum insulin, blood glucose, and metabolism-associated gene expression in C57Bl/6J female mice. Compared to mice treated with vehicle, female mice treated with risperidone or olanzapine gained weight at higher rates during treatment and maintained higher body weights for months following treatment cessation. High-fat diet feeding did not produce a robust difference in weight gain in previously treated vs. control groups. Finally, female mice previously treated with olanzapine also exhibited increased expression of genes associated with inflammation and lipogenesis. These findings suggest that pediatric use of SGA medications that induce excess weight gain during treatment may exert persistent effects on body weight and gene expression and such outcomes may form an important aspect of assessing risk-to-benefit ratios in prescribing decisions.

GW117 functions as both an MT1/MT2 receptor agonist and a 5-HT2C receptor antagonist. This study aimed to investigate the anxiolytic effects of GW117 through behavioral assessments, including the open field test and novelty-suppressed feeding test (NSFT) within a chronic unpredictable mild stress (CUMS) model. GW117 was administered via oral gavage for 21 days to evaluate its sustained anxiolytic effects, with behavioral tests including the NSFT, the Vogel-conflict test, and the O-maze test. To explore the underlying mechanisms, we performed Western blot analyses to assess the expression levels of BCL2-Associated X (Bax), cleaved caspase-3, B-cell lymphoma-2 (Bcl-2), brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP). Additionally, BrdU labeling and immunofluorescence staining were used to examine changes in neuronal regeneration and astrocytogenesis. Our results demonstrated that GW117 produced significant anxiolytic effects across all behavioral assays, both in the CUMS model and during long-term administration. Mechanistic studies revealed that GW117 notably increased the expression of BDNF, GFAP, and Bcl-2, while reducing Bax and cleaved caspase-3 levels in the hippocampus of CUMS model rats. Furthermore, the populations of BrdU-positive and GFAP-positive cells were elevated. These findings suggest that GW117 exerts anxiolytic effects, potentially through enhancements in hippocampal function.

Cannabidiol (CBD), the major non-psychotomimetic compound of the Cannabis sativa plant, has shown promising effects in addressing various symptoms associated with autism spectrum disorder (ASD). This neurodevelopmental disorder typically impacts cognitive, behavioral, social communication, and motor skills domains. However, effective treatments for the wide range of symptoms associated with the disorder are limited and may trigger undesirable effects. Embryonic exposure to valproic acid (VPA, 500 mg/kg at 12^° day embryonic age) in rodents is a consolidated environmental model for studying behavioral and molecular characteristics related to ASD. Therefore, this study aimed to evaluate whether acute CBD could reverse behavioral impairments in adult mice (eight weeks) exposed to VPA in the embryonic period in four distinct trials. In independent groups of animals, the following assays were conducted: I) Pre-Pulse Inhibition Test (PPI), II) Marble Burying, III) Social Interaction, IV) Actimeter Test, and V) Novel Object Recognition Test (NOR). In the PPI paradigm, mice exposed to VPA showed PPI impairment, and CBD (30 and 60 mg/kg) reversed this disruption. CBD (60 mg/kg) respectively decreased the number of buried marbles, improved social interaction time, but failed to reduce stereotyped-like movements in the VPA group. In NOR test CBD at both doses reversed the impairment in index of recognition induced in VPA group. These findings suggest that acute CBD administration can ameliorate behavioral impairments associated with ASD in a well-established animal model for studying this neurodevelopmental disorder.

In the present study authors studied the effect of caffeic acid (CA) in chronic unpredictable mild stress (CUMS) and dexamethasone (DEXA) model of depression. CUMS (21 days) and DEXA (1.5 mg/kg × 21 days) was used for the induction of depression and anxiety related behavior. Locomotor activity was determined using actophotometer. Depression related behavior was determined using tail suspension test (TST) and forced swim test (FST) whereas for the determination of anxiety related behavior elevated plus maze (EPM) test was used. Following behavioral studies, mice were sacrificed by decapitation method. Hippocampus was dissected and was used for the neurochemical assays including 5-HT (serotonin), glutamate, nitrite and gamma-aminobutyric acid (GABA). The results obtained suggested that the CA (25-100 mg/kg, i.p.) did not affect the activity count in CUMS exposed and DEXA treated mice. CA (50 mg/kg) evoked anxiogenic reactions in CUMS model by increasing the hippocampal nitrite and glutamate level while CA (50 mg/kg) exerted anxiolysis in DEXA model by reducing the level of 5-HT. In CUMS model, CA exerted antidepressant like effect by increasing the hippocampal nitric oxide (NO) level, in DEXA model CA exerted antidepressant like effect by reducing the hippocampal glutamate level. CA failed to reverse DEXA mediated nNOS inhibition and therefore decreases hippocampal glutamate level to exert antidepressant like effect. Thus, CA modulate anxiety and depression related neurobehavioral alterations in both CUMS and DEXA models.

Individuals seeking treatment for their cocaine use often report depressive systems and nearly half meet criteria for major depressive disorder (MDD). This descriptive study aimed to assess the effects of the antidepressant venlafaxine alone and in combination with gabapentin on depressive symptoms, subjective effects of cocaine, and cocaine self-administration in depressed and non-depressed people who use cocaine. The effects of medication condition on mood and on the effects of smoked cocaine were compared between a group of clinically depressed people who use cocaine (n = 5) and a control group of non-depressed people who use cocaine (n = 5) using laboratory-based measures. In the MDD group, venlafaxine (300 mg/day) was associated with reduced mean Beck Depression Inventory (BDI) scores (35 to <5) and marginally lower ratings of "good drug effect" without affecting cocaine "wanting" or cocaine (0-50 mg) self-administration. In both groups, venlafaxine treatment increased resting heart rate, systolic pressure, and diastolic pressure. The addition of gabapentin (2400 mg/day) had no effect relative to venlafaxine alone for either group. Conclusions regarding venlafaxine's effectiveness in treating depression in the MDD group are tempered by the lack of a venlafaxine placebo condition and by reductions in BDI scores associated with abstinence prior to venlafaxine administration. Further research is necessary to identify effective treatments for depressed people who use cocaine.

Pain is one of the principal non-motor symptoms of Parkinson's disease (PD), negatively impacting the patient's quality of life. This study aimed to demonstrate whether an effective dose of pramipexole (PPX) can modulate the NF-κB/p-p65 activation in glial cells (astrocytes and microglia) and diminish the hypersensitivity (allodynia and hyperalgesia) in male Wistar rats with PD. For this, 2 μl of 6-hydroxydopamine (6-OHDA, 8 μg/μL/0.2 μl/min) was administered unilaterally in the Substantia Nigra of the Pars Compacta (SNpc) to establish a PD model rat. Motor behavioral tests were used to validate the PD model, and von Frey filaments were used to evaluate allodynia and hyperalgesia. Immunohistochemical and immunofluorescence were used to analyze the level of tyrosine hydroxylase in SNpc and striatum as well as the expression of GFAP, Iba-1, NF-κB/p-65 in the L4-L6 spinal cord dorsal horn. Unilateral 6-OHDA-lesion reduces motor capacity and produces long-term allodynia and hyperalgesia in both hind paws. L4-L6 spinal cord dorsal horn astrocytes and microglia were active in these 6-OHDA-lesioned rats. Moreover, PPX (1 and 3 mg/Kg, i.p./10 days, n = 10 per group) inhibited the bilateral mechanical hypersensitivity, and PPX (3 mg/Kg/i.p./10 days) reduced 6-OHDA-induced astrocyte and microglia activation, as well as reduced NF-κB/p-p65 expression only in astrocytes of dorsal horn spinal cord in the L5-L6. These findings suggest that PPX could alleviate pain by decreasing the activation of microglia and astrocytes through the NF-κB/p-p65 pathway in the dorsal horn spinal cord. Therefore, PPX could be considered an optional tool for improving pain hypersensitivity in PD patients.

Mu-opioid receptors (MORs) in the amygdala and striatum are important in addictive and rewarding behaviors. The transcription factor Foxp2 is a genetic marker of intercalated (ITC) cells in the amygdala and a subset of striatal medium spiny neurons (MSNs), both of which express MORs in wild-type mice and are neuronal subpopulations of potential relevance to alcohol-drinking behaviors. For the current series of studies, we characterized the behavior of mice with genetic deletion of the MOR gene Oprm1 in Foxp2-expressing neurons (Foxp2-Cre/Oprm1^fl/fl). Male and female Foxp2-Cre/Oprm1^fl/fl mice were generated and heterozygous Cre+ (knockout) and homozygous Cre- (control) animals were tested for aversion-resistant alcohol consumption using an intermittent access (IA) task, operant responding for a sucrose reward, conditioned place aversion (CPA) to morphine withdrawal, and locomotor sensitization to morphine. The results demonstrate that deletion of MOR on Foxp2-expressing neurons renders mice more sensitive to quinine-adulterated alcohol. Mice with the deletion (vs. Cre- controls) also consumed less alcohol during the final sessions of the IA task, were less active at baseline and following morphine injection, and there was a trend toward less responding for sucrose under an FR3 schedule. Foxp2-MOR deletion did not impair the ability to learn to respond for reward or develop a conditioned aversion to morphine withdrawal. Together, these investigations demonstrate that Foxp2-expressing neurons may be involved in escalation of alcohol consumption and the development of compulsive-like alcohol drinking.

Impulsivity and behavioral inhibition are measures commonly associated with substance misuse, particularly cocaine use disorder. However, patterns of impulsive behaviors have been shown to differ based on cocaine use history and level of cocaine dependence. Extended cocaine access, which more closely models neural and behavioral changes that take place during the development of problematic cocaine use, has been shown to decrease behavioral inhibition in comparison to limited cocaine access. However, previous preclinical studies investigating these relationships have been mostly correlational and only utilize non-drug rewards. This study aims to utilize a differential rates of low reinforcement (DRL) schedule to investigate the impact of extended access to cocaine on behavioral inhibition toward a cocaine reinforcer. Male Sprague Dawley rats first self-administered intravenous cocaine infusions on a DRL schedule of reinforcement before being split into two groups: one given 6-h extended cocaine access (LgA) and one given 1-h short cocaine access (ShA) for 10 daily sessions. Following a washout period, the rats were placed back on DRL cocaine self-administration sessions. Results revealed that LgA rats showed impaired performance on the behavioral inhibition measure during the DRL self-administration sessions compared to baseline DRL performance and compared to ShA post-access behavioral inhibition measures. These results indicate that extended cocaine access impairs an organism's behavioral inhibition toward future cocaine use, indicating that those individuals with a history of heavy cocaine use will have impaired behavioral inhibition toward future cocaine use.