Behavioural Pharmacology最新文献

The gut-brain axis plays a significant role in maintaining cognitive health. Akkermansia muciniphila-derived extracellular vesicles (Akk.m-EVs) improve postoperative cognitive dysfunction (POCD) induced by intestinal ischemia-reperfusion, but their role in elderly POCD is unclear. Therefore, this study investigates whether Akk.m-EVs affect POCD in elderly patients by mediating intestinal barrier dysfunction. Akk.m-EVs were obtained via ultracentrifugation. Sevoflurane (sevo; 3%) was used to induce POCD in mouse models. The cognitive function of mice was assessed by novel objective recognition and Morris water maze tests. Levels of proinflammatory cytokines in hippocampal tissues were detected by ELISA. The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation was analyzed by, while tight junction proteins were detected by immunofluorescence western blot. Akk.m-EVs elevated exploration time, percentage of time spent exploring, identification index for novel objects, decreased escape latency, and enhanced the frequency of crossing the initial platform in sevo-induced POCD mice, highlighting the potential of Akk.m-EVs in improving cognitive, memory, and spatial learning abilities in POCD mice. In addition, Akk.m-EV treatment decreased inflammatory response and suppressed NLRP3 inflammasome activation in hippocampal tissues of POCD mice, accompanied by elevated zona occludens 1 and occludin protein levels in colonic tissues, suggesting that Akk.m-EVs reduced neuroinflammation and improved intestinal barrier disorder. Akk.m-EVs ameliorate POCD in elderly patients by decreasing neuroinflammation and improving intestinal barrier dysfunction, providing a theoretical basis for the development of prevention and treatment strategies for POCD based on probiotic extracellular vesicles.

Stimulant misuse is strongly associated with behavioral impulsivity, including impairments in behavioral inhibition, yet few studies have examined drug self-administration in ways that directly assess inhibitory control. This study aimed to discover if intravenous (IV) self-administration of cocaine and d-amphetamine could be established using a differential reinforcement of low rates (DRL) schedule in rats and whether stimulant intake altered behavioral inhibition. Male Sprague-Dawley rats were trained to lever press under DRL schedules with food reinforcement, then transitioned to IV cocaine (0.3 mg/kg/infusion) or d-amphetamine (0.06 mg/kg/infusion) self-administration sessions. Following the acquisition, full dose-effect curves were established with cocaine (DRL > 10 s) and d-amphetamine (DRL > 7 s), resulting in inverted-U-shaped curves for both active lever presses and infusions earned. The most active lever presses occurred at the second-highest dose for cocaine (0.3 mg/kg/infusion) and d-amphetamine (0.02 mg/kg/infusion). Analysis of cumulative probabilities of interresponse times (IRTs) revealed drug-specific effects on behavioral inhibition. At peak cocaine intake (0.1 mg/kg/infusion), approximately 65% of lever presses occurred before the DRL 10 s requirement, indicating a failure to inhibit responses. In contrast, at the highest (0.06 mg/kg/infusion) and lowest (0.006 mg/kg/infusion) doses of d-amphetamine self-administration, we observed increased long IRTs beyond the 300 s limited hold contingency, similar to saline. These findings demonstrate rats will self-administer stimulants under a DRL schedule, and cocaine and d-amphetamine differentially disrupt behavioral inhibition. This approach provides novel insight into the complex relationships between stimulant use and behavioral control and provides a foundation for future investigations into the mechanisms of behavioral inhibition.

Ethanol and nicotine are among the most widely used drugs in the USA, and their combined use is associated with increased health risks. This study aimed to investigate the acute effects of ethanol alone and in combination with nicotine on risky choice in rats using a probability-discounting task. Sprague-Dawley rats chose between a smaller, certain reinforcer (one food pellet) and a larger, probabilistic reinforcer (two food pellets). In Experiment 1, effects of acute ethanol administration were assessed. In Experiment 2, acute nicotine was administered either alone or in combination with ethanol. Ethanol was delivered via oral 'Jell-O shots' and nicotine was delivered via subcutaneous injection. Ethanol (2.0 g/kg) and nicotine (0.3 mg/kg) each increased risky choice compared with vehicle controls. The highest combined dose of ethanol (2.0 g/kg) and nicotine (1.0 mg/kg) further increased risky choice compared with the same ethanol dose paired with a lower nicotine dose (0.3 mg/kg), although there was no evidence that the combination increased risky choice beyond either drug alone. These findings highlight drug interactions that may contribute to heightened risk-taking behaviors associated with comorbid use. Future studies should explore the influence of ethanol dose, concentration, vehicle, and administration route on risky choice to further characterize these effects. This study underscores the need for basic investigations to inform interventions targeting the combined use of ethanol and nicotine.

Cocaine produces effects including euphoria, local anesthesia, hypophagia/anorexia, and anxiogenesis. The novelty-suppressed feeding (NSF) task is often used as a measure of anxiety-like behavior, except that this task is sensitive to changes in hunger state. First, we determined whether cocaine impacts behavior in the NSF task in male and female Long-Evans rats. Then, to determine whether cocaine-induced alterations in NSF behaviors are due to changes in motivated feeding, we measured the effects of cocaine on operant responding maintained by sucrose. Our results indicate that cocaine administration reduces sucrose consumption in a novel context in a manner indicative of anxiety-like states but does not impact the reinforcing efficacy of sucrose measured by operant responding under a progressive ratio schedule. These results indicate that cocaine's anxiogenic properties play a greater role than its hypophagic properties in its effect on NSF behaviors.

This randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of Qudu Huiyuan Pills (QHP), a novel Traditional Chinese Medicine (TCM) formulation, in treating opioid withdrawal syndrome (OWS). The study involved 124 adults (aged 18-65 years) diagnosed with opioid dependence and the TCM syndrome of Qi-blood deficiency and toxin-stasis. Participants were randomized to receive either QHP ( n  = 63) or a placebo ( n  = 61) at a dosage of 10 g three times daily for 5 months. Primary outcomes included changes in major and minor TCM symptom scores. Secondary outcomes encompassed neurobiological markers, liver function tests, and safety assessments. QHP treatment resulted in a statistically significant reduction in both major and minor TCM symptom scores compared with baseline and the placebo group ( P  < 0.01 for both). The safety profile of QHP was favorable; reported adverse events were predominantly mild and transient gastrointestinal discomfort. Notably, QHP treatment was associated with improved liver function markers, suggesting potential hepatoprotective effects. No significant between-group differences were observed in the assessed neurotransmitter or cytokine levels at the study endpoint. In conclusion, QHP appears to be an effective and safe therapeutic option for individuals with OWS, particularly in alleviating the constellation of symptoms defined by TCM. Further research is warranted to explore its long-term efficacy and underlying mechanisms of action.

Psilocybin is found in a family of mushrooms commonly known as Psilocybe. We aimed to study the antinociceptive efficacy of psilocybin using formalin-induced noxious stimuli, a model that comprises both acute and persistent pain in rats. Adult male Sprague-Dawley rats were used. Psilocybin (0.1, 0.3, and 1 mg/kg, IP) or vehicle was administered, and 6 h later, formalin (5%, 50 µL, subcutaneous) was injected into the hindpaw, and the number of flinches and time spent for licking were recorded for 0-10 and 20-60 min for acute and tonic phases, respectively. Another set of rats was used to examine if the antinociceptive effect of psilocybin is via 5-hydroxytryptamine 2a receptor (5-HT 2A R). For this aim, rats were pretreated with volinanserin (0.1 mg/kg, highly selective 5-HT 2A R antagonist) or vehicle 30 min before psilocybin (0.3 mg/kg). Six hours later, formalin was injected, and the number of flinches and time spent for licking were recorded. Psilocybin (0.1 and 0.3 mg/kg) significantly reduced flinching and licking behaviors in both acute and late pain phases and pretreatment with volinanserin blocked the antinociceptive effect of psilocybin. Our results suggest that psilocybin produces an analgesic effect for acute and tonic inflammatory pain, at least in part, by activating 5-HT 2A R.

In our clinical study, we found that itching had many different expressions (or qualities), including ' muzumuzu ' (creepy-crawly itching, somewhat like tickling) and 'itch like mosquito bites'. Therefore, we investigated whether there were behavioral differences in response to different pruritogens in mice. In addition, we compared the behavioral characteristics of spontaneous scratching in mice with atopic-like dermatitis. In this study, we used six pruritogens [histamine, 5-hydroxytryptamine (5-HT), substance P, α-melanocyte-stimulating hormone (α-MSH), protease-activated receptor 2 agonist Ser-Leu-Ile-Gly-Arg-Leu-NH2 (SLIGRL), and chloroquine]. Pruritogen was intradermally injected into the rostral back skin of institute of cancer research (ICR) mice. Nishiki-nezumi Cinnamon/Nagoya (NC/Nga) mice infected with mites were used as animal model of atopic dermatitis (dermatitis NC/Nga mice). Their behavior was recorded using a digital video camera. The number of scratching behaviors was divided according to the presence or absence of precursor behaviors, such as shivering and body grooming-like behavior with the forelimbs, to scratching behaviors. Intradermal injection of histamine and substance P induced scratching without precursor behavior. On the other hand, intradermal injection of 5-HT and α-MSH-induced scratching after precursor behaviors. SLIGRL elicited scratching both with and without precursor behavior. In dermatitis NC/Nga mice, spontaneous scratching was induced mainly following precursor behaviors. These results suggest that itch-related behavior in mice is also characterized by the type of itching. Itching in atopic dermatitis is resistant to antihistamines. In this study, we demonstrated that the characteristics of histamine-induced scratching and dermatitis-induced spontaneous itching are different. This suggests that behavioral analyses may be useful for developing drugs to treat itching caused by diseases.

Neuropsychiatric disorders, such as depression and anxiety, are frequently associated with neuropathic pain. Despite the availability of various analgesics, their efficacy in treating neuropathic pain comorbidities has been limited. The aim of this study was to evaluate the impact of a 5-hydroxytryptamine 7 agonist (LP-211) in combination with gabapentin on two distinct models of neuropathic pain in rats, namely streptozotocin-induced diabetic neuropathic pain and partial sciatic nerve ligation. The sensory-discriminative parameter of mechanical allodynia was assessed using Von Frey monofilaments. We evaluated the affective components of neuropathic mechanical allodynia, such as depression and anxiety, using a forced swim test, sucrose preference test, elevated plus maze, and novelty-induced hypophagia, respectively. We measured the levels of monoamines in the hippocampus using HPLC. The electrical activity of neurons was estimated through in-vivo electrophysiology. LP-211 alone did not result in a significant increase in paw withdrawal thresholds, but when combined with gabapentin, it showed a significant increase. Furthermore, the combination treatment reduced the neuronal response of wide dynamic range neurons because of mechanical stimulation, and a significant modulation of monoamines in the hippocampus was observed. Importantly, the combination treatment exhibited antidepressant-like activity, by a significant decrease in immobility time and an increase in percentage sucrose preference. It also demonstrated anxiolytic-like activity, as indicated by an increase in time spent in open arms and an increase in food intake in a novel environment. Overall, the results of this study provide evidence that multiple therapies with different mechanisms may alleviate mechanical allodynia and its comorbidities.

Xylazine is a veterinary drug and α2-adrenoceptor agonist that has been increasingly misused as an adulterant in illicit opioids; however, only a few preclinical studies have investigated xylazine's pharmacological profile and impact on opioid-derived behaviors. We investigated the behavioral effects of xylazine alone and in combination with morphine in planarians, which are the simplest living animals having a central nervous system with cephalization. Planarians also express mammalian-like behaviors and neurotransmitters. Our specific experiments investigated the effects of xylazine, morphine, and combinations thereof on stereotyped movements (C-shapes, corkscrews, scrunches, head swings, and head bops) and motility. Clonidine, a xylazine analog and Food and Drug Administration-approved α2-adrenoceptor agonist, was tested for comparison. Both xylazine (1-1000 µM) and clonidine (1-1000 µM), at concentrations greater than or equal to 100 µM, increased stereotypies and reduced motility. Xylazine produced greater maximal effects, and clonidine was more potent. Morphine (1-1000 pM) elicited stereotypies and reduced motility. For combination experiments, morphine (0, 10, and 100 pM) was tested with different concentrations (1, 10, 100, or 1000 µM) of xylazine or clonidine. In the presence of morphine, stereotypies elicited by xylazine or clonidine were further increased, with a particularly robust enhancement of head swings. A notable distinction was that C-shapes and corkscrews were further increased by cotreatment of morphine with xylazine but not with clonidine. Our results identified xylazine-opioid interactions in planarians and showed that xylazine and clonidine elicited stereotyped movements that were enhanced further by cotreatment with morphine.

Heroin, a widely abused opioid, is frequently consumed via inhalation; however, the majority of existing studies have focused on traditional administrations. This study aimed to compare the analgesic effects of heroin across different deliveries to elucidate the unique characteristics of inhalation. Two distinct inhalation exposure systems (nasal and systemic) were established and validated for stability. Liquid chromatography-tandem mass spectrometry was used to quantify blood concentrations of heroin and its metabolite 6-monoacetylmorphine following subcutaneous injection and three intratracheal/inhalation administrations, establishing dose-concentration linearity for cross-comparison at equivalent blood concentration levels. The analgesic of heroin across four different administrations were assessed by the hot plate pain test while comparing outcomes based on both blood and intracerebral drug concentrations. The findings indicated that both inhalation systems exhibited stable drug delivery, with linear correlations between exposure chamber concentration, administered dose, and resultant blood concentration. A logarithmic correlation was identified between the administration duration and blood concentration levels. Analgesic assessments revealed that significantly enhanced effects in both inhalation groups compared to subcutaneous injection, despite lower delivered doses. At the median effective dose (ED 50 ), olfactory bulb drug concentrations in inhalation were approximately eight-fold higher than in subcutaneous and intratracheal groups, while blood concentrations showed no statistical difference. This study validated that inhaled heroin produces stronger analgesic effects than subcutaneous injection, likely attributed to the mechanism of direct brain entry via the olfactory pathway, which enhances psychoactive potency. These findings highlight the distinct pharmacological properties of inhaled heroin, providing critical insights into its abuse potential.