Behavioural Pharmacology最新文献

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.

Neuronal glycogen synthase kinase-3s (GSK-3α and the more abundant GSK-3β) are serine/threonine kinases that have been postulated to play roles in neuronal adaptations, including those that come from exposures to substances of abuse; however, there is only modest information about ways in which GSK-3 alters the effects of the widely abused psychostimulant, methamphetamine (METH). To evaluate the effects of GSK-3 inhibition on METH-induced symptoms, mice were treated with LY2090314, a potent and selective GSK-3 inhibitor, followed by METH. Horizontal locomotion, vertical rearing, and stereotyped behaviors were measured. Pretreatment with LY2090314 (2.5, 10, and 25 mg/kg) significantly inhibited stereotypic behavior induced by METH (10 mg/kg) in a dose-dependent fashion. Stereotyped biting was most robustly reduced by LY2090314. By contrast, LY2090314 had no significant effect on METH (3 mg/kg)-induced hyperlocomotion. GSK-3 signaling pathways appear to be differentially involved in acute METH effects on locomotion. GSK-3 appears essential for the expression of METH-induced stereotypy but not hyperlocomotion.

Ketamine, a noncompetitive N-methyl- d -aspartate receptor antagonist, and crocin, the bioactive components of Crocus sativus L. , affect anxiety, depression, memory, and pain processes. It has not yet been clarified that crocin can potentiate the analgesic and antidepressant effects of ketamine, as well as attenuate the anxiogenic and amnesic impacts of ketamine in adolescent rodents. This study was designed to explain this issue in adolescent female Wistar rats. For this aim, elevated plus-maze, forced swim test, step-through, and tail-flick tests were utilized. The results indicated that the adolescent female Wistar rats' body weight increased across 10 days of drug treatment, but it did not differ between the groups. Pretreatment with ketamine [20 mg/kg, intraperitoneally (i.p.)] induced anxiogenic- and antidepressant-related behaviors, as well as amnesic and analgesic impacts in adolescent female Wistar rats. Furthermore, alone injection of crocin (30 mg/kg, i.p.) exerted an antidepressant-related behavior. When ketamine (20 mg/kg, i.p.) and crocin (30 mg/kg, i.p.) were coinjected, crocin could potentiate the analgesic and antidepressant effects of ketamine, as well as attenuate the anxiogenic and amnesic properties of ketamine in adolescent female Wistar rats. These results suggested that crocin causes a modulatory effect on ketamine's anxiogenic- and antidepressant-related behaviors, as well as amnesic and analgesic effects in adolescent female Wistar rats.

Drug-resistant epilepsy (DRE) remains a major clinical challenge, with up to one-third of patients experiencing uncontrolled seizures despite polytherapy. Ivermectin (IVM), a macrocyclic lactone with antiparasitic, neuromodulatory, and anti-inflammatory properties, has recently emerged as a candidate adjunctive therapy. We conducted an observational study including 146 patients with highly refractory epilepsy treated with IVM in addition to standard antiseizure medication (ASM). Clinical outcomes were assessed before and after IVM initiation, with seizure frequency recorded from patient diaries and seizure control classified according to International League Against Epilepsy criteria. IVM was administered orally, dissolved in propylene glycol, at doses ranging from 30 to 280 mg/week. After treatment, mean annual seizure frequency decreased by 88.9%, with consistent benefits across subgroups, including patients with cluster seizures (86.4% reduction). More than 90% of participants achieved seizure freedom, and all patients reported some degree of seizure reduction. Concomitant ASM burden decreased by 22%, reflecting improved tolerability and adherence, and no major safety concerns were observed. Mechanistically, the antiseizure potential of IVM may involve modulation of neuronal excitability, neuroinflammatory pathways, and blood-brain barrier transport dynamics, as supported by experimental evidence. These findings align with epidemiological data on onchocerciasis-associated epilepsy and recent controlled trials of IVM formulations in focal epilepsy. While further randomized studies are needed to confirm optimal dosing, safety monitoring, and mechanistic correlates, our results provide real-world evidence that IVM represents a promising adjunctive option for the management of refractory epilepsy.

Pre- and probiotics promote a diverse and functional gut microbiota and have demonstrated both anxiolytic and antidepressant effects; however, how synbiotic diet interacts with antidepressant medications has not been fully investigated. This study sought to evaluate the potential anxiolytic or antidepressant effects of a synbiotic diet in an avian model that presents homologies with treatment-resistant depression. In addition, we sought to evaluate the potential interaction of a synbiotic diet combined with select doses of ketamine. Socially raised Black Australorp chicks were given either standard or synbiotic feed for 7 days. At 7 days posthatch, chicks from each feed condition were administered either 0, 5, or 10 mg/kg/ml ketamine 15 min before a 90-min isolation stressor, which elicits distress vocalizations (DVocs) that temporally represent a panic-like phase followed by a depression-like phase. Saline-treated chicks given the synbiotic diet displayed significantly higher DVoc rates in the depression-like phase compared with saline-treated animals in the standard feed condition, indicative of attenuation of behavioral despair [F(1,22) = 5.45, P < 0.05]. Similarly, in the standard diet condition, ketamine 10 mg/kg produced elevated DVoc rates; however, under the synbiotic diet, both doses of ketamine produced a suppression of DVoc rates in the depression-like phase. These findings suggest that a synbiotic diet produces antidepressant-like effects in the model and a possible negative interaction between synbiotics and ketamine. While preliminary, the findings suggest the concurrent use of pre- and probiotic supplements and ketamine may produce contradictory effects and warrant further investigation.

Chronic unpredictable mild stress (CUMS) is widely used as a reliable method to induce depressive states and anhedonia in rodents. Lithium is one of the well-known drugs used for the alleviation of symptoms in different neuropsychiatric disorders such as depression and bipolar disorder. In this research, we evaluated the efficacy of several doses of lithium on behavioral changes induced by CUMS. Also, the expression level of brain-derived neurotrophic factor (BDNF) and glycogen synthase kinase-3 beta (GSK-3beta) in the prefrontal cortex was evaluated. CUMS was done using various unpredictable stressors for 14 days. Lithium was injected at the doses of 10, 30, and 50 mg/kg. Locomotor activity, anxiety-like behavior, pain perception, and depressive-like behavior were assessed using the open field test, the novelty-suppressed feeding test, the hot plate test, and the forced swim test, respectively. The results revealed that CUMS decreased locomotor activity, increased anxiety- and depressive-like behaviors, increased pain threshold, decreased climbing, decreased BDNF level, and increased GSK-3beta level in the prefrontal cortex. However, lithium dose-dependently restored all these effects. In control rats, lithium (50 mg/kg) decreased locomotion and GSK-3beta expression levels. In conclusion, the results suggested that deleterious effects of CUMS may be mediated via BDNF and GSK-3beta in the prefrontal cortex, and lithium via suppressing GSK-3beta and upregulating BDNF expression levels in the prefrontal cortex can restore CUMS effects.