Behavioural Pharmacology最新文献

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.

The fear of predation is pervasive among vertebrate prey species, being characterized by neurobiological and behavioral changes induced by risk exposure. To understand the acquisition and attenuation of fearful phenotypes, such as dimensions of posttraumatic stress, researchers often use animal models, with prey fishes recently emerging as a nontraditional but promising model. Much is known about fear acquisition in prey fishes such as the Trinidadian guppy, Poecilia reticulata, which inhabit high and low predation sites. Little is known, however, about whether a guppy model shows fear attenuation via therapeutic treatments, such as commonly prescribed anxiolytic drugs, like benzodiazepines. In this study, we used Trinidadian guppies from wild populations to explore the interactive effects of exposure to the anxiolytic drug, diazepam, and exposure to predation risk in the form of injured conspecific cues (i.e. alarm cues) that reliably indicate a predator attack. In Experiment 1, juvenile guppies from both high- and low-predation populations were given a 10-min exposure to diazepam (160 µg/l), resulting in the loss of fear behavior when simultaneously presented with alarm cues. In Experiment 2, we found that a prior 10-min exposure to diazepam (160 µg/l) for adult guppies significantly reduced their subsequent fear behavior toward a separate exposure to alarm cues, revealing that diazepam was having direct effects on guppy cognition rather than simply inactivating the alarm cues via chemical alteration. These anxiolytic effects thus add to the growing support for the predictive validity of prey fishes as animal models for exploring fear attenuation in humans.

This study aimed to evaluate the pharmacological effects of haloperidol on the antinociceptive effects of buprenorphine and tramadol in rats. Dose-response curves were constructed for the individual administration of haloperidol, buprenorphine, and tramadol in rats subjected to the formalin (1%) test. All the compounds demonstrated dose-dependent antinociceptive effects when administered individually. Pharmacological interactions were assessed using an isobolographic method. The doses required to achieve 50% of the maximal antinociceptive effect (ED50) for each drug were combined at a fixed 1 : 1 ratio to establish a combination series of haloperidol + buprenorphine and haloperidol + tramadol. The results showed that buprenorphine achieved a higher maximal antinociceptive effect (98%) compared with tramadol (85%) and haloperidol (84.9%) when administered individually. Isobolographic analysis revealed that the experimental values (Zexp) for haloperidol + buprenorphine (Zadd = 27.6 ± 5.5 vs. Zexp = 5.47 ± 1.2) and haloperidol + tramadol (Zadd = 4987.68 ± 651.5 vs. Zexp = 1678.23 ± 89.8) were significantly lower than the theoretical values (Zadd), indicating synergistic interactions. On the basis of the experimental data, haloperidol potentiated the antinociception in the following order: haloperidol + buprenorphine, followed by haloperidol + tramadol. These findings suggest that such drug combinations could have potential applications in the ongoing research of treatments for chronic pain, depression-related pain, and cancer-associated pain.

Chronic unpredictable mild stress (CUMS) is an approved method for the induction of depression in rodents. Lithium, as one of the oldest psychiatric drugs, can induce beneficial effects on mood state under stressful conditions. On the other hand, crocin (active component of Saffron) has antioxidant, procognitive, and mood-enhancer effects. In this study, we aimed to investigate the interaction effect of lithium and crocin on mood disturbances and cognitive impairments induced by CUMS. CUMS was performed for 3 weeks. Lithium (100 mg/kg, i.p.), or crocin (30 mg/kg, i.p.), or combination of both was injected during CUMS period (21 injections). Open field test, hot plate, forced swimming test, shuttle box, and Morris water maze were used to evaluate locomotor activity, pain perception, depressive-like behavior, passive avoidance memory, and spatial memory, respectively. The results showed that lithium decreased locomotion and climbing, increased pain threshold and immobility, and impaired passive avoidance and spatial memory in control rats. CUMS also showed all these effects, with more intensity. However, lithium partly reversed the effect of CUMS on locomotion and spatial memory, and completely restored the effect of CUMS on immobility and passive avoidance memory. Also, lithium did not change the effect of CUMS on pain threshold and climbing. Crocin alone, and in combination with lithium significantly reversed all the effects of CUMS. In conclusion, for the first time, the results of the present research showed that the combination of lithium and crocin leads to stronger therapeutic effects on mood disturbances and cognitive impairments induced by chronic stress.

Morphine dependence is a complex clinical issue, coinciding with oxidative stress and increased neurotransmitter levels as key factors in this drug's reliance and tolerance. This study examines how l-carnitine, ketotifen, and their combination prevent and treat morphine dependence in mice. Seventy-two male mice (20-25 g) were randomly divided into nine groups. The morphine group received morphine (50 mg/kg/i.p.) for 4 days, while the control group was given saline (10 ml/kg/i.p.). After the morphine administration, three groups received l-carnitine at doses of 25, 50, and 75 mg/kg/i.p., and the following three groups received ketotifen at doses of 4, 8, and 16 mg/kg/i.p. The final group was treated with l-carnitine (25 mg/kg/i.p.) and ketotifen (4 mg/kg/i.p.) after the morphine administration. The morphine dependence was assessed using the jumping and standing on feet indices in the naloxone test. Oxidative stress was evaluated through total antioxidant capacity (TAC) and malondialdehyde (MDA) biomarkers in blood samples. l-carnitine (25, 50, and 75 mg/kg) and ketotifen (4, 8, and 16 mg/kg) reduced the naloxone jumping index. l-carnitine (50 mg/kg) and ketotifen (8 and 16 mg/kg) reduced the standing on feet index. In addition, combining these two medications at modest doses decreased behavioral indices. All three l-carnitine doses and two ketotifen doses lowered MDA and increased TAC. Treating with ketotifen at 4 mg/kg was ineffective; however, when combined with l-carnitine (25 mg/kg), it provided antioxidant benefits. Ketotifen and l-carnitine, by affecting the oxidative stress pathway, reduce the symptoms of morphine dependence and act as potential pharmacological treatments for this condition.