Behavioural Pharmacology最新文献

Depression, a major psychiatric disorder with profound societal impact, remains incompletely understood in its etiology. Identifying novel pathogenic pathways is therefore essential. The gut microbiota ('second brain') critically regulates bidirectional gut-brain axis (GBA) communication with the central nervous system. Dysbiosis correlates strongly with depression, positioning microbiota restoration as a promising therapeutic strategy. Critically, gut microbial metabolic processes - particularly involving amino acids and short-chain fatty acids (SCFAs) - have emerged as key contributors to depression pathogenesis; however, depression-specific alterations in gut microbiota and their metabolic signatures are inadequately characterized, and the molecular mechanisms linking microbial metabolites to depression require further elucidation. This review synthesizes recent advances on GBA-mediated depression pathogenesis, with emphasis on gut dysbiosis-induced disruptions in amino acid and SCFA metabolism, and delineates their mechanistic links to depressive pathophysiology.

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.

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.

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.

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.

Clinical evidence highlights the central nervous system as a key target in type-2 diabetes-related complications, yet the mechanisms underlying the increased prevalence of mood disorder issues, mainly depression, in patients with diabetes remain poorly understood. Leptin, an adiposity hormone known for its role in energy homeostasis, has been shown to improve insulin sensitivity and regulate blood glucose levels in diabetic populations. Beyond its metabolic effects, leptin also has the potential to mitigate psychiatric complications such as depression and anxiety. Notably, leptin receptors are predominantly expressed on dopamine (DA) neurons in the brain, hinting that leptin may orchestrate DA activity by serving as its endogenous modulator. This review examines the role of leptin as a potential common link between type-2 diabetes and mood disorders, particularly through its effects on DA function. This article proposes defective leptin signaling as a vital mechanism contributing to psychiatric complications and compromised DA functions in type-2 diabetes, highlighting leptin as a promising therapeutic target for addressing metabolic and psychiatric comorbidities.

This study aimed to investigate and characterize Parkinson's-like behavioral, histological, and biochemical changes induced by feeding fructose (10% w/v) for 24 weeks in rats. Additionally, we aimed to evaluate the potential protective effect of dulaglutide and empagliflozin either individually or combined with pirfenidone on fructose-induced Parkinsonian features. Rats were given 10% w/v fructose solution for 24 weeks and cotreated for the last 4 weeks with either empagliflozin (30 mg/kg/day orally), dulaglutide (0.2 mg/kg/week subcutaneously), pirfenidone (100 mg/kg/day orally), or the combination of the latter with empagliflozin or dulaglutide at the same mentioned doses. Behavioral testing was done at the end of the study period, and brain tissue samples were taken at sacrifice. Fructose-fed rats showed aberrations in cognitive function and motor coordination constellated with loss of substantia nigra neurons, dopamine deficiency, and altered α-synuclein , LRRK2 , and parkin expression. This was associated with insulin resistance, dyslipidemia, enhanced neuroinflammation, and apoptosis. All treatments ameliorated these perturbations with more pronounced effects observed in the combination groups. Current results revealed the neuroprotective potential of dulaglutide, empagliflozin, and pirfenidone against fructose-induced neurobehavioral alterations in rats with an additive effect observed with the combined therapy.

The present study examined the impact of the N-type calcium channel blocker gabapentin (GBP) and the partial glycine agonist D-cycloserine (CYC) to attenuate the behavioral effects of naloxone in opioid-dependent humans responding under a naloxone discrimination procedure. Methadone-maintained participants were trained to distinguish between a low dose of naloxone (0.15 mg/70 kg, i.m.; i.e., drug A) and placebo (i.e. drug B) under an instructed novel-response drug discrimination procedure, in which participants identify the drug condition as 'A', 'B', or 'N' (neither A nor B - 'novel'). Once the discrimination was acquired, doses of CYC (0, 500, and 625 mg) and GBP (0, 100, 200, and 400 mg) each alone and in combination with the training dose of naloxone were tested. GBP alone produced only placebo-appropriate responding and did not significantly alter naloxone discrimination when coadministered with naloxone, though it modestly reduced naloxone-induced visual analog scale ratings of drug 'strength'. CYC alone also produced predominantly placebo-appropriate responding and did not modulate naloxone-appropriate responding, but increased ratings of bad effects and decreased ratings of like placebo relative to naloxone alone at the 500 mg dose. These null findings regarding the modulation of naloxone discrimination highlight the limited efficacy of GBP and CYC in this context, contributing to the understanding of pharmacological interactions with opioid antagonists and their potential implications for opioid withdrawal treatment.

Mild forms of hearing loss (HL) have been linked to cognitive impairments in children, yet the neurobiological mechanisms underlying this connection remain unclear. Existing research using animal models mostly focuses on more severe levels of HL or investigates only limited aspects of cognition. To gain a broader understanding of how slight/hidden HL affects cognitive behaviors, we induced HL in 4-week-old Wistar rats through noise exposure. Auditory brainstem response measurements confirmed slight and hidden HL, but this auditory impairment did not alter the density of inner hair cells or their synapses with the spiral ganglion (primary auditory) neurons. Both short- and long- term memory formation were tested using the object location, novel object recognition, and social recognition task. Behaviorally, rats with slight/hidden HL performed better than normal hearing (NH) rats during short-term cognition tests. However, long-term memory was impaired in rats with slight/hidden HL when compared to NH controls. Slight/hidden HL also did not consistently affect (social) exploration. In conclusion, this study demonstrates that slight and hidden HL differentially affect short- and long-term cognitive processes in an animal model of early (noise-induced) HL, without affecting (social) exploration. These results suggest a nuanced relationship between slight and hidden HL and both short- and long-term memory formation, underscoring the importance of broader cognitive phenotyping and further investigation into the neurobiological structures linking hearing impairment with cognitive function.

This study was conducted to characterize the interaction between the systemic and local peripheral antinociceptive effect of diclofenac, a nonsteroidal anti-inflammatory drug. As well as the effect of local peripheral administration of NG -nitro-L-arginine methyl ester (L-NAME) - a nitric oxide synthesis inhibitor - on the antinociceptive effect of diclofenac. The antinociceptive effect of diclofenac in a fixed-ratio combination of local or intraperitoneal delivery diclofenac was evaluated using the formalin test. Pain-related behavior was quantified in terms of the number of flinches of the injected paw with formalin. Isobolographic analysis was employed to characterize the interaction between the two routes. ED 30 values were estimated for each route, and an isobologram was constructed. Diclofenac and its fixed-ratio combination produced a dose-dependent antinociceptive effect in the second phase, but not in the first phase of the formalin test. The analysis revealed that the simultaneous administration of diclofenac through the two routes was synergistic. Pretreatment of the injured paw with L-NAME partially blocked local, systemic, and simultaneous local and systemic diclofenac-induced antinociception. The obtained results show a synergism after simultaneous administration of diclofenac through two different routes. In addition, it is found that either the local or systemic antinociceptive effect of diclofenac involves the activation of the nitric oxide pathway at the peripheral level.