Behavioural Pharmacology最新文献

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.

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.

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.

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.

This study explored a potential role for the 5-hydroxytryptamine 2A (5-HT 2A ) serotonin receptor in opiate physical dependence. Rats were rendered opiate-dependent by 7 days of continuous subcutaneous (s.c.) morphine sulfate infusion. Pimavanserin is a selective 5-HT 2A receptor inverse agonist in current medical use. A day after termination of drug infusion, rats were injected s.c. with 0.3 or 1.0 mg/kg pimavanserin or saline alone. A nondependent control group was infused with saline alone and injected with saline. One hour after injections, all rats were observed under blind conditions for somatically expressed spontaneous withdrawal signs. While both pimavanserin doses significantly reduced withdrawal signs in the dependent rats, the higher dose reduced those signs to the level exhibited by the nondependent group. In a second experiment, utilizing only nondependent, saline-infused rats, pimavanserin had no significant effect vs. saline injection on overall signs. A third experiment extended these findings to naloxone-precipitated morphine withdrawal. Relative to saline injection, pimavanserin, 1.3 mg/kg s.c., significantly reduced withdrawal signs precipitated by 0.3 mg/kg naloxone 1 h later. This effect was reconfirmed in a separate experiment. The pimavanserin injection also significantly attenuated the aversiveness of morphine withdrawal, as indicated by reduced conditioned avoidance of the chamber where precipitated withdrawal had occurred. These results indicate a major role for the 5-HT 2A receptor in opiate physical dependence and withdrawal syndrome, suggesting this receptor as a potential therapeutic target.

Paclitaxel (PTX), a widely used chemotherapeutic agent, causes both peripheral and central neurotoxicity, leading to significant behavioral impairments. However, inadequate literature is available on PTX-induced neurobehavioral sequelae associated with anxiety, depression, and cognition in adults during and after chemotherapy. Therefore, the present study aimed to investigate neurobehavioral impairments in adult female rats following PTX exposure, with a specific focus on anxiety-like behaviors and cognitive functions such as learning and memory. In this study, we used adult female Wistar rats aged 10-12 weeks (average weight: 180 ± 5 g) and administered clinically relevant therapeutic doses of PTX (1.6 and 3.2 mg/kg body weight) intravenously once weekly for 6 weeks, simulating the clinical chemotherapy regimen. Neurobehavioral assessments were conducted after the first and sixth doses of PTX using validated mazes, including the photoactometer, open-field maze, elevated plus-maze (EPM; for anxiety-like behaviors), and the step-down latency test (SDL; for cognitive performance). Neurobehavioral patterns were recorded using autotracking software (ANY-maze, Stoelting Co., Wood Dale, Illinois, USA). Our findings revealed substantially reduced locomotor activity in the photoactometer, increased anxiety-like behaviors with amplified fear emotionality in the open-field and EPM tests, and memory impairment in the SDL test. These results suggest that the manifestation of anxiogenic and cognitive behavioral changes is associated with the administration of a higher dose (3.2 mg/kg) of PTX. In conclusion, our study indicates that PTX causes significant neurobehavioral impairments in rats after exposure to equivalent therapeutic doses of PTX.

The serotonin 2C receptor (5-HT 2C ) has been investigated as a potential therapeutic target for a variety of psychiatric disorders, as well as the treatment of obesity. A stumbling block in the development of these medications is identifying agonists with selectivity for 5-HT 2C over 5-HT 2A and 5-HT 2B . Lorcaserin (Belviq) is a serotonin 5-HT 2C agonist that was previously marketed as a weight-loss medication but was voluntarily withdrawn from the market because of a small, but an increased risk of serious side effects. The present study examined the discriminative stimulus properties of 2.0 mg/kg lorcaserin in a two-lever drug discrimination assay in male C57BL/6 mice using a fixed ratio 12 reinforcement schedule. A generalization curve with lorcaserin yielded an effective dose 50 (ED 50 ) = 0.56 mg/kg for substitution for the training dose. Lorcaserin produced a rapid onset, but short-acting (~60 min), discriminative stimulus, as full generalization was found as early as 15 min after drug administration. The 5-HT 2C agonist meta-chlorophenylpiperazine fully substituted for lorcaserin with an ED 50  = 0.31 mg/kg, and the 5-HT 2C antagonist SB 242084 significantly blocked lorcaserin-lever responding (maximal effect at 0.25 mg/kg dose). Conversely, the 5-HT 1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin did not substitute for lorcaserin. Thus, lorcaserin's discriminative stimulus appears to be mediated by agonist activity at 5HT 2C receptors in C57BL/6 mice. These results demonstrated that lorcaserin drug discrimination can be trained in C57BL/6 mice and that it is a useful in-vivo assay for the future development of psychotherapeutic drugs for psychiatric disorders with selective 5-HT 2C agonist activity.

Cannabidiol (CBD) is a phytocannabinoid without intoxicating properties. While CBD can improve neurophysiological functions and subjective symptoms, its effect on cognitive function remains unclear. We summarized the available randomized controlled trials investigating CBD administration and cognitive function. A review of the literature was conducted using the following keywords on PubMed/Medline: (cannabis OR cannabidiol OR cannabinoid OR CBD OR Δ 9 -tetrahydrocannabinol OR tetrahydrocannabinol) AND (neurology OR brain OR psychiatric OR neuroscience OR psychology OR cognition) AND (human) AND (randomized controlled trial OR RCT). The search yielded 1038 articles with 36 total included for this literature review. The articles included healthy participants, neurological disease, psychiatric disease, psychosis, paranoia, schizophrenia, and drug-use disorders. Studies with healthy participants included a variety of dosing strategies, suggesting an effect on cognitive function and sleep quality. In Parkinson's disease, 75-300 mg CBD resulted in mild improvements in daily life activities. Decreases in subjective anxiety were found in patients with psychiatric disease using CBD doses ranging from 300 to 400 mg. In patients with psychosis and paranoia, 600 mg CBD showed inconsistent results in cognitive function. In patients with schizophrenia, up to 1000 mg CBD per day had minimal effects on cognition. Finally, up to 800 mg CBD had minimal effects on cognitive function in patients with substance use disorders. The findings are limited by utilization of acute dosing, variations in CBD dose, and different routes of administration. Standardized dosing and CBD formulations are needed to assess its efficacy for improving cognition.

The societal consensus on the need for smoking cessation is well-established, yet the number of tobacco users continues to rise. This trend is largely driven by the potent physiological effects of nicotine, which significantly increase the likelihood of tobacco use initiation. Certain compounds found in everyday foods, such as theobromine and caffeine in cocoa products, also exhibit psychostimulatory properties. However, comprehensive studies on the effects of consuming these compounds in the context of tobacco use are limited. This study investigates the role of theobromine, a primary active component in cocoa, in modulating the positive physiological effects of nicotine and explores the underlying mechanisms. Our findings reveal that while low doses of theobromine do not alter nicotine's addictive properties, they amplify its positive physiological effects. Notably, theobromine's impact on nicotine varies significantly between the hippocampus and cerebellum, highlighting region-specific interactions.

Opioids, prescribed for pain relief or as maintenance therapies for opioid use disorder, induce constipation, which can lead to medication compliance issues. However, it is not known how dietary manipulation might impact opioid-induced constipation. To test the hypothesis that eating a high fat diet exacerbates opioid-induced constipation, male and female Sprague-Dawley rats ( n  = 8/diet/sex) were fed either a low fat (standard) diet, a high fat/high carbohydrate diet, or a ketogenic diet. Rats were injected with either saline or morphine (1-10 mg/kg) and constipation was measured by counting fecal boli hourly for 6 h. Morphine-induced comparable constipation in all groups; however, rats eating a high fat/high carbohydrate or ketogenic diet produced significantly less feces following injections of saline or morphine as compared to rats eating a standard diet ( P  < 0.05). Dietary considerations might be important for patients prescribed opioid medications.