Behavioural Pharmacology最新文献

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.

Cannabidiol (CBD) was first isolated in the 1940s and its drug structure was established in the 1960s. It has risen significantly in popularity since then and has been observed to reduce inflammation and anxiety in patients. CBD is easy to obtain and consume, therefore, its common use is rising and has spread to use in pets and children. Few studies have focused on the use of CBD as a solution to aggression. In our study, we tested if CBD is effective in reducing aggression in Siamese fighting fish ( Betta splendens ) induced by territorial interactions. Betta fish were exposed to controls (water or acetone) and CBD treatments ranging from low, medium, and high (2, 10, and 20 mg CBD/L, respectively), and their behaviors after the visual introduction of an intruder fish were recorded. CBD reduced the odds of aggressive behavior in treated fish. Seventy-five percent of all control fish exhibited aggressive behaviors, while only 17% of CBD-treated fish displayed aggression. Especially, the low CBD dose seemed effective at preventing aggressive behaviors but fish also appeared more lethargic than in any of the other treatments. However, when CBD-treated fish displayed aggressive behaviors, CBD did not appear to reduce the amount of time fish spent being aggressive compared to aggressive fish that did not receive any CBD treatment. While the long-term effects of CBD still have to be examined, our study indicates that CBD might be effective in reducing aggression in Betta fish and potentially other pets.

Research has indicated a strong link between exposure to aluminum (Al) and the development of Alzheimer's disease (AD). Given the rising use of Al nanoparticles, which are far more neurotoxic than Al, it is noteworthy to investigate the possible protective properties of natural substances. Curcumin, an important component of turmeric, has demonstrated neuroprotective effects in some animal studies. The main objective of this study was to examine the protective effects of curcumin on the memory deficit induced by subcutaneous aluminum oxide nanoparticles (Al-NP) administration in mice. Additionally, considering the roles of the hippocampal brain-derived neurotrophic factor (BDNF) and Akt pathway in AD pathology, their levels were evaluated. Adult male Swiss mice (SWR/J) were administered Al-NP (10 mg/kg/s.c.) with or without curcumin (2.5, or 25 mg/kg/P.O) for 10 days. Memory and anxiety-like behavior were assessed using passive avoidance and elevated plus maze tasks, respectively. Western blot analysis was employed to measure hippocampal BDNF and Akt proteins in the hippocampus. The findings revealed that Al-NP induced memory impairment in mice, whereas curcumin at 25 mg/kg prevented this memory deficit. Additionally, Al-NP significantly reduced the hippocampal BDNF and phosphorylated Akt levels, while curcumin increased BDNF and phosphorylated Akt to a nonsignificant level compared to the control group. These results not only suggest the neuroprotective properties of curcumin but also suggest a possible association between hippocampal BDNF and Akt signaling in the neuroprotective mechanism of this compound against Al-NP toxicity.

There are complex dysregulated pathways behind the pathogenesis of pain and inflammation. Because most of the present drugs have certain side effects or are not effective enough, providing novel multitargeting and potent therapeutic agents is of particular importance. This study investigates the antinociceptive effects of pelargonidin, an anthocyanin derived from various plants, through the modulation of the L-arginine/nitric oxide (NO)/cyclic GMP (cGMP)/ATP-sensitive potassium channel (K ATP ) signaling pathway. We also evaluated the anti-inflammatory role of pelargonidin passing through gamma-aminobutyric acid (GABA) and opioidergic receptors. Two experimental models were utilized. In the carrageenan model, 42 rats were divided into control, diclofenac, and three doses of pelargonidin (3, 6, and 9 mg/kg). In addition, two groups received pelargonidin 9 mg/kg + naloxone and pelargonidin 9 mg/kg + flumazenil. For the formalin model, 90 male mice were assigned to control, diclofenac, and three doses of pelargonidin, and 10 groups receiving L-arginine, S-nitroso- N -acetylpenicillamine (SNAP), N (gamma)-nitro-L-arginine methyl ester (L-NAME), glibenclamide, and sildenafil individually or alongside pelargonidin 9 mg/kg. Our results indicated that pelargonidin significantly decreased inflammation and pain in a dose-dependent manner. Notably, groups of pelargonidin 9 mg/kg + naloxone and pelargonidin 9 mg/kg + flumazenil diminished pelargonidin's anti-inflammatory effectiveness, underscoring the significant role of these receptors. Mechanistically, it was shown that the antinociceptive effects of pelargonidin were mediated by the NO signaling pathway. While L-NAME and glibenclamide reduced pelargonidin's antinociceptive efficacy, supplementation with sildenafil and SNAP enhanced the effect. This investigation demonstrated that pelargonidin possesses dose-dependent antinociceptive and anti-inflammatory actions through L-arginine/NO/cGMP/K ATP pathways, and opioidergic and GABA receptors, respectively.

Ketamine displays efficacious rapid-acting antidepressant (RAAD) activity in the rat chronic mild stress (CMS) model. It rapidly reverses anhedonia (CMS-induced sucrose consumption deficit) and attenuates working memory deficit (novel object recognition: NOR) following both systemic (intraperitoneal, i.p.) administration or local administration in the prefrontal cortex (PFC). However, the receptor mechanisms underlying these effects remain to be clarified and may involve activation of serotonin 5-HT 1A receptors, as previously found in experiments using the forced swim test. The present study explored the contribution of PFC 5-HT 1A receptors in ketamine's RAAD activity in the CMS model. Ketamine (10 mg/kg i.p.) reversed CMS-induced sucrose consumption and working memory (NOR test) deficits. Notably, unilateral PFC microinjections of a 5-HT 1A receptor antagonist, WAY-100635 (2 µg), prevented the antidepressant-like and pro-cognitive activity of systemic ketamine on sucrose consumption and working memory deficits. These data indicate that the RAAD activity of ketamine in the rat CMS model requires activation of PFC 5-HT 1A receptors. They also reinforce the notion that drugs that directly activate PFC 5-HT 1A receptors could constitute an alternative to ketamine as a promising strategy to achieve RAAD effects, with additional benefits against cognitive deficits in depressed patients, but without ketamine's troublesome side-effects and requirements for in-patient supervision.