Behavioural Pharmacology最新文献

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. ED30 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.

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.

Recent evidence suggests that cannabis can impair simple auditory processes, and these alterations might be due to cannabinoid agonism. The effect of cannabinoid agonism on relatively complex processes such as auditory discrimination is unknown. The goal of this study was to examine the impact of WIN 55,212-2, a CB 1 receptor and CB 2 receptor agonism, on auditory discrimination using a go/no-go task. Twenty-two male and female Sprague-Dawley rats were initially trained to lever-press for sucrose to either a pure tone or white noise cue in a go/no-go paradigm, where rats were reinforced for lever-pressing during one cue and punished for lever-pressing during the other auditory cue. After criterion performance was met, rats were then injected with WIN 55,212-2 at 1.2 mg/kg, 3 mg/kg, or a corresponding vehicle (saline) and were tested on auditory discrimination. On day 3, active lever-pressing was higher in both the low- and high-dose WIN groups compared with the saline group. Overall lever-pressing decreased over time in the high-dose WIN 55,212-2 group. There were no effects of the drug on discrimination or errors, suggesting that cannabinoid agonism did not negatively affect auditory discrimination. This is the first study to examine the impact of cannabinoids on the discrimination of tones, finding that, contrary to previous research, the low and high doses of WIN 55,212-2 did not adversely impact auditory-linked behaviors.

Memory retrieval involves recalling previously consolidated information, while memory extinction refers to the gradual weakening of such memories after recall. Stress and glucocorticoids influence the retrieval and extinction of memory. This study employed a passive avoidance task to examine the impact of acute mild stress and equivalent doses of exogenous corticosterone on fear memory retrieval and extinction in male mice. Subsequently, we investigated the potential therapeutic effects of Ginkgo biloba extract, EGb 761, on memory impairments induced by stress and corticosterone. Corticosterone was administered systemically 30 min before memory reactivation to model glucocorticoid activity during retrieval. Mild acute stress, like the stress levels typically experienced before an exam, was induced through 20-min restraint immediately before reactivation in separate groups. EGb 761 was injected 30 min before corticosterone or stress exposure. Results demonstrated that both corticosterone and acute stress impaired context-specific fear memory retrieval and enhanced subsequent extinction. Pretreatment with EGb 761 inhibited these impairing effects of acute stress and corticosterone on avoidance memory retrieval and extinction. Our findings suggest that the glucocorticoid system and acute stress markedly influence avoidance memory retrieval and extinction. Ginkgo biloba may possess therapeutic and memory-enhancing effects, particularly in stressful situations.

Maternal separation as an early life stress can lead to long-lasting deleterious effects on cognitive and behavioral functions, and the mood state. On the other hand, Psilocybe cubensis (as one of the most well-known magic mushrooms) may be beneficial in the improvement or the treatment of neuropsychiatric disorders. In the present study, we aimed to investigate the effect of P. cubensis extract (PCE) on depressive-like and anxiety-like behaviors, and locomotor activity in mice exposed to early maternal separation. Also, we assessed the expression and methylation level of Slc6a4 and Nr3c1 in the hippocampus. Maternal separation was done in postnatal days (PNDs) 2-18. PCE was intraperitoneally injected at the dose of 20 mg/kg at PND 60, and our tests were done at days 1, 3, and 10, of administration. The results showed that maternal separation significantly induced depressive-like behavior in the forced swim test and anxiety-like behavior in the open field test (OFT). Also, maternal separation decreased locomotor activity in the OFT. In addition, maternal separation decreased the expression and increased the methylation level of both Slc6a4 and Nr3c1 in the hippocampus. However, PCE significantly reversed all these effects. In conclusion, it seems that P. cubensis affects serotonergic signaling via altering Slc6a4 expression and methylation level in the hippocampus of mice. The effect of P. cubensis on Nr3c1 expression and methylation level may also lead to alter the function of the hypothalamus-pituitary-adrenal axis and the stress response in mice exposed to maternal separation.

Mood disorders are a prevalent global health concern with natural health products, including herbal supplements, an increasingly popular choice as an alternative or complementary therapy. Despite their widespread use, few studies have tested the clinical efficacy of natural health products or explored their underlying mechanisms in animal models. Modification of affective biases has been linked to mood in humans and animal models and may provide insights into potential antidepressant effects. In this study, we used a translational rodent model of affective bias modification to investigate the effects of five commonly used supplements: Hypericum perforatum, that is, St. John's Wort (SJW), Mucuna pruriens, Rhodiola rosea root extract, Valerian root extract and 5-hydroxytryptophan. Exercise is also thought to improve mood disorders, but clinical studies reveal mixed results therefore we also tested the effect of involuntary exercise on affective biases. In separate experiments, male Lister Hooded rats were acutely treated with SJW, Mucuna pruriens, Rhodiola rosea root extract, Valerian root extract and 5-hydroxytryptophan, or underwent an involuntary exercise manipulation. Our results showed a significant positive affective bias following treatment with SJW, whilst the involuntary exercise induced a negative affective bias in rats. No effects were found following the other acute treatments. These data suggest SJW has similar effects in terms of affective bias modification as conventional antidepressants. The negative affective bias observed with involuntary exercise suggests the animals experience a negative affective state and suggests exercise-based therapy may be less effective if the patient perceives this as involuntary.

Increased voluntary consumption of alcohol has been demonstrated in male rats exposed to frustrative reward downshift (the emotional self-medication effect). Access to a wheel for voluntary running abolished this effect in male rats, suggesting an attenuating effect of physical exercise on the negative affect induced by reward downshift and its consequences on drug intake. The present study analyzed this effect in female rats. Sixty-four food-deprived female Wistar rats received 32% sucrose [4% (Experiment 1) or 2% (Experiment 2) in controls] during 10, 5-min preshift sessions followed by 4% (Experiment 1) or 2% (Experiment 2) sucrose during 5 postshift sessions. Immediately after each consummatory session, animals were exposed to a 2-h, two-bottle preference test involving 32% alcohol vs. water. Half of the animals also had access to a running wheel during the preference test. The results showed (a) lower sucrose consumption in the downshifted groups (32-4% and 32-2%) compared to the unshifted controls (4-4% and 2-2%, respectively); (b) higher alcohol preference in downshifted groups without access to a wheel compared with downshifted groups with access to the wheel (Experiments 1 and 2); and (c) increased alcohol intake (g/kg) after experiencing reward downshift in animals without access to the wheel (Experiment 1). Voluntary wheel running thus reduced alcohol intake in female rats experiencing reward downshift. These findings are comparable to previous results reported in male rats and support the usefulness of physical exercise to prevent alcohol self-medication induced by frustrative nonreward.

This study aimed to determine whether the second-generation cannabinoid receptor subtype 1 (CB 1 ) antagonist, monlunabant - designed to treat obesity by targeting peripheral receptors - might actually exert its effects through CB 1 receptors in the central nervous system. In adult male mice, both monlunabant and rimonabant reduced appetite and antagonized CB 1 agonist-induced hypothermia. Monlunabant was consistently less potent than rimonabant in both appetite suppression and blocking hypothermia. The cannabinoid agonist HU-210 produced profound hypothermia, which was significantly attenuated by 10 mg/kg of either drug and by 3 mg/kg of rimonabant. Similarly, both drugs reduced appetite in food-deprived mice with limited access to preferred food at the same doses that were effective in the hypothermia assay. Lower doses of monlunabant, which likely saturated peripheral receptors, had no effect on appetite. These findings suggest that monlunabant suppresses appetite mainly through antagonism of central CB 1 receptors. Consequently, monlunabant and other second-generation CB 1 antagonists being developed for obesity may carry a similar risk of adverse psychiatric effects, as previously observed with rimonabant.

Hesperidin treatments reduce depressive symptoms in mouse models of depression, but the mechanism that mediates its antidepressant effects is unclear. This study shows that hesperidin exerts its antidepressant effects by activating α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor to promote synaptic and neuronal function in the hippocampus. The optimal dose of hesperidin (10 mg/kg) for the antidepressant potential was determined after 7 consecutive days of treatments, demonstrating decreased latency to eat and increased food consumption in novelty suppressed feeding, and decreased immobility time in tail suspension test (TST). Moreover, the optimal dose also reversed the depressive phenotypes of Institute of Cancer Research mice exposed to chronic unpredictable mild stress (CUMS), including reduced immobility time in the TST and increased sucrose preference in the sucrose preference test. In addition, hesperidin increased the expression of AMPA receptor protein (Glur1) and synaptic proteins (BDNF, PSD95, synapsin1) in the hippocampus of CUMS-exposed mice. Furthermore, inhibition of AMPA receptor activity by NBQX blocked the effect of hesperidin in reversing the depressive phenotypes, upregulated the expression of synaptic proteins (BDNF, PSD95, synapsin1) and cFOS-positive cells in the hippocampus, and increased the number of Ki67-positive cells in the dentate gyrus of the hippocampus of CUMS-exposed mice. These results help to further understand the antidepressant mechanism of hesperidin and provide new ideas for the future development of antidepressant drugs.

Despite the efforts of the Drug Enforcement Administration to safeguard the public from hazardous analogs of synthetic hallucinogens, these compounds have increasingly been observed in the illicit drug market. Four novel compounds were found to be similar in structure to the previously described 25X-NBOMe synthetic hallucinogens. These four compounds, 25B-NBOH, 25C-NBOH, 25E-NBOH, and 25I-NBOH were evaluated for their ability to modify spontaneous locomotor activity in mice to obtain dose range and time-course information and were then tested for discriminative stimulus effects similar to the prototypical hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM). All four test compounds decreased locomotor activity. The locomotor depressant effects were similar in magnitude and potency to DOM, but less potent than the 25X-NBOMe compounds in previous reports. 25B-NBOH, 25C-NBOH, and 25E-NBOH fully substituted (≥80%) in DOM-trained rats, whereas 25I-NBOH failed to fully substitute for DOM even at doses that suppressed responding. The discriminative stimulus effects were more potent than those of DOM and the 25X-NBOMe compounds. These findings suggest that three of the four test compounds are most likely to be used as recreational hallucinogens in a similar manner to DOM and the 25X-NBOMe compounds, whereas 25I-NBOH may be less liable to illicit use.