Behavioural Pharmacology最新文献

Traumatic stress exposure increases noradrenaline (NA) release, which contributes to anxiety and impaired risk-appraisal. Guanfacine, a selective alpha-2A adrenergic receptor agonist, has been used to treat stress-related disorders characterised by impaired prefrontal cortex function. By acting on both presynaptic inhibitory autoreceptors and postsynaptic heteroreceptors, guanfacine attenuates stress reactivity and enhances cognition. However, its effectiveness in treating trauma-related anxiety and risk-taking behaviour remains unclear. Leveraging the advantages of zebrafish (Danio rerio ) as a sensitive and efficient preclinical model which is ideal for stress research, we explored the impact of traumatic stress exposure combined with varying concentrations of guanfacine in adult zebrafish. Zebrafish were evaluated for trauma-related anxiety using both the novel tank test (NTT) and a novel version of the open-field test (nOFT), the latter which was also used to investigate risk-taking behaviour. We found that (1) traumatic stress exposure led to heightened risk-taking behaviour in the nOFT, and (2) low-to-moderate concentrations of guanfacine (3-20 µg/L) attenuated anxiety-like, but not risk-taking behaviour, with the highest concentration (40 µg/L), showing no effect. These results highlight the complex role of NA in modulating dysregulated behaviours during traumatic events and indicate the potential of guanfacine for improving trauma-related anxiety and risk-taking behaviour.

Parkinson's disease (PD), characterized by death of dopaminergic neurons in the substantia nigra, is the second most prevalent progressive neurodegenerative disease. However, the etiology of PD is largely elusive. This study employed the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rodent model to examine the effectiveness of 1,4-dihydroxy-2-naphthoic acid (1,4-DHNA), an aryl hydrocarbon receptor (AhR) active gut bacteria-derived metabolite, in mitigating MPTP's motoric deficits, and the role of AhR in mediating these effects. Male C57BL/6 mice were fed daily with vehicle, 20 mg/kg 1,4-DHNA, or AhR-inactive isomer 3,7-DHNA, for 3 weeks before administration of 80 mg/kg MPTP or vehicle. Four weeks later, mice were assessed for motoric functions. Both 1,4-DHNA and 3,7-DHNA prevented MPTP-induced deficits in the motor pole test and in the adhesive strip removal test. Additionally, 1,4-DHNA improved balance beam performance and completely prevented MPTP-induced reduction in stride length. In contrast, 3,7-DHNA, an AhR-inactive compound, did not improve balance beam performance and had only a partial effect on stride length. This study suggests that natural metabolites of gut microbiota, such as 1,4-DHNA, could be beneficial to counteract the development of motor deficits observed in PD. Thus, this study further supports the hypothesis that pathological and mitigating processes in the gut could play an essential role in PD development. Moreover, this indicates that 1,4-DHNA's ability to combat various motor deficits is likely mediated via multiple underlying molecular mechanisms. Specifically, AhR is involved, at least partially, in control of gait and bradykinesia, but it likely does not mediate the effects on fine motor skills.

Exposure to stressful conditions such as forced swim stress (FSS) induces antinociception. Previous reports determined that dopamine receptors in the CA1 hippocampal area are important in chronic pain processing. Considering that neural mechanisms behind acute and chronic pain differ significantly, in this study, we have investigated the role of dopamine receptors within the CA1 region in the FSS-induced antinociceptive response in the acute pain induced by the tail-flick test in the rat. The cannula was implanted unilaterally in the CA1 region of the animal brain. Animals received drugs or vehicles 5 min before FSS exposure. SCH23390 as the D1-like dopamine receptor (D1R) antagonist and Sulpiride as the D2-like dopamine receptor (D2R) antagonist were microinjected into the CA1 area at three doses (0.25, 1, and 4 μg/0.5 μl vehicle); the vehicle groups received saline instead of SCH23390 and dimethyl sulfoxide instead of Sulpiride. After exposure to FSS, the tail-flick test was done. The findings of this study revealed that FSS significantly attenuates nociceptive response during the tail-flick test ( P  < 0.0001). Moreover, intra-CA1 microinjection of SCH23390 and Sulpiride significantly reduces the FSS-induced antinociception in the inducing acute pain ( P  < 0.0001). The comparison of effective dose of 50% for D1R and D2R antagonists showed that both receptors in the CA1 almost equally reduce the FSS-induced antinociception in the tail-flick test. The result of this study supports the hypothesis, that the dopaminergic system in CA1 is involved in triggering a stress-induced antinociceptive response in acute pain conditions.

Opioid use disorder (OUD) is a crisis in the USA. Despite advances with medications for OUD, overdose deaths have continued to rise and are largely driven by fentanyl. We have previously found that male rats readily self-administer fentanyl, with evident individual differences in fentanyl taking, seeking, and reinstatement behaviors. We also have shown that acute treatment with the glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, can reduce fentanyl seeking behavior in male rats. However, given that females are significantly more vulnerable to drug-related cues, drug cravings, and to the development of OUD compared to males, it is imperative that we investigate the biological risk factors on fentanyl use disorder. Further, preclinical models report that females in estrus have increased fentanyl intake, more rapid development of OUD, and enhanced relapse vulnerability compared to those in a non-estrus phase. Thus, we aimed here to understand the effect of estrus phase on our model of OUD and on the effectiveness of acute liraglutide treatment. Herein, we show that female rats readily self-administer fentanyl (1.85 μg/infusion) intravenously, with marked individual differences in fentanyl taking behavior. Additionally, rats in the estrus phase exhibited greater fentanyl intake compared with those in a non-estrus phase, greater cue-induced fentanyl seeking, and greater drug-induced reinstatement of fentanyl seeking. Finally, acute liraglutide treatment (0.3 mg/kg s.c.) reduced cue-induced fentanyl seeking and blocked drug-induced reinstatement of fentanyl seeking, particularly when tested in estrus. Overall, these data support the broad effectiveness of acute GLP-1R agonists as a promising non-opioid treatment for OUD.

Opioid use disorder is a public health problem that includes symptoms such as withdrawal syndrome and opioid-induced hyperalgesia. Currently, drugs to treat side effects of opioids also have undesirable effects, which lead to limitations. This study investigated the effect of a treatment with cannabidiol in morphine-induced hyperalgesia and withdrawal behavior in morphine-dependent rats. Male and female rats were submitted to a morphine-induced physical dependence protocol consisting of a twice daily treatment with morphine (filtered solution, dose of 7.89 mg/kg, 1 ml/kg, s.c.) for 10 days. Nociception was measured using the hot plate test and morphine-induced thermal hyperalgesia was equally achieved following 7-10 days of morphine administration in male and female rats. Repeated treatment with cannabidiol (30 mg/kg) was sufficient to prevent thermal hyperalgesia in male and female rats. Subsequently, rats received an acute administration of naloxone (2 mg/kg. s.c.), 90 min after the morphine treatment on day 11, the number of withdrawal behaviors was scored. Rats that received treatment exclusively with morphine presented significant withdrawal behaviors compared to control (Water). Morphine-dependent female rats showed a prevalent stereotyped behavior of rearing, whereas male rats had teeth chattering behavior as the most preeminent. Treatment with cannabidiol on day 11 partially attenuated withdrawal behavior in morphine-dependent male rats, with mild effects in female rats (high withdrawal responders only). Altogether, our data provide evidence of an anti-hyperalgesic effect of cannabidiol in rats. Male and female rats treated chronically with morphine exhibited withdrawal behaviors in different ratios, and cannabidiol treatment attenuated withdrawal behavior in a sex-dependent manner.

Cigarette smoking is at an all-time low. However, nicotine consumption has diversified with the introduction of commercial tobacco products that include Electronic Nicotine Delivery Systems. Nicotine is the main psychoactive component of tobacco and contributes to the addictive properties of tobacco products. Prolonged nicotine exposure induces neural adaptations that promote addiction-related behaviors in an age-dependent manner. Here, we investigated nicotine sensitivity among young adult and middle-aged male mice by comparing initial responses to nicotine tartrate from different suppliers. We observed that all nicotine compounds tested in the present study induced a robust reduction in locomotor activity and body temperature, and nicotine exposure resulted in increased serum cotinine concentration. We observed age-related differences in the magnitude and the time course of nicotine responses for locomotor and hypothermic effects. Reduction in locomotor activity was larger among young adult mice, but the time course of this response was similar for both age groups. Nicotine-induced reduction in body temperature was of a comparable magnitude for both age groups but young adults showed a faster decrease than middle-aged mice. These results suggest that age of exposure is a key factor contributing to nicotine sensitivity and its potential addictive effects. These responses were consistently produced for nicotine tartrate from different sources. Our findings reveal distinct responses between young adults and middle-aged mice, suggesting that age-specific neurobiological mechanisms in nicotine sensitivity continue developing into adulthood. These age-related variations in nicotine response are crucial for developing targeted interventions and understanding the risk factors for nicotine dependence across the lifespan.

In recent years, the recreational use of xylazine has increased dramatically in the USA. Although xylazine has been used as an anesthetic in veterinary medicine for decades, little is known about its behavioral effects. We took advantage of the planarian's innate negative phototaxis, the reliable movement from the light side to the dark side of a Petri dish, to explore the organism's suitability as an animal model for investigating the preclinical pharmacology of xylazine. In two experiments, we tested the effects of several doses of xylazine on locomotion by recording the latency to transition into an opaque area. Xylazine disrupted locomotion in a dose-dependent fashion. Larger doses first produced a period of hyperkinesia without forward motion. This was followed by a period of sedation. Physical stimulation disrupted sedation and evoked the resumption of locomotion. Data on the behavioral effects of xylazine outside of anesthesia and sedation are limited; therefore, the current study adds to a relatively small literature on the behavioral effects of xylazine.

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 CB1 receptor and CB2 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.

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-HT1A receptors, as previously found in experiments using the forced swim test. The present study explored the contribution of PFC 5-HT1A 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-HT1A 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-HT1A receptors. They also reinforce the notion that drugs that directly activate PFC 5-HT1A 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.

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.