Behavioural Pharmacology最新文献

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.

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.

Medications known as 'cognitive enhancers' are increasingly being consumed off-label by healthy people, raising concerns about their safety. The aim of our study was to profile behavioral performance upon oral administration of methylphenidate (2.5 mg/kg) and modafinil (64 mg/kg) - two popular cognitive enhancers - and upon their discontinuation. We modeled cognitively demanding challenges in neurotypical individuals using a behavioral task where Wistar - Lewis rats had to withhold responses for a specified time to obtain food rewards. This task allowed us to extract several measures of behavioral performance associated with clinically meaningful indices, such as compulsive-like responding, incapacity to wait (impulsivity), time estimation (precision and accuracy), and attentional lapses. Our study design involved examining these behavioral indices in subjects administered either methylphenidate, modafinil, or vehicle. We found that subjects administered modafinil obtained fewer rewards and were less efficient in reward pursuing than the vehicle group; this result was likely due to a drug-induced inability to wait. Upon modafinil discontinuation, subjects earned more rewards but did not entirely catch up with the vehicle group. As for methylphenidate, neither favorable nor unfavorable effects were found in our main analyses. However, an exploratory analysis of changes in behavioral performance within sessions suggested that methylphenidate fostered favorable, yet short-lived, effects. We discuss our results in terms of the risks and cost-benefits of doses above or below the effective dose of cognitive enhancement drugs.

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.