Behavioural Pharmacology最新文献

The results from clinical trials have indicated that the tau aggregation inhibitor hydromethylthionine mesylate (HMTM) produces disease-modifying effects in Alzheimer's disease (AD) patients when administered alone, but less of an effect when administered in conjunction with cholinesterase inhibitors (ChEIs). The use of ChEIs for AD has been supported by their ability to reverse scopolamine-induced cognitive impairments in rodents reminiscent of those seen in AD patients. We have previously shown that another tau aggregation inhibitor, methylthionine chloride (MTC), is able to reverse scopolamine-induced deficits in spatial learning and memory. The objective here was to determine the symptomatic efficacy of HMTM and rivastigmine, alone or in combination, in a scopolamine model of AD. Female NMRI mice were treated systemically with scopolamine (0.5 mg/kg) or vehicle in combination with ChEI rivastigmine (0.5 mg/kg) or HMTM (5 or 15 mg/kg) daily before assessment of spatial learning and memory performance in a reference memory task in the water maze. Systemic administration of scopolamine induced significant impairments in the spatial learning of the mice compared to vehicle treatment. These deficits were reversed by treatment with HMTM at both doses and with rivastigmine when given alone. Furthermore, coadministration of rivastigmine with HMTM ameliorated the impairments induced by scopolamine. These findings extend our previous observations with MTC and confirm that HMTM also has a dual mode of action, disease modification through tau aggregation inhibition, but also having symptomatic effects through its normalisation of cholinergic activity.

Overdose deaths involving opioids and xylazine, a nonopioid adulterant with sedative, analgesic, and muscle-relaxant properties, have increased dramatically over the past decade. Anecdotal reports suggest xylazine enhances some effects of opioids; however, motivations for their co-use remain unclear. This study examined the reinforcing effects of fentanyl/xylazine mixtures in nonhuman primates responding under a food-versus-drug choice procedure. Rhesus monkeys ( n  = 4) responded under a concurrent schedule where responding on one lever delivered a sucrose pellet while responding on the other lever delivered an intravenous infusion of fentanyl (0.032-1.0 µg/kg/infusion) alone or in combination with xylazine (1.0-100 µg/kg/infusion). Unit dose of drug increased across blocks within each session, and the ratio of xylazine to fentanyl (10 : 1, 32 : 1, 100 : 1, and 320 : 1) varied across conditions. Choice of infusions increased and choice of food decreased with increasing unit dose of fentanyl, whether available alone or in combination with xylazine. Xylazine increased the choice of otherwise ineffective doses of fentanyl, resulting in a shift in the fentanyl dose-effect curve leftward 2- to 6-fold across monkeys. Combining xylazine with relatively small doses of fentanyl increased choice of infusions over food compared with fentanyl alone. These data suggest that xylazine enhanced the potency (and possibly effectiveness) of fentanyl to function as a reinforcer, which might contribute to increased potential for abuse.

Stimulant misuse is strongly associated with behavioral impulsivity, including impairments in behavioral inhibition, yet few studies have examined drug self-administration in ways that directly assess inhibitory control. This study aimed to discover if intravenous (IV) self-administration of cocaine and d-amphetamine could be established using a differential reinforcement of low rates (DRL) schedule in rats and whether stimulant intake altered behavioral inhibition. Male Sprague-Dawley rats were trained to lever press under DRL schedules with food reinforcement, then transitioned to IV cocaine (0.3 mg/kg/infusion) or d-amphetamine (0.06 mg/kg/infusion) self-administration sessions. Following the acquisition, full dose-effect curves were established with cocaine (DRL > 10 s) and d-amphetamine (DRL > 7 s), resulting in inverted- U -shaped curves for both active lever presses and infusions earned. The most active lever presses occurred at the second-highest dose for cocaine (0.3 mg/kg/infusion) and d-amphetamine (0.02 mg/kg/infusion). Analysis of cumulative probabilities of interresponse times (IRTs) revealed drug-specific effects on behavioral inhibition. At peak cocaine intake (0.1 mg/kg/infusion), approximately 65% of lever presses occurred before the DRL 10 s requirement, indicating a failure to inhibit responses. In contrast, at the highest (0.06 mg/kg/infusion) and lowest (0.006 mg/kg/infusion) doses of d-amphetamine self-administration, we observed increased long IRTs beyond the 300 s limited hold contingency, similar to saline. These findings demonstrate rats will self-administer stimulants under a DRL schedule, and cocaine and d-amphetamine differentially disrupt behavioral inhibition. This approach provides novel insight into the complex relationships between stimulant use and behavioral control and provides a foundation for future investigations into the mechanisms of behavioral inhibition.

The gut-brain axis plays a significant role in maintaining cognitive health. Akkermansia muciniphila -derived extracellular vesicles (Akk.m-EVs) improve postoperative cognitive dysfunction (POCD) induced by intestinal ischemia-reperfusion, but their role in elderly POCD is unclear. Therefore, this study investigates whether Akk.m-EVs affect POCD in elderly patients by mediating intestinal barrier dysfunction. Akk.m-EVs were obtained via ultracentrifugation. Sevoflurane (sevo; 3%) was used to induce POCD in mouse models. The cognitive function of mice was assessed by novel objective recognition and Morris water maze tests. Levels of proinflammatory cytokines in hippocampal tissues were detected by ELISA. The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation was analyzed by, while tight junction proteins were detected by immunofluorescence western blot. Akk.m-EVs elevated exploration time, percentage of time spent exploring, identification index for novel objects, decreased escape latency, and enhanced the frequency of crossing the initial platform in sevo-induced POCD mice, highlighting the potential of Akk.m-EVs in improving cognitive, memory, and spatial learning abilities in POCD mice. In addition, Akk.m-EV treatment decreased inflammatory response and suppressed NLRP3 inflammasome activation in hippocampal tissues of POCD mice, accompanied by elevated zona occludens 1 and occludin protein levels in colonic tissues, suggesting that Akk.m-EVs reduced neuroinflammation and improved intestinal barrier disorder. Akk.m-EVs ameliorate POCD in elderly patients by decreasing neuroinflammation and improving intestinal barrier dysfunction, providing a theoretical basis for the development of prevention and treatment strategies for POCD based on probiotic extracellular vesicles.

Ethanol and nicotine are among the most widely used drugs in the USA, and their combined use is associated with increased health risks. This study aimed to investigate the acute effects of ethanol alone and in combination with nicotine on risky choice in rats using a probability-discounting task. Sprague-Dawley rats chose between a smaller, certain reinforcer (one food pellet) and a larger, probabilistic reinforcer (two food pellets). In Experiment 1, effects of acute ethanol administration were assessed. In Experiment 2, acute nicotine was administered either alone or in combination with ethanol. Ethanol was delivered via oral 'Jell-O shots' and nicotine was delivered via subcutaneous injection. Ethanol (2.0 g/kg) and nicotine (0.3 mg/kg) each increased risky choice compared with vehicle controls. The highest combined dose of ethanol (2.0 g/kg) and nicotine (1.0 mg/kg) further increased risky choice compared with the same ethanol dose paired with a lower nicotine dose (0.3 mg/kg), although there was no evidence that the combination increased risky choice beyond either drug alone. These findings highlight drug interactions that may contribute to heightened risk-taking behaviors associated with comorbid use. Future studies should explore the influence of ethanol dose, concentration, vehicle, and administration route on risky choice to further characterize these effects. This study underscores the need for basic investigations to inform interventions targeting the combined use of ethanol and nicotine.

To investigate the risk factors associated with nonadherence to antidepressive drugs in patients with recurrent major depressive disorder (MDD). A total of 847 patients undergoing maintenance treatment for recurrent MDD were prospectively enrolled. One year after discharge, patients' adherence to the prescribed antidepressants was tracked over a 30-day period using the medication event monitoring system. Low adherence was identified in 30.7% of cases. Patients with more than three exacerbations had a 2.040-fold higher risk of low adherence ( P  < 0.025). Those with drug concentrations below or above the recommended therapeutic range had a 2.096-fold ( P  < 0.025) and 2.361-fold ( P  < 0.05) increased risk of low adherence. Patients rating their depression severity from mild-to-severe showed a trend toward increased risk of low adherence, with odds ratios (ORs) of 2.020 (NS), 4.644 ( P  < 0.025), and 5.347 ( P  < 0.025). Patients reporting mild to severe side effects exhibited higher risks of low adherence, with ORs of 2.212 (NS), 3.993 ( P  < 0.05), and 10.965 ( P  < 0.001), respectively. Conversely, older age and Drug Attitude Inventory-10 scores greater than 0 were positive predictors of adherence. A prognostic index greater than or equal to 0.800 indicated a high risk of developing low adherence. A predictive model was established to assess adherence after 1 year of maintenance treatment for recurrent MDD. Patients at high risk of low adherence could be promptly identified and closely monitored, enabling physicians to develop targeted strategies to improve adherence.

Serotonin 1b (5-HT 1b ) receptors play an important role in preclinical cocaine effects. Zolmitriptan, a commercially available 5-HT 1b / 1d agonist migraine medication, selectively attenuates the reinforcing and other abuse-related effects of cocaine. This project sought to advance these promising preclinical findings into humans, thereby demonstrating that the 5-HT 1b/1d system plays a key role in the abuse-related effects of cocaine in people with cocaine use disorder (CUD). Twelve nontreatment-seeking individuals (four female human subjects) with CUD participated in this within-subject human laboratory study. Participants were maintained on 0, 2.5, 5, and 10 mg oral zolmitriptan/day in random order. After at least 3 days of maintenance on each target dose, participants completed experimental sessions in which the reinforcing, subjective, physiological, and cognitive-behavioral effects of 0, 10, and 30 mg/70 kg of intravenous cocaine were determined. Cocaine functioned as a reinforcer and produced prototypic dose-related subjective and physiological effects (e.g. increased ratings of 'stimulated' and heart rate). Zolmitriptan produced limited changes in oral temperature after 10 mg/70 kg cocaine. Cocaine administration improved working memory impairments observed under the 5 mg zolmitriptan condition. Zolmitriptan did not alter any other effects of cocaine. Data indicate that activating the 5-HT 1b/1d systems through zolmitriptan maintenance produces limited changes in the pharmacodynamic effects of cocaine in humans, contrasting preclinical findings, suggesting this may not be a promising pharmacotherapeutic strategy for CUD. Failing to translate from preclinical to clinical models could be because of methodological or species differences, suggesting the field needs to better address this translational gap.

Neuroinflammation mediated by the activation of microglia and subsequent release of proinflammatory cytokines is a key contributor to the pathogenesis of neurodegenerative disorders. In this study, we investigated the neuroprotective effects of p-coumaric acid (PCA) in a lipopolysaccharide (LPS)-induced rat model of neuroinflammation and cognitive impairment. Neuroinflammation was induced by intracerebroventricular (ICV) administration of 150 µg/kg bacterial endotoxin LPS into the fourth ventricle of Sprague-Dawley rats, whereas PCA (160 mg/kg), Donepezil (DON, 5 mg/kg) were administered orally for a period of 14 days, post-LPS administration. PCA has been reported to be active against LPS-induced sickness behavior and chronic unpredictable mild stress models in mice, whereas DON is a centrally acting acetylcholinesterase inhibitor with documented antineuroinflammatory property. Animals were subjected to the Morris Water Maze to assess spatial memory. ICV administration of LPS caused a significant decline in cognitive ability. PCA and DON treatment effectively attenuated this LPS-induced cognitive deficits. In addition to the behavioral improvements, both treatments significantly reduced the central levels of proinflammatory cytokine, interleukin-1β, and lipid peroxidation marker, malondialdehyde levels. Our findings suggest that PCA exerts neuroprotective effects against LPS-induced neuroinflammation and cognitive impairment in rats by plausible modulation of proinflammatory cytokines and oxidative stress pathways.

Phosphatidylinositol 3-kinase (PI3K) (EC2.7.1.137) is an enzyme essential for a variety of biological processes, including inflammation and neuroplasticity. There is a close, positive relationship between these biological functions and the action of psychostimulant drugs such as cocaine and methamphetamine (METH). This suggests that the inhibition of PI3K might regulate METH-induced behavior such as hyperlocomotion and stereotyped behavior. To evaluate the effects of PI3K inhibition on METH-induced behavior, mice were treated with wortmannin, a potent PI3K inhibitor, followed by METH. Horizontal locomotion, vertical rearing, and stereotyped behaviors were measured. In addition, additional experiments were conducted to examine the effects of wortmannin on other aspects of behavior. Pretreatment of mice with wortmannin (3 and 10 mg/kg) significantly inhibited METH (10 mg/kg)-induced stereotyped behavior in a dose-dependent fashion. Stereotyped biting was most robustly reduced by wortmannin, ameliorating the frequency of total stereotypy. Wortmannin (10 but not 3 mg/kg) had a significant inhibitory effect on METH (3 mg/kg)-induced hyperlocomotion. Wortmannin had no effect on other aspects of behavior relevant to emotion or memory. In conclusion, non-glycogen synthase kinase-3β (GSK3β) mediated PI3K signaling pathways appear to contribute to the expression of acute METH effects on locomotion and stereotyped behavior in a manner that is different from PI3K-GSK3β mediated signaling.

Cocaine produces effects including euphoria, local anesthesia, hypophagia/anorexia, and anxiogenesis. The novelty-suppressed feeding (NSF) task is often used as a measure of anxiety-like behavior, except that this task is sensitive to changes in hunger state. First, we determined whether cocaine impacts behavior in the NSF task in male and female Long-Evans rats. Then, to determine whether cocaine-induced alterations in NSF behaviors are due to changes in motivated feeding, we measured the effects of cocaine on operant responding maintained by sucrose. Our results indicate that cocaine administration reduces sucrose consumption in a novel context in a manner indicative of anxiety-like states but does not impact the reinforcing efficacy of sucrose measured by operant responding under a progressive ratio schedule. These results indicate that cocaine's anxiogenic properties play a greater role than its hypophagic properties in its effect on NSF behaviors.