Behavioural Pharmacology最新文献

Opioid action in the brain involves the dopamine-reward system as well as non-dopamine pathways. Since vitamin D also modulates the brain's dopamine system, the question of this study was how vitamin D might affect the opioid influences on the reward system. Therefore, the objective of this study was to investigate the possible effect of vitamin D on the conditioned place preference (CPP) induced by morphine, as a valuable model of assessment of the reinforcing properties of opioids by associating the context to the rewarding properties of the addictive drugs. Male Wistar rats were randomly divided into two main groups that either received saline (morphine vehicle) or morphine (5 mg/kg, intraperitoneally) for CPP. Each of the main groups was divided into three vitamin D treatment subgroups: vitamin D vehicle and vitamin D (5 and 10 μg/kg, intraperitoneally). Vitamin D injections were started 1 week ahead of the experiment (two injections) or immediately after post-conditioning and in both cases, it was continued twice weekly throughout the CPP. Administration of vitamin D (10 μg/kg) before conditioning in CPP markedly attenuated morphine expression in the post-conditioning test. Receiving vitamin D (5 or 10 μg/kg) before or after conditioning significantly attenuated morphine reinstatement. Administration of vitamin D after opioid conditioning facilitated morphine memory extinction and attenuated morphine reinstatement. Vitamin D is probably a valuable addition to be considered as a part of the treatment for prevention or minimizing the dependency or relapse to opioids.

Sensorimotor gating disruptions have been noted in several psychiatric and neurodegenerative disorders. However, the involvement of sensorimotor gating processes in eating disorders has not been well characterized. Our objective was to examine the sensorimotor gating of the acoustic startle response following dietary-induced binge eating and high-fat diet (HFD) induced weight gain in male C57B/6J mice. Acute administration of the norepinephrine reuptake inhibitor, nisoxetine (0.5 and 5 mg/kg), and a dopamine reuptake inhibitor, GBR 12783 (1.6 and 16 mg/kg), were either given alone or in combination to assess norepinephrine and dopamine alterations, respectively. Male mice with repeated bouts of calorie restriction (Restrict) and with limited access to a sweetened fat food (Binge) demonstrated an escalation of intake over 2.5 weeks under standard chow conditions. Restrict Binge (RB) mice had a reduced startle response to the startle pulse (110 dB) compared with the Naive control group at 5 mg/kg nisoxetine. There was an overall effect of nisoxetine (0.5 and 5 mg/kg) to increase percent inhibition at pre-pulse (74 dB), %PP74. Under HFD conditions, the RB group did not demonstrate a binge-like eating phenotype. The RB group on HFD had a higher response to 74 dB with nisoxetine (5.0 mg/kg) compared with a combinational dose of nisoxetine (5.0 mg/kg) and GBR 12783 (1.6 mg/kg). These findings suggest that dietary conditions that promote binge-like eating can influence the central noradrenergic and dopaminergic controls of the acoustic startle response and potentially influence sensorimotor gating.

Objectives: The purpose of this review is to examine human study evidence on the effectiveness of oxytocin in this patient population. Despite stimulant use disorder being a major public health concern, there are no validated pharmacological treatments. Psychosocial interventions show limited effectiveness especially in the more severe cases of stimulant use disorder, whereas animal models suggest that oxytocin may be a useful treatment.

Methods: A literature search using Medline, Embase, and PsychInfo was undertaken. Search results were subsequently imported into Covidence to identify relevant studies.

Results: Six studies were included in this review, two of which were pilot studies. Although oxytocin was well tolerated across studies, no study showed a statistically significant reduction in reported cocaine use or cravings. One study suggested oxytocin increased the desire to use cocaine, although the population of participants should be taken into consideration. In contrast, one study showed a trend towards reduced self-reported cocaine use.

Conclusion: Available research does not support the use of oxytocin in the management of stimulant use disorder; however, included studies are small in sample size and limited in number. There were several noteworthy findings unrelated to this review's primary and secondary outcomes, which are of interest and warrant further research. We provide suggestions for future studies in this area of research. Considering the limited data available at this time, further studies are required before any definitive conclusions can be made regarding the use of oxytocin in stimulant use disorder management.

Cognitive rigidity (CR) refers to inadequate executive adaptation in the face of changing circumstances. Increased CR is associated with a number of psychiatric disorders, for example, obsessive-compulsive disorder, and improving cognitive functioning by targeting CR in these conditions, may be fruitful. Levetiracetam (LEV), clinically used to treat epilepsy, may have pro-cognitive effects by restoring balance to neuronal signalling. To explore this possibility, we applied apomorphine (APO) exposure in an attempt to induce rigid cue-directed responses following a cue (visual pattern)-reward (social conspecifics) contingency learning phase and to assess the effects of LEV on such behaviours. Briefly, zebrafish were divided into four different 39-day-long exposure groups ( n  = 9-10) as follows: control (CTRL), APO (100 µg/L), LEV (750 µg/L) and APO + LEV (100 µg/L + 750 µg/L). The main findings of this experiment were that 1) all four exposure groups performed similarly with respect to reward- and cue-directed learning over the first two study phases, 2) compared to the CTRL group, all drug interventions, but notably the APO + LEV combination, lowered the degree of reward-directed behaviour during a dissociated presentation of the cue and reward, and 3) temporal and spatial factors influenced the manner in which zebrafish responded to the presentation of the reward. Future studies are needed to explore the relevance of these findings for our understanding of the potential cognitive effects of LEV.

Recent studies had reported that compounds that stimulate microglia could be developed as potential drugs for the treatment of depression due to their reversal effect on depression-like behaviors in chronically stressed mice. Zymosan A is a cell wall preparation of Saccharomyces cerevisiae composed of β-glucans. Based on its immuno-stimulatory activities, we hypothesized that zymosan A might have a therapeutic effect on depression. Our results showed that a single injection of zymosan A 5 h before behavioral tests at a dose of 1 or 2 mg/kg, but not at a dose of 0.5 mg/kg, reversed chronic unpredictable stress (CUS)-induced depression-like behaviors in mice in the tail suspension test, forced swimming test, and sucrose preference test. Time-dependent analysis showed that the antidepressant effect of zymosan A (2 mg/kg) in CUS mice became statistically significant at 5 and 8 h, but not at 3 h, and persisted for at least 7 days. Fourteen days after a single injection of zymosan A, no antidepressant effect was observed anymore. However, the disappeared antidepressant effect of zymosan A was restored by a second zymosan A injection (2 mg/kg, 5 h) 14 days after the first zymosan A injection. Stimulation of microglia was essential for the antidepressant effect of zymosan A because pre-inhibition of microglia by minocycline or pre-depletion of microglia by PLX3397 prevented the antidepressant effect of zymosan A. Based on these effects of zymosan A, zymosan A administration could be developed as a new strategy for the treatment of depression.

Epidemiological studies have mentioned that cocaine use disorder (CUD) has increased in the last decade among women; these show endocrine and reproductive disorders and a high propensity to stress and depression disorders. Mirtazapine-a tetracyclic antidepressant-decreases cocaine-induced locomotor activity and locomotor sensitization in male rats. The objective of this study was to evaluate if estradiol alters the efficacy of mirtazapine to decrease cocaine-induced locomotor activity in sham and ovariectomized female rats. Three hundred and twenty adult female Wistar rats were assigned to three experimental protocols. For experiments, 1-3, female rats were daily dosed with 10 mg/kg of cocaine during the 10 days of induction and expression of locomotor sensitization. During drug withdrawal (30 days), cocaine was withdrawn and the groups received daily mirtazapine, estradiol, or saline. In addition, the females underwent sham or ovariectomy surgery. Tamoxifen was administered during the antagonism phase. After each administration, locomotor activity for each animal was recorded for 30 min in activity chambers. The dosage of mirtazapine reduces estradiol-induced enhancement in cocaine-dependent locomotor activity during the expression of locomotor sensitization in sham and ovariectomized female rats. As well as they showed that estradiol co-dosed with mirtazapine enhances the efficacy of mirtazapine to decrease cocaine-induced locomotor activity. Finally, tamoxifen enhanced the estradiol and mirtazapine-induced decrease in the cocaine motor effect in female rats. Mirtazapine may be considered an effective therapeutic option for the treatment of CUD in women, even in those who are on hormonal treatment or antidepressant therapy with estradiol.

The present experiment examined the contribution of the β-adrenergic receptor system in mediating the unconditioned (i.e. pharmacological) and conditioned (i.e. learned) hyperactive effects of methamphetamine. To this end, mice underwent an 8-day conditioning procedure involving two different, alternating session types (chamber and home-cage days). On chamber days (1, 3, 5, and 7), mice were injected (intraperitoneally) with vehicle (dH 2 O) or propranolol (16 or 32 mg/kg) and were injected (subcutaneously) 30 min (min) later by either vehicle (saline; unpaired) or methamphetamine (1.0 mg/kg; paired). On home-cage days (2, 4, 6, and 8), mice were injected (subcutaneously) with either vehicle (saline; paired) or methamphetamine (1.0 mg/kg; unpaired) in their home cages. The test day for conditioned hyperactivity occurred 48 h after the last chamber day. Propranolol dose-dependently blocked the unconditioned and conditioned hyperactive effects of methamphetamine, implicating a role for the β-adrenergic system in mediating these effects of methamphetamine.

Stress contributes to numerous psychopathologies, including memory impairment, and threatens one's well-being. It has been reported that creatine supplementation potentially influences cognitive processing. Hence, in this study, we examined the effects of creatine supplementation on memory, synaptic plasticity, and neuronal arborization in the CA1 region of the hippocampus in rats under chronic restraint stress (CRS). Thirty-two adult male Wistar rats (8 weeks old) weighing 200-250 g were randomly divided into four groups (n = 8/per group): control, stress, creatine, and stress + creatine. CRS was induced for 6 h per day for 14 days, and creatine supplementation was carried out by dissolving creatine (2 g/kg body weight per day) in the animals' drinking water for 14 days. We used the Barnes maze and shuttle box for spatial and passive avoidance memory examination. The in-vivo field potential recording and Golgi-Cox staining were also used to investigate long-term potentiation (LTP) and dendrite arborization in the CA1 pyramidal neurons. Chronic stress impaired spatial memory, dysregulated LTP parameters, and decreased the number of dendrites in the CA1 pyramidal neurons of stressed rats, and creatine supplementation modified these effects in stressed rats. It seems that creatine supplementation can improve spatial memory deficits and synaptic plasticity loss induced by CRS in hippocampal CA1 neurons, possibly by reducing the dendrite arborization damages. However, understanding its mechanism needs further investigation.

Deletion of the tryptophan 2,3-dioxygenase ( TDO2 ) gene induces an anxiolytic-like behaviour in mice and TDO inhibition by allopurinol elicits an antidepressant-like effect in rats exposed to restraint stress. Chronic nicotine administration inhibits TDO activity, enhances brain serotonin synthesis and exerts anxiolytic- and antidepressant-like effects in rodent models. There is a strong association between anxiety, depression and tobacco use, which is stronger in women than in men. The present study aimed to examine the relationship between behavioural measures of anxiety and depression with liver TDO activity, brain tryptophan concentration and serotonin synthesis in rats treated chronically with nicotine. Behavioural measures included the elevated plus maze (EPM), open field (OFT) and forced swim (FST) tests. Biochemical measures included TDO activity, serum corticosterone and brain Trp, 5-HT and 5-HIAA concentrations. Anxiolytic-like and antidepressant-like effects of chronic nicotine were confirmed in association with TDO inhibition and elevation of brain Trp and 5-HT. Sex differences in behaviour were independent of the biochemical changes. At baseline, female rats performed better than males in OFT and FST. Nicotine was less anxiolytic in females in the open arm test. Nicotine treatment did not elicit different responses between sexes in the FST. Our findings support the notion that liver TDO activity exhibits a strong association with behavioural measures of anxiety and depression in experimental models, but provide little evidence for sex differences in behavioural response to nicotine. The TDO-anxiety link may be underpinned by kynurenine metabolites as well as serotonin.

Objectives: The mGlu2/3 receptor agonist LY379268 reduces sucrose-seeking, but not sucrose-taking, in male rats. This study explored the generality of this effect across the sexes. In addition, the effect of the drug on motivation to receive sucrose was assessed.

Methods: Adult male and female Long-Evans rats ( N  = 91) were challenged with LY379268 in three experiments: (1) a fixed ratio (FR) schedule of reinforcement (taking), (2) extinction of responding previously reinforced on the FR (seeking) or (3) responding reinforced on a progressive ratio (PR) schedule of reinforcement (motivation). For each experiment, rats first responded to 10% liquid sucrose on an FR in 10 daily 2-h sessions. For the PR study, this was followed by training on a PR for 7 daily 3-h sessions. Rats were then challenged in a counterbalanced order with LY379268 (0, 1.5, 3 and 6 mg/kg; IP; 30-min pretreatment) on test days, followed by either three reacquisition days of FR (experiments 1 and 2) or PR (experiment 3) responding.

Results: Female rats responded more to sucrose on the FR and PR. LY379268 reduced responding in all three experiments. LY379268 challenge to sucrose taking on the FR produced an inverted U-shaped function while extinction responding and responding for sucrose on the PR were decreased dose-dependently, with PR responding insensitive to the 1.5 mg/kg dose. There were no sex-dependent effects of the drug on sucrose-directed responding.

Conclusions: The sucrose anti-taking, -seeking, and -motivation effects of LY379268 across male and female rats support further evaluation of glutamate modulation as an antiaddiction pharmacotherapy.