Behavioural Pharmacology最新文献

Autism spectrum disorder (ASD) describes a heterogeneous group of neurodevelopmental conditions characterized by deficits in social communication and repetitive behaviors. Aripiprazole (APZ) is an atypical antipsychotic that can safeguard mice against autism-like behavior induced by valproic acid (VPA). In the present study, we examined the effects of maternal treatment with APZ (10 mg/kg) in juvenile mice prenatally exposed to VPA on neurodevelopmental behaviors, social interactions, communication, and working memory, as well as synaptophysin (SYP), synaptosomal-associated protein, 25 kDa (SNAP-25) and microtubule-associated protein 2 (MAP-2) expression in the medial prefrontal cortex (mPFC) and cell viability in the hippocampus. In addition, to evaluate possible APZ interference with the anticonvulsant properties of VPA on pentylenetetrazole (PTZ)-induced seizures were evaluated. Maternal treatment with APZ significantly prevented body weight loss, self-righting, eye-opening, social interactions, social communication, and working memory deficits in mice prenatally exposed to VPA. Additionally, the decrease in the SYP, SNAP-25, and MAP-2 expressions in the mPFC and cell death in the hippocampus was prevented by APZ. Furthermore, APZ (10 mg/kg) did not interfere with the anticonvulsant effect of VPA (15 mg/kg) in animals with PTZ-induced seizures. These findings indicate that maternal treatment with APZ in pregnant mice exposed to VPA protects animals against the ASD-like behavioral phenotype, and this effect may be related, at least in part, to synaptic plasticity and neuronal protection in the PFC and hippocampus. APZ may serve as an effective pharmacological therapeutic target against autistic behaviors in the VPA animal model of ASD, which should be further investigated to verify its clinical relevance.

Opioid withdrawal significantly impacts drug dependence cycles as hyperalgesia associated with withdrawal is often a reason for continued drug use. Animal models of addiction are important tools for studying how drug dependence and withdrawal impact not only normal neurocircuitry but also the effectiveness of potential treatments for dependence and withdrawal. We conducted a study of the time course of spontaneous morphine withdrawal in outbred male and female mice that can be used to examine sex differences in male and female mice using both traditional somatic endpoints and mechanical hyperalgesia as an endpoint of withdrawal. Male and female national institute of health (NIH) Swiss mice were made dependent upon morphine using an escalating dosing schedule. Injections were stopped after 5 days. Withdrawal behavior was assessed at time intervals up to 106 h after the final injection. Numbers of forepaw tremors, wet-dog shakes, jumps and other behaviors were scored to create a global score. Paw pressure readings were then also taken to track changes in sensitivity to a painful stimulus over time. Male and female mice had approximately similar withdrawal severity peaking at 24 h after the final injection as measured by composite global scores. Females did exhibit an earlier and greater frequency of tremors than males. Although males and females showed similar hyperalgesia during withdrawal, females recovered faster. Spontaneous opioid withdrawal peaking at 24 h was demonstrated in male and female NIH Swiss mice. We also successfully demonstrated that hyperalgesia is an endpoint that varies over the course of withdrawal.

Attention-deficit/hyperactivity disorder (ADHD), a common behavioral disorder in children and young adults, is characterized by symptoms of impulsivity, inattention, and hyperactivity. The purpose of this study was to evaluate the Lewis rat strain as a model of ADHD by testing their impulsive choices. Lewis rats were compared to their source strain, the Wistar rat, on an impulsive choice task. Rats completed the tasks on and off methylphenidate, a commonly prescribed medication for ADHD. Off methylphenidate, Lewis rats made more impulsive choices than Wistar rats. Analyses of acquisition of choice behavior suggested that both strains were able to discriminate reward sizes, but Lewis rats still chose the smaller-sooner option more than the larger-later (LL) option when the delays to reward were the same. This may be due to an aversion to the LL lever, which was associated with the longest delays to reward. Higher doses of methylphenidate increased LL choices in Lewis rats but decreased LL choices in Wistar rats. Altogether, these results suggest Lewis rats may be a viable model for ADHD in individuals whose symptoms are characterized by impulsive choices.

Schizophrenia is a serious neuropsychiatric disorder characterized by the presence of positive symptoms (hallucinations, delusions, and disorganization of thought and language), negative symptoms (abulia, alogia, and affective flattening), and cognitive impairment (attention deficit, impaired declarative memory, and deficits in social cognition). Dopaminergic hyperactivity seems to explain the positive symptoms, but it does not completely clarify the appearance of negative and cognitive clinical manifestations. Preclinical data have demonstrated that acute and subchronic treatment with NMDA receptor antagonists such as ketamine (KET) represents a useful model that resembles the schizophrenia symptomatology, including cognitive impairment. This latter has been explained as a hypofunction of NMDA receptors located on the GABA parvalbumin-positive interneurons (near to the cortical pyramidal cells), thus generating an imbalance between the inhibitory and excitatory activity in the corticomesolimbic circuits. The use of behavioral models to explore alterations in different domains of memory is vital to learn more about the neurobiological changes that underlie schizophrenia. Thus, to better understand the neurophysiological mechanisms involved in cognitive impairment related to schizophrenia, the purpose of this review is to analyze the most recent findings regarding the effect of KET administration on these processes.

2,5-dimethoxy-4-methylamphetamine (DOM) is a kind of hallucinogen of phenylalkylamine. Psychedelic effects mainly include audiovisual synesthesia, complex imagery, disembodiment etc. that can impair control and cognition leading to adverse consequences such as suicide. By now, there are no specific drugs regarding the management of classic hallucinogen use clinically. We evaluated the effects of three 5-HT 2A receptor antagonists ketanseirn, M100907 and olanzapine on hallucination-like behavior in therapeutic and preventive administration with male C57BL/6J mice. Two models were used to evaluate the therapeutic potential of antagonists, one is head-twitch response (HTR) and the other is locomotion. Effects of ketanserin, M100907 and olanzapine on DOM-induced HTR were studied in preventive and therapeutic administration, respectively. In the preventive administration, the ID 50 values of ketanseirn, M100907 and olanzapine were 0.4 mg/kg, 0.005 mg/kg and 0.25 mg/kg. In the therapeutic administration, the ID 50 values of ketanseirn, M100907 and olanzapine were 0.04 mg/kg, 0.005 mg/kg and 0.03 mg/kg. Secondly, locomotor activity induced by DOM was performed to further evaluate the efficacy of three compounds. In locomotion, M100907(0.005 mg/kg) whenever in preventive or therapeutic administration, reduced the increase of movement distance induced by DOM. Although ketanserin (0.4 mg/kg) in the preventive administration also decreased the movement distance induced by DOM, it was alone administrated to influence the locomotor activity. Through HTR and locomotion, we compared the efficacy and latent side effects of ketanserin, M100907 and olanzapine against hallucinogenic like action induced by DOM. Our study provided additional experimental evidence on specific therapeutic drugs against hallucinogenic behavior induce by representative hallucinogen DOM.

Naringin (Nr) has been identified to have antidepressant-like effects through repeated treatment. However, the underlying mechanism of the rapid antidepressant-like effects of Nr was still unclear. The present study used behavioral tests, classic depressive model and pharmacological methods to reveal the rapid antidepressant-like potential of Nr. We found that a single dose of Nr (20 mg/kg) produced antidepressant-like action after 2 h in the tail suspension test (TST) and forced swimming test (FST). Moreover, ketamine-like effects were also demonstrated by using the chronic mild stress model (CMS) and learned helplessness (LH), and the results showed that Nr reversed all behavioral defects, TST, FST, source preference test (SPT) in CMS, and LH testing, TST, FST in LH model, at 2 h after a single administration. In addition, Nr (20 mg/kg) could improve the abnormal expressions of NMDA receptor NR1 and PKA/CREB/BDNF pathway in hippocampus 2 h after a single administration in CMS mice. Further investigation revealed that activation of NMDA receptors by NMDA (750 mg/kg) could block the antidepressant effects of acute administration of Nr (20 mg/kg). However, the inhibition of NMDA receptors by MK-801 (0.05 mg/kg) promoted the subdose of Nr (10 mg/kg) to have antidepressant effect, which was similar to the effective dose Nr (20 mg/kg). Taken together, acute dose of Nr produces rapid antidepressant-like action, and the underlying mechanism could be through inhibiting NMDA receptors in the hippocampus.

Mitragynine (MG) is a pharmacologically active alkaloid derived from the leaves of Mitragyna speciosa Korth (Kratom). This plant has sparked significant interest as a potential alternative treatment for managing opioid dependence and withdrawal due to its opioid-like pharmacological effects. However, whether MG exposure would trigger opioid-seeking behaviour following abstinence has not been investigated. The present study examined the effects of MG priming on morphine-seeking behaviour in rats. Male Sprague-Dawley rats were initially trained to intravenously self-administer morphine (0.5 mg/kg/infusion) under a fixed ratio-3 schedule of reinforcement. Removal of both morphine infusions and drug-associated cues led to the subsequent extinction of the drug-seeking behaviour. Tests of reinstatement were made following exposure to a randomised order of intraperitoneal injections of MG (3, 10 and 30 mg/kg), morphine (5 mg/kg) and vehicle. Significant levels of drug-seeking behaviour were observed following extended access to morphine self-administration, which was extinguished following removal of morphine and cues indicative of morphine-seeking behaviour, supporting the relapse model. The present finding demonstrated that MG priming in a dose of 10 mg/kg resulted in the reinstatement of morphine-seeking behaviour, whereas the higher MG dose (30 mg/kg) tested suppressed the seeking response. This study indicated that exposure to a low MG dose may increase the likelihood of relapsing to opioids, suggesting that the potential of MG as a treatment for opioid management merits further scientific assessment of its ability to trigger relapse to opioid abuse.

On the basis of our previous research, miR-124 and autophagy have been shown to be associated with depression and antidepressant treatment, respectively. However, whether miR-124 is involved in depressive-like behavior and antidepressant efficacy through regulating autophagy remains poorly understood. The chronic unpredictable mild stress (CUMS) depression model in mice was established, and then intraperitoneal fluoxetine injections (10 mg/kg) were administered for a duration of 4 weeks. The behavioral changes induced by CUMS were evaluated by the tail suspension test, open field test, sucrose preference test, and elevated plus maze test. Quantitative real-time PCR was used to detect expression levels of miR-124 and its three precursor genes in hippocampus of mice. Western blotting was used to detect the expressions of Ezh2 and autophagy proteins (P62, Atg3, Atg7, LC3-I, and LC3- II) in hippocampus of mice. Depression-like behaviors were successfully induced in CUMS models and reversed by SSRI treatments. The expression levels of miR-124 and its precursor gene ( miR-124-3 ) were significantly increased in the hippocampus of CUMS mice, while the expression levels were significantly decreased after 4 weeks of fluoxetine treatment. The mRNA and protein expressions of Ezh2, a validated target of miR-124, were decreased in the hippocampus of CUMS mice, and the fluoxetine treatment could reverse the expressions. A correlation analysis suggested that miR-124 had a significant negative correlation with Ezh2 mRNA expression. The protein levels of LC3-II/I, P62, and Atg7, which were found to be regulated by Ezh2, were increased in the hippocampus of CUMS mice and decreased after fluoxetine treatment. We speculated that autophagy was enhanced in the CUMS model of depression and might be mediated by miR-124 targeting Ezh2.

Dopaminergic and glucocorticoid activity has been associated with reduced food consumption; however, their possible synergic action has not yet been studied. With the aim of examining the effect of the co-administration of the dopamine receptor D2 agonist bromocriptine and corticosterone on palatable food intake, male Wistar rats were administered either bromocriptine (1 mg/kg), corticosterone (2 mg/kg), bromocriptine + corticosterone (1 mg + 2 mg/kg) or a vehicle, with a fifth group used as a control. In all cases, substances were administered 30 min before exposure to standard food or palatable food, the latter high in carbohydrates [high carbohydrate food (HCF), 75%] or high-fat food (HFF, 67%). Food consumption and body weight were recorded daily. Results showed higher consumption of standard food but lower consumption of HCF and HFF in the groups that received bromocriptine, alone or in combination. In general, lower total kcal intake was observed in the bromocriptine and bromocriptine + corticosterone groups during the period of pharmacological treatment and following re-exposure to palatable food. The low HFF intake in the bromocriptine + corticosterone group persisted 10 days after the pharmacological treatment was interrupted. This effect suggests plastic changes in either the mechanisms involved in the incentive value of palatable food - particularly foods with high-fat content - or those that regulate lipid metabolism. Our findings suggest that homeostatic and reward mechanisms could be influenced by the co-participation of the dopaminergic and hypothalamic-pituitary-adrenal systems, and the macronutrient content of food.