Behavioural Pharmacology最新文献

Commodity purchase tasks provide a useful method for evaluating behavioral economic demand in the human laboratory. Recent research has shown how responding to purchase tasks for blinded drug administration can be used to study abuse liability. This analysis uses data from a human laboratory study to highlight how similar procedures may be particularly useful for understanding momentary changes in drug valuation when screening novel interventions. Eight nontreatment-seeking participants with cocaine use disorder (one with partial data) were enrolled in a cross-over, double-blind, randomized inpatient study. Participants were maintained on the Food and Drug Administration-approved insomnia medication suvorexant (oral; 0, 5, 10, 20 mg/day) in randomized order with experimental sessions completed after at least 3 days of maintenance on each suvorexant dose. Experimental sessions included administration of a sample dose of 0, 10 and 30 mg/70 kg intravenous cocaine. Analyses focused on purchase tasks for the blinded sample dose as well as alcohol, cigarettes and chocolate completed 15 min after the sample dose. As expected based on abuse liability, near zero demand was observed for placebo with dose-related increases in cocaine demand. Suvorexant maintenance increased cocaine demand in a dose-related manner with the greatest increase observed for the 10 mg/kg cocaine dose. Increased demand under suvorexant maintenance was also observed for alcohol. No effect of cocaine administration was observed for alcohol, cigarette, or chocolate demand. These data support the validity of demand procedures for measuring blinded drug demand. Findings also parallel self-administration data from this study by showing increases in cocaine use motivation under suvorexant maintenance.

Temozolomide is used commonly in the treatment of some types of cancers, but it may also result in cognitive impairments such as memory deficits. l -Dopa, a well known medicine for the central nervous system, has been shown to have positive effects on some cognitive disorders. Here we sought to investigate the effect of l -Dopa on temozolomide-induced cognitive impairments. BALB/c mice were subjected to 3-days temozolomide and 6-days concomitant l -Dopa/benserazide administration in six groups (control, l -Dopa 25 mg/kg, l -Dopa 75 mg/kg, temozolomide, temozolomide +  l -Dopa 25 mg/kg, and temozolomide +  l -Dopa 75 mg/kg). Open field test, object location recognition, novel object recognition test, and shuttle-box test were carried out to determine the locomotor, anxiety-like behavior, and memory function of subjects. TNF-α and brain-derived neurotrophic factor (BDNF) gene expression in the hippocampus was measured by real-time PCR. Mice treated with temozolomide showed recognition memory impairment, along with hippocampal TNF-α and BDNF mRNA expression level raise, and detection of histological insults in hematoxylin and eosin hippocampal slides. Mice that received temozolomide +  l -Dopa showed normal behavioral function and lower TNF-α and BDNF hippocampal mRNA expression levels, and histologically normal hippocampal CA1 region in comparison with mice in the temozolomide group. Our results provide evidence that l -Dopa prevents temozolomide-induced recognition memory deficit in mice at the acute phase probably via l -Dopa antineuroinflammatory effects.

The growing usage of aluminum nanoparticles (Al-NP) and their exposure may influence body function. Considering the proposed relationship between Al and the pathogenesis of Alzheimer's disease and the concern about the effect of this nanoparticle on brain health and cognitive function, the use of neuroprotective agents might be helpful. According to the reported neuroprotective effects of agmatine, in the present study, the possible protective effect of agmatine was assessed in mice model of Al-NP-induced memory impairment. In addition, due to the roles of hippocampal Glycogen synthase kinase-3 beta (GSK-3β) and ERK signaling in memory and its disorders, these pathways were also investigated. Al-NP (10 mg/kg/p.o.) with/without agmatine (5 or 10 mg/kg/i.p.) was administered to adult male NMRI mice for 5 days. Novel object recognition (NOR) test session was used to assess cognitive function. Following the behavioral assessments, the hippocampi were used to determine the phosphorylated and total levels of GSK-3β and ERK as well as GAPDH using western blot analysis. The results showed that Al-NP impaired NOR memory in mice while agmatine 10 mg/kg prevented the memory deficit induced by Al-NP. Furthermore, Al-NP activated GSK-3β as well as ERK signals within the hippocampus while agmatine prevented the effects of Al-NP on GSK-3β and ERK signals within the hippocampus. Besides supporting the neuroprotective effects of agmatine, these findings suggest the possibility of the connection of hippocampal GSK-3β and ERK signaling in the neuroprotective effect of this polyamine against Al-NP.

Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in social communication and repetitive behavior. Many studies show that the number of cognitive impairmentscan be reduced by antagonists of the histamine H3 receptor (H3R). In this study, the effects of ciproxifan (CPX) (1 and 3 mg/kg, intraperitoneally) on cognitive impairments in rat pups exposed to valproic acid (VPA) (600 mg/kg, intraperitoneally) wereexamined on postnatal day 48-50 (PND 48-50) using marble-burying task (MBT), open field, novel object recognition (NOR), and Passive avoidance tasks. Famotidine (FAM) (10, 20, and 40 mg/kg, intraperitoneally) was also used to determine whether histaminergic neurotransmission exerts its procognitive effects via H2 receptors (H2Rs). Furthermore, a histological investigation was conducted to assess the degree of degeneration of hippocampal neurons. The results revealed that repetitive behaviors increased in VPA-exposed rat offspring in the MBT. In addition, VPA-exposed rat offspring exhibited more anxiety-like behaviors in the open field than saline-treated rats. It was found that VPA-exposed rat offspring showed memory deficits in NOR and Passive avoidance tasks. Our results indicated that 3 mg/kg CPX improved cognitive impairments induced by VPA, while 20 mg/kg FAM attenuated them. We concluded that 3 mg/kg CPX improved VPA-induced cognitive impairments through H3Rs. The histological assessment showed that the number of CA1 neurons decreased in the VPA-exposed rat offspring compared to the saline-exposed rat offspring, but this decrease was not significant. The histological assessment also revealed no significant differences in CA1 neurons in VPA-exposed rat offspring compared to saline-exposed rat offspring. However, CPX3 increased the number of CA1 neurons in the VPA + CPX3 group compared to the VPA + Saline group, but this increase was not significant. This study showed that rats prenatally exposed to VPA exhibit cognitive impairments in the MBT, open field, NOR, and Passive avoidance tests, which are ameliorated by CPX treatment on PND 48-50. In addition, morphological investigations showed that VPA treatment did not lead to neuronal degeneration in the CA1 subfield of the hippocampus in rat pups.

Cannabidiol is a phytocannabinoid that lacks the psychotomimetic properties of Δ9-tetrahydrocannabinol (THC), the main psychoactive Cannabis sativa component. Cannabidiol has several potential therapeutic properties, including anxiolytic, antidepressant, and antipsychotic; however, cannabidiol has low oral bioavailability, which can limit its clinical use. Here, we investigated if two cannabidiol analogs, HU-502 and HU-556, would be more potent than cannabidiol in behavioral tests predictive of anxiolytic, antidepressant, and antipsychotic effects. Different doses (0.01-3 mg/kg; intraperitoneally) of HU-556 and HU-502 were tested in male Swiss mice submitted to the elevated plus maze (EPM), forced swimming test (FST), and amphetamine-induced-prepulse inhibition (PPI) disruption and hyperlocomotion. Cannabidiol is effective in these tests at a dose range of 15-60 mg/kg in mice. We also investigated if higher doses of HU-556 (3 and 10 mg/kg) and HU-502 (10 mg/kg) produced the cannabinoid tetrad (hypolocomotion, catalepsy, hypothermia, and analgesia), which is induced by THC-like compounds. HU-556 (0.1 and 1 mg/kg) increased the percentage of open arm entries (but not time) in the EPM, decreased immobility time in the FST, and attenuated amphetamine-induced PPI disruption. HU-502 (1 and 3 mg/kg) decreased amphetamine-induced hyperlocomotion and PPI impairment. HU-556, at high doses, caused catalepsy and hypolocomotion, while HU-502 did not. These findings suggest that similar to cannabidiol, HU-556 could induce anxiolytic, antidepressant, and antipsychotic-like effects and that HU-502 has antipsychotic properties. These effects were found at a dose range devoid of cannabinoid tetrad effects.

Although ethanol administration produces a range of physiological effects, the rewarding aspect associated with its consumption is a major contributory factor to its abuse liability. Recently, lateral habenula (LHb) has been shown to be engaged by both rewarding and aversive stimuli. Its major glutamatergic output, the fasciculus retroflexus, projects to the rostromedial tegmental nucleus (RMTg) and controls the activity of the ventral tegmental area (VTA) dopaminergic system to promote reward circuitry. While several attempts have been made to understand the relationship between LHb and addiction, there is still a lack of knowledge in relation to ethanol addiction. In the present study, by pharmacologically exacerbating or inhibiting the LHb or RMTg neuronal activity during a post-conditioning test, we investigated the role of LHb-RMTg fasciculus retroflexus in ethanol-induced reward behavior using the conditioned place preference (CPP) test. We found that activation of LHb glutamatergic system by intra-LHb administration of l-trans-2,4-pyrrolidine dicarboxylate (PDC) (glutamate transporter inhibitor) significantly decreased CPP score; on the contrary, lamotrigine (inhibits glutamate release) significantly increased CPP score and showed a rewarding effect in CPP. Instead, intra-RMTg administration of muscimol (GABAA receptor agonist) significantly increased CPP score, whereas bicuculline (GABAA antagonist) treatment decreased CPP score. In immunohistochemistry, we found that PDC administration significantly decreased, whereas lamotrigine treatment significantly increased tyrosine hydroxylase immunoreactivity (TH-ir) in VTA and nucleus accumbens (NAc). Furthermore, while intra-RMTg administration of muscimol increased, the bicuculline treatment significantly decreased the TH-ir in VTA and NAc. Together, our behavioral and immunohistochemical results signify the role of LHb and RMTg in the expression of ethanol-conditioned reward behavior.

Posttraumatic stress disorder (PTSD) is a serious neuropsychiatric disorder that occurs after exposure to stressful, fearful, or troubling events. Cerebrolysin (CBL), consists of low molecular weights neurotrophic factors and amino acids obtained from purified porcine brain proteins. This study aimed to evaluate the possible therapeutic effects of enriched environment (EE) and CBL alone or combined for reducing anxiety and cognitive deficits in PTSD-like mouse models. For this purpose, inescapable electric foot shocks were delivered to Balb/c mice for two consecutive days. Then mice were treated with CBL (2.5 mL/kg) and/or were kept in EE (2 h per day) or received their combination for 14 consecutive days. The hole-board test and Lashley III paradigm were used to assess anxiety and spatial learning and memory, respectively. Changes in the serum corticosterone level and expression of synaptic elements, including; growth-associated protein 43, post-synaptic density 95, and synaptophysin were assessed in the hippocampus. This model caused anxiety and spatial memory impairment associated with increased serum corticosterone levels and decreased synaptic elements. Nevertheless, CBL and/or combination treatment could reverse behavioral and molecular alterations. Our findings indicated that CBL, separately or in combination with EE, is effective in reducing anxiety and spatial memory impairment in PTSD-like mice.

Preclinical behavior models used for screening pharmacological treatments for mental disorders have generally used only male research subjects, and for studies that have included female subjects, few have utilized sex as a study variable. In fact, many mental disorders vary by prevalence and symptomatology between sexes, creating a need to evaluate established subject models for sex differences. Compulsive behavior is a feature shared across many mental disorders and effective treatments have been examined pre-clinically using the schedule-induced polydipsia procedure in rats. Drugs effective for reducing polydipsia include psychostimulants, such as d -amphetamine. Virtually no studies have examined sex differences using this procedure. For the present study, male and female rats were examined in the schedule-induced polydipsia paradigm. Rats were food-restricted and trained on a fixed-interval food reinforcement schedule and given free access to water during experimental sessions. Estrous stages were assessed during training and test sessions. The psychostimulant d -amphetamine was also tested once stable water consumption occurred. Excessive water intake developed over the course of training. Females required significantly more sessions to reach a stable level of drinking. Treatment with d -amphetamine (1.0 mg/kg, but not 0.25 or 0.5 mg/kg) significantly reduced drinking in both male and female rats. No sex differences were observed across other study variables including comparisons between diestrus and proestrus stages. Overall, these findings suggest that schedule-induced polydipsia procedures that employ similar methods can produce results generalizable across male and female subjects.

Propranolol is the treatment of choice for infantile hemangioma. We investigated the effects of long-term propranolol use in early infancy on learning and memory later in life in mice. At three weeks of age, mice were randomly divided into six experimental groups. Groups 1 and 2 (controls) received only saline for 21 days. Groups 3 and 4 received propranolol (2.5 mg/kg) for 21 days. Groups 5 and 6 received propranolol (5 mg/kg) for 21 days. Groups 1, 3 and 5 were tested at the end of 21 days of treatment (week 6). However, groups 2, 4 and 6 received a 2-week break and then (week 8) exposed to tests. In the Morris water maze test, propranolol (2.5 and 5 mg/kg) dose-dependently increased the time spent in the target quadrant in mice at weeks 6 and 8. However, propranolol did not affect the swimming speed in both time periods. There were no significant effects of propranolol on the number of errors evaluated during the radial arm maze tests. In conclusion, long-term use of propranolol in early infancy did not disrupt the learning and memory of mice.

Electronic nicotine delivery system (ENDS) use is maintained by the positive reinforcement associated with preferred flavors. These flavors become conditioned reinforcers through pairings with primary reinforcers. This study sought to extend prior research with intravenous nicotine self-administration and develop a more ecologically valid preclinical model of aerosol self-administration in rats that incorporated flavors paired with sucrose. Rats were first trained to respond for oral sucrose with or without raspberry flavor to establish the flavor as a conditioned reinforcer for some groups. Rats were then exposed to aerosol self-administration. All groups responded for raspberry-flavored aerosol with or without nicotine. Rats responded more for raspberry flavored sucrose than unflavored sucrose. Despite raspberry increasing responding for sucrose, the flavor did not function as a conditioned reinforcer during aerosol self-administration and did not increase responding for nicotine. Throughout the aerosol self-administration phase, most groups responded more on the active than inactive lever, and some groups increased their response when the fixed ratio value was increased. At the end of the study, rats in nicotine groups earned similar or fewer aerosol deliveries than rats in vehicle groups. Aerosolized nicotine did not function as a reinforcer in this study, whereas aerosolized raspberry flavor may have maintained self-administration. Further preclinical investigation is needed to articulate the impact of flavors on ENDS use and whether they offset some aversive effects of nicotine or maintain responding on their own. If flavors reduce some aversive effects of self-administered nicotine, then policies to regulate flavors in e-liquids are prudent.