Pharmacology Biochemistry and Behavior最新文献

Adolescent alcohol exposure is associated with lasting behavioral changes in humans and in mice. Prior work from our laboratory and others have demonstrated that C57BL/6J and DBA/2J mice differ in sensitivity to some effects of acute alcohol exposure during adolescence and adulthood. However, it is unknown if these strains differ in cognitive, anxiety-related, and addiction-related long-term consequences of adolescent intermittent alcohol exposure. This study examined the impact of a previously validated adolescent alcohol exposure paradigm (2–3 g/kg, i.p., every other day PND 30–44) in C57BL/6J and DBA/2J male and female mice on adult fear conditioning, anxiety-related behavior (elevated plus maze), and addiction-related phenotypes including nicotine sensitivity (hypothermia and locomotor depression) and alcohol sensitivity (loss of righting reflex; LORR). Both shared and strain-specific long-term consequences of adolescent alcohol exposure were found. Most notably, we found a strain-specific alcohol-induced increase in sensitivity to nicotine's hypothermic effects during adulthood in the DBA/2J strain but not in the C57BL/6J strain. Conversely, both strains demonstrated a robust increased latency to LORR during adulthood after adolescent alcohol exposure. Thus, we observed strain-dependent cross-sensitization to nicotine and strain-independent tolerance to alcohol due to adolescent alcohol exposure. Several strain and sex differences independent of adolescent alcohol treatment were also observed. These include increased sensitivity to nicotine-induced hypothermia in the C57BL/6J strain relative to the DBA/2J strain, in addition to DBA/2J mice showing more anxiety-like behaviors in the elevated plus maze relative to the C57BL/6J strain. Overall, these results suggest that adolescent alcohol exposure results in altered adult sensitivity to nicotine and alcohol with some phenotypes mediated by genetic background.

Increasing evidence indicates that sleep deprivation (SD) can exert multiple negative effects on neuronal circuits, resulting in memory impairment, depression, and anxiety, among other consequences. The long-term effects of SD during early life on behavioral phenotypes in adulthood are still poorly understood. In this study, we investigated the long-lasting effects of SD in adolescence on social behaviors, including empathic ability and social dominance, and the role of the gut microbiota in these processes, using a series of behavioral paradigms in mice combined with 16S rRNA gene pyrosequencing. Behavioral assay results showed that SD in adolescence significantly reduced the frequency of licking, the total time spent licking, and the time spent sniffing during the emotional contagion test in male mice, effects that were not observed in female mice. These findings indicated that SD in adolescence exerts long-term, negative effects on empathic ability in mice and that this effect is sex-dependent. In contrast, SD in adolescence had no significant effect on locomotor activities, social dominance but decreased social interaction in male mice in adulthood. Meanwhile, 16S rRNA gene pyrosequencing results showed that gut microbial richness and diversity were significantly altered in adult male mice subjected to SD in adolescence. Our data provide direct evidence that SD in youth can induce alterations in empathic ability in adult male mice, which may be associated with changes in the gut microbiota. These findings highlight the long-lasting effects of sleep loss in adolescence on social behaviors in adulthood and the role played by the brain–gut axis.

In the search for anxiolytic drugs with fewer adverse effects, calcium blockers were proposed as a benzodiazepines (BZDs) alternative. In this context, the anxiolytic effect of nimodipine has been demonstrated. However, its low bioavailability and solubility could be improved by using nanostructured drug delivery systems such as liposomes. In this way, liposomal formulation containing nimodipine (NMD-Lipo) was developed. The NMD-lipo is a formulation capable of improving the kinetic characteristics of the drug, as well as the anxiolytic effect of nimodipine. In this work, the serotonergic system participation in the anxiolytic mechanism of the liposomal formulation containing nimodipine (NMD-Lipo) was investigated. A possible 5-HT1A receptor mediation on the NMD-Lipo anxiolytic effect was demonstrated by using WAY 100635 (5-HT1A receptor antagonist) since the antagonist reversed the NMD-Lipo anxiolytic effect in the light/dark test and elevated plus maze test. The results demonstrated that the NMD-Lipo administration had anxiolytic activity through 5-HT1A receptors without causing sedation or compromising the motor coordination of the tested animals.

Schizophrenia is a chronic, debilitating mental illness that has not yet been completely understood. In this study, we aimed to investigate the effects of different doses of ketamine, a non-competitive NMDA receptor antagonist, on the positive- and negative-like symptoms of schizophrenia. We also explored whether these effects are related to changes in the immunoreactivity of GAD₆₇, TH, and PPAR-γ in brain structures. To conduct the study, male mice received ketamine (20–40 mg/kg) or its vehicle (0.9 % NaCl) intraperitoneally for 14 consecutive days. We quantified stereotyped behavior, the time of immobility in the forced swimming test (FST), and locomotor activity after 7 or 14 days. In addition, we performed ex vivo analysis of the immunoreactivity of GAD, TH, and PPAR-γ, in brain tissues after 14 days. The results showed that ketamine administration for 14 days increased the grooming time in the nose region at all tested doses. It also increased immobility in the FST at 30 mg/kg doses and decreased the number of rearing cycles during stereotyped behavior at 40 mg/kg. These behavioral effects were not associated with changes in locomotor activity. We did not observe any significant alterations regarding the immunoreactivity of brain proteins. However, we found that GAD and TH were positively correlated with the number of rearing during the stereotyped behavior at doses of 20 and 30 mg/kg ketamine, respectively. GAD was positively correlated with the number of rearing in the open field test at a dose of 20 mg/kg. TH was inversely correlated with immobility time in the FST at a dose of 30 mg/kg. PPAR-γ was inversely correlated with the number of bouts of stereotyped behavior at a dose of 40 mg/kg of ketamine. In conclusion, the behavioral alterations induced by ketamine in positive-like symptoms were reproduced with all doses tested and appear to depend on the modulatory effects of TH, GAD, and PPAR-γ. Conversely, negative-like symptoms were associated with a specific dose of ketamine.

Nicotine is a significant public health concern because it is the primary pharmacological agent in tobacco use disorder. One neural system that has been implicated in the symptoms of several substance use disorders is the melanin-concentrating hormone (MCH) system. MCH regulates various motivated behaviors depending on sex, yet little is known of how this interaction affects experience with drugs of abuse, particularly nicotine. The goal of this study was to determine the effect of MCH receptor antagonism on experience-dependent nicotine-induced locomotion after chronic exposure, particularly on the expression of locomotor sensitization. Adult female and male Wistar rats were given saline then cumulative doses of nicotine (0.1, 0.32, 0.56, and 1.0 mg/kg) intraperitoneally to determine the acute effects of nicotine (day 1). Next, rats were treated with 1.0 mg/kg nicotine for 6 days, given an identical series of cumulative doses (day 8), and then kept in a drug-free state for 6 days. On day 15, rats were pretreated with vehicle or the MCH receptor antagonist GW803430 (10 or 30 mg/kg) before another series of cumulative doses to assess response to chronic nicotine. After vehicle, male rats increased nicotine locomotor activation from day 1 to day 15, and both sexes showed a sensitized response when normalized to saline. The lower dose of GW803430 decreased locomotion compared to vehicle in females, while the higher dose decreased locomotion in males. Both sexes showed nicotine dose-dependent effects of GW803430, strongest at lower doses of nicotine. Controlling for sex-based locomotor differences revealed that females are more sensitive to GW803430. The high dose of GW803430 also decreased saline locomotion in males. Together, the results of our study suggest that MCH is involved in the expression of nicotine locomotor sensitization, and that MCH regulates these nicotine behavioral symptoms differently across sex.

Anxiety disorders, characterized by high prevalence rates, cause psychiatric disabilities and are related to impairments in serotoninergic system function. Frequent anxiety recurrence, resistance, and drug adverse effects have driven searches for new therapies. We initially evaluated the anxiolytic-like activity of 3-selanyl-benzo[b]furan compounds (SeBZF1–5) (50 mg/kg, i.g.) in male Swiss mice using the light-dark test (LDT). The compound 3-((4-methoxyphenyl)selanyl)-2-phenylbenzofuran (SeBZF3) exhibited anxiolytic-like activity. SeBZF3 anxiolytic-like effects were also observed in the novelty-suppressed feeding test (NSFT) (50 mg/kg) and elevated plus-maze test (EPMT) (25 and 50 mg/kg). In the EPMT, anxiolytic-like effects of SeBZF3 (50 mg/kg) were abolished by pretreatment with p-chlorophenylalanine, a selective tryptophan hydroxylase inhibitor (100 mg/kg, i.p. for 4 days), suggesting the involvement of serotonergic mechanisms. Furthermore, we conducted experiments to investigate the synergistic effects of SeBZF3 subeffective doses (5 mg/kg, i.g.) in combination with fluoxetine (a selective serotonin reuptake inhibitor, 5 mg/kg, i.p.) or buspirone (a partial agonist of the 5-HT_1A receptor, 2 mg/kg, i.p.). This coadministration resulted in pronounced synergistic effects. We also examined the effects of repeated oral treatment with SeBZF3 at doses of 1 and 5 mg/kg over 14 days and both reduced anxiety signals. In vitro and ex vivo findings revealed that SeBZF3 inhibited cerebral MAO-A activity. These findings collectively imply the potential involvement of serotonergic mechanisms in the anxiolytic-like activity of SeBZF3 in mice. These data offer contributions to the research field of organoselenium compounds and anxiolytics, encouraging the broadening of the search for new effective drugs while offering improved side effect profiles.

Fatty acid binding protein 5 (FABP5) interacts with the endocannabinoid system in the brain via intracellular transport of anandamide, as well as Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis. Previous work has established the behavioral effects of genetic deletion of FABP5, but not in the presence of THC. The present study sought to further elucidate the role of FABP5 on the pharmacokinetic and behavioral response to THC through global deletion. Adult FABP5^+/+ and FABP5^−/− mice were tested for behavioral response to THC using Open Field (OF), Novel Object Recognition (NOR), T-Maze, Morris Water Maze (MWM), and Elevated Plus Maze (EPM). An additional cohort of mice was used to harvest blood, brains, and liver samples to measure THC and metabolites after acute administration of THC. Behavioral tests showed that some cognitive deficits from FABP5 deletion, particularly in MWM, were blocked by THC administration, while this was not observed in other measures of memory and anxiety (such as T-Maze and EPM). Measurement of THC and metabolites in blood serum and brain tissue through UPLC-MS/MS analysis showed that the pharmacokinetics of THC was altered by FABP5. The present study shows further evidence of the importance of FABP5 in cognitive function. Additionally, results showed that FABP5 is an important regulator of the physiological effects and pharmacokinetics of THC.

Research suggests that certain gut and dietary factors may worsen behavioral features of autism spectrum disorder (ASD). Treatment with propionic acid (PPA) has been found to create both brain and behavioral responses in rats that are characteristic of ASD in humans. A consistent male bias in human ASD prevalence has been observed, and several sex-differential genetic and hormonal factors have been suggested to contribute to this bias. The majority of PPA studies in relation to ASD focus on male subjects; research examining the effects of PPA in females is scarce. The present study includes two experiments. Experiment 1 explored sex differences in the effects of systemic administration of PPA (500 mg/kg, ip) on adult rodent social behavior and anxiety (light-dark test). Experiment 2 investigated differential effects of systemic administration of PPA (500 mg/kg) on social behavior and anxiety in relation to fluctuating estrogen and progesterone levels during the adult rodent estrous cycle. PPA treatment impaired social behavior and increased anxiety in females to the same degree in comparison to PPA-treated males. As well, females treated with PPA in their diestrus phase did not differ significantly in comparison to females administered PPA in their proestrus phase, in terms of reduced social behavior and increased anxiety.

Early life adversity in the form of poor postnatal care is a major developmental stressor impacting behavior later in life. Previous studies have shown the impact of early life stress on neurobehavioral abnormalities. Specifically, research has demonstrated how limited bedding and nesting (LBN) materials can cause behavioral deficits in adulthood. There is, however, a limited understanding of how LBN influences sex-specific neurobehavioral adaptation in adolescence, a developmental stage susceptible to psychiatric diseases including substance use disorder. LBN and stress-naive c57BL/6 adolescent male and female mouse offspring were tested for a battery of behaviors including open field, novel object recognition, elevated plus maze, social preference, and morphine-induced conditioned place preference. There was a significant sex-specific deficit in social preference in male mice exposed to LBN compared to stress-naïve counterparts and both LBN males and females had a higher preference towards the drug-paired chamber in the morphine-induced conditioned place preference test. These behavioral deficits were concomitant with sex-specific increases in the transcription factor, Klf9 in the deep cerebellar nuclei (DCN) of males. Further, mRNA levels of the circadian gene Bmal1, which is known to be transcriptionally regulated by Klf9, were decreased in the DCN. Since Bmal1 has recently been implicated in extracellular matrix modulation, we examined perineuronal nets (PNN) and observed depleted PNN in the DCN of males but not female LBN mice. Overall, we provide a novel understanding of how postpartum adversity impinges on the cerebellar extracellular matrix homeostasis, likely, through disruption of the circadian axis by Klf9 that might underlie sex-specific behavioral adaptations in adolescence.