Pharmacology Biochemistry and Behavior最新文献

Background

Methods

Results

Conclusion

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.

Food restriction augments drug seeking in abstinent rats. The underlying motivational mechanisms, however, remain unclear. We hypothesized that caloric restriction enhances the incentive value attributed to drug-associated cues and, in turn, augments drug seeking. Male rats were trained to lever-press for heroin, and then moved to the animal colony for a forced-abstinence period. Rats were maintained on free access to food (Sated) or subjected to 14 days of food restriction (FDR). In a series of experiments, we assessed the effect of food-restriction on the incentive value of heroin-associated cues. Tests included performance under a progressive ratio (PR) schedule of reinforcement maintained by heroin-associated cues, acquisition of a novel operant response reinforced by drug-associated cues, effect of food-restriction on operant response reinforced by neutral cues, acquisition of a novel operant response reinforced by drug-associated or neutral cues, and the effect of food-restriction on operant response reinforced by drug-associated or neutral cues, under a discrete choice procedure.

Food-restriction did not change breakpoints in PR maintained by heroin-associated cues. FDR rats acquired the novel response at a greater level compared to the Sated group. Food-restriction-induced increase in novel-response rate was observed for both heroin-paired and the neutral cue. Responding for a heroin-associated cue was greater than for the neutral cue in both Sated and FDR groups. Response rate for the neutral cue, however, was greater in the FDR versus Sated group.

Our findings suggest that food restriction increases the conditioned motivational properties of environmental stimuli, including, but not exclusive to, heroin-paired cues.

Introduction

Early adversity, impulsivity and sex all contribute to the risk of developing substance use disorder. Using rats, we examined how juvenile stress interacts with sex and cocaine to affect performance on a serial reversal task and a differential reinforcement of low rates 10 s (DRL10) task. The expression of dopamine-related proteins in several brain areas was also assessed.

Methods

From postnatal days (PND) 25–29, rats were exposed to a variable stress protocol. In adulthood, rats were trained on the reversal task and the effects of cocaine (0, 10, or 20 mg/kg, IP) on performance were assessed. Next, rats were trained on the DRL10 task and the effects of cocaine on performance were assessed. Finally, brains were extracted, and Western blot analyses conducted.

Results

Juvenile stress did not affect behavior. Sex did not affect baseline performance in either task. In the reversal task, cocaine decreased % high probability responses and the number of rewards earned in both sexes. Cocaine had sex-dependent effects on omissions, low probability responses and response latencies. In the DRL10 task, cocaine decreased the peak latency to respond and the number of rewards earned in both sexes. Cocaine had sex-dependent effects on peak rate of responding, response efficiency, burst responses and long responses. Female rats exhibited increased expression of DRD1 receptors in the striatum.

Discussion

These data contribute to the growing literature demonstrating sex differences in the behavioral effects of cocaine and suggest that DRD1 receptors could contribute to the observed behavioral sex differences.