Role of preexisting inhibitory control deficits vs. drug use history in mediating insensitivity to aversive consequences in a rat model of polysubstance use.

RATIONALE: The nature and predictors of insensitivity to aversive consequences of heroin + cocaine polysubstance use are not well characterized. OBJECTIVES: Translational methods incorporating a tightly controlled animal model of drug self-administration and measures of inhibitory control and avoidance behavior might be helpful for clarifying this issue. METHODS: The key approach for distinguishing potential contributions of pre-existing inhibitory control deficits vs. drug use history in meditating insensitivity to aversive consequences was comparison of two rat strains: Wistar (WIS/Crl), an outbred strain, and the spontaneously hypertensive rat (SHR/NCrl), an inbred strain shown previously to exhibit heightened cocaine and heroin self-administration and poor inhibitory control relative to WIS/Crl. RESULTS: In separate tasks, SHR/NCrl displayed greater impulsive action and compulsive-like behavior than WIS/Crl prior to drug exposure. Under two different schedules of drug delivery, SHR/NCrl self-administered more cocaine than WIS/Crl, but self-administered a similar amount of heroin + cocaine as WIS/Crl. When half the session cycles were punished by random foot shock, SHR/NCrl initially were less sensitive to punishment than WIS/Crl when self-administering cocaine, but were similarly insensitive to punishment when self-administering heroin + cocaine. Based on correlation analyses, only trait impulsivity predicted avoidance capacity in rats self-administering cocaine and receiving yoked-saline. In contrast, only amount of drug use predicted avoidance capacity in rats self-administering heroin + cocaine. Additionally, baseline drug seeking and taking predicted punishment insensitivity in rats self-administering cocaine or heroin + cocaine. CONCLUSIONS: Based on the findings revealed in this animal model, human laboratory research concerning the nature and predictors of insensitivity to aversive consequences in heroin and cocaine polysubstance vs. monosubstance users is warranted.

An Actn3 knockout mouse provides mechanistic insights into the association between alpha-actinin-3 deficiency and human athletic performance.

A common nonsense polymorphism (R577X) in the ACTN3 gene results in complete deficiency of the fast skeletal muscle fiber protein alpha-actinin-3 in an estimated one billion humans worldwide. The XX null genotype is under-represented in elite sprint athletes, associated with reduced muscle strength and sprint performance in non-athletes, and is over-represented in endurance athletes, suggesting that alpha-actinin-3 deficiency increases muscle endurance at the cost of power generation. Here we report that muscle from Actn3 knockout mice displays reduced force generation, consistent with results from human association studies. Detailed analysis of knockout mouse muscle reveals reduced fast fiber diameter, increased activity of multiple enzymes in the aerobic metabolic pathway, altered contractile properties, and enhanced recovery from fatigue, suggesting a shift in the properties of fast fibers towards those characteristic of slow fibers. These findings provide the first mechanistic explanation for the reported associations between R577X and human athletic performance and muscle function.

Ovarian hormones control the changing expression of claudins and occludin in rat uterine epithelial cells during early pregnancy.

Regulation of the uterine luminal environment is important for successful attachment and implantation of the blastocyst. The contents and volume of luminal fluid are regulated in part by the tight junctions. Using immunofluorescence microscopy, protein and RNA analysis, the cellular distributions of tight junction components claudins and occludin were observed during early pregnancy and under various hormonal regimens. Results indicate that occludin and claudin-4 distribution changed during early pregnancy and in response to ovarian hormones. At the time of implantation and in response to progesterone administration to ovariectomised rats, occludin and claudin-4 showed increased immunolabelling in luminal epithelium. Interestingly, occludin protein detection in uterine luminal epithelial cells at the time of implantation was statistically significantly decreased at the time of implantation compared to day 1 of pregnancy. This suggests that a cytoplasmic pool of occludin is present at day 1 of pregnancy and is redistributed to the tight junctions at the time of implantation. The presence of occludin and claudin-4 in the tight junctions at the time of implantation and in response to progesterone suggests that the paracellular pathway is impermeable to water and Na(+) at this time, and that the transport of such substances takes place via the transcellular pathway.