The Effects of Bisphenol A Exposure at Different Developmental Time Points in an Androgen-Sensitive Neuromuscular System in Male Rats.

The industrial plasticizer bisphenol A (BPA) is a ubiquitous endocrine disruptor to which the general human population is routinely exposed. Although BPA is well known as an estrogenic mimic, there have been some suggestions that this compound may also alter activity at the androgen receptor. To determine whether BPA does have antiandrogenic properties, we evaluated BPA effects in the spinal nucleus of the bulbocavernosus and dorsolateral nucleus, sexually dimorphic groups of motor neurons in the lumbar spinal cord that are critically dependent on androgens for survival and maintenance, as well as the monomorphic retrodorsolateral nucleus. In experiment 1, we administered varying concentrations of BPA to juvenile rats pre- and postnatally and examined both the number and size of motor neurons in adulthood. In experiment 2, different doses of BPA were given to adult rats for 28 days, after which the soma size of motor neurons were measured. Although no effect of BPA on neural survival or soma size was noted after perinatal BPA exposure, BPA exposure did result in a decrease in soma size in all motor neuron pools after chronic exposure in adulthood. These findings are discussed with regard to putative antiandrogenic effects of BPA; we argue that BPA is not antiandrogenic but is acting through nonandrogen receptor-dependent mechanisms.

Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice.

BACKGROUND: Amyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer's disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification of nuclear and cytoplasmic proteins slows neurodegeneration and blocks the formation of NFTs in a tauopathy mouse model. It remains unknown, however, if O-GlcNAc can influence the formation of amyloid plaques in the presence of tau pathology. RESULTS: We treated double transgenic TAPP mice, which express both mutant human tau and amyloid precursor protein (APP), with a highly selective orally bioavailable inhibitor of the enzyme responsible for removing O-GlcNAc (OGA) to increase O-GlcNAc in the brain. We find that increased O-GlcNAc levels block cognitive decline in the TAPP mice and this effect parallels decreased ß-amyloid peptide levels and decreased levels of amyloid plaques. CONCLUSIONS: This study indicates that increased O-GlcNAc can influence ß-amyloid pathology in the presence of tau pathology. The findings provide good support for OGA as a promising therapeutic target to alter disease progression in Alzheimer disease.

Discounting of money and sex: effects of commodity and temporal position in stimulant-dependent men and women.

Research on delay discounting has contributed to the understanding of numerous addiction-related phenomena. For example, studies have shown that substance dependent individuals discount their addictive substances (e.g., cocaine) more rapidly than they do other commodities (e.g., money). Recent research has shown that substance dependent individuals discount delayed sex more rapidly than delayed money, and their discounting rates for delayed sex were higher than those of non-addicted individuals. The particular reason that delay discounting rates for sex are higher than those for money, however, are unclear. Do individuals discount delayed sex rapidly because immediate sex is particularly appealing or because delayed sex does not retain its value? Moreover, do the same factors influence men and women's choices? The current study examined delay discounting in four conditions (money now versus money later; sex now versus sex later; money now, versus sex later; sex now versus money later) in cocaine dependent men and women. The procedures used isolated the role of the immediate versus delayed commodity. For men, the higher rates of delay discounting for sex were because delayed sex did not retain its value, whereas both the immediate and delayed commodity influenced the female participants' decisions.

Androgen insensitive male rats display increased anxiety-like behavior on the elevated plus maze.

Male rats carrying the testicular feminization mutation (Tfm-affected males) are insensitive to androgens, resulting in a female-typical peripheral phenotype despite possession of inguinal testes that are androgen secretory. Androgen-dependent neural and behavioral processes may likewise show atypical sexual differentiation. Interestingly, these mutant rats display elevated serum corticosterone, suggesting a chronic anxiety phenotype and dysregulated hypothalamic-pituitary-adrenal axis. In order to understand if elevated anxiety-like behavior is a possible mediating variable affecting the display of certain androgen-dependent behaviors, we compared the performance of Tfm-affected males to wild type males and females in the elevated plus maze (EPM). Two well-established indicators of anxiety-like behavior in the EPM were analyzed: total percentage of time spent on the open arms, and the percentage of open arm entries. We also analyzed the total number of open arm entries. Interestingly, Tfm-affected males spent less percentage of time on the open arms than both males and females, suggesting increased anxiety-like behavior. Percentage of open arm entries and the total number of arm entries was comparable between the groups, indicating that the observed decrease in the percentage of time spent on the open arms was not due to a global reduction in exploratory behavior. These data, in contrast to earlier reports, thus implicate androgen receptor-mediated functions in the expression of anxiety behaviors in male rats. Given that anxiety is widely reported as a precipitating factor in depression, studying the role of the androgen receptor in anxiety may give insights into the pathogenesis of major depressive disorder.

Perinatal BPA exposure demasculinizes males in measures of affect but has no effect on water maze learning in adulthood.

Bisphenol A (BPA) is an endocrine disrupting agent that can alter the normal gonadal steroid-sensitive sexual differentiation of the brain and behavior. While reproductive behavior and physiology are known to be altered by perinatal exposure to this compound, less is known about BPA's effects on sex differences in learning and measures of affect. In order to evaluate the effects of perinatal BPA treatment on learning and affect in adulthood, we exposed rats to one of five doses of BPA through gestation and lactation then examined adult behavior in the Morris Water Maze (MWM), the Elevated Plus Maze (EPM) and the Forced Swim Test (FST). No effect of BPA was observed in the MWM, but on both the EPM and FST, low doses (5 µg/kg) of BPA eliminated sex differences found between controls; furthermore, a non-monotonic dose-response observed in previous studies was confirmed for these tasks. Overall, our study adds to the growing data suggesting that BPA interferes with the normal development of affective behaviors in a non-linear, dose-dependent manner.

Delay discounting predicts adolescent substance abuse treatment outcome.

The purpose of the current study was to identify predictors of delay discounting among adolescents receiving treatment for marijuana abuse or dependence, and to test delay discounting as a predictor of treatment outcome. Participants for this study were 165 adolescents (88% male) between the ages of 12 and 18 (mean age = 15.8 years; standard deviation = 1.3 years) who enrolled in a clinical trial comparing three behavioral treatments for adolescent marijuana abuse or dependence. Participants completed a delay discounting task at treatment onset for $100 and $1,000 of hypothetical money and marijuana. Overall, smaller magnitude rewards were discounted more than larger magnitude rewards. Delay discounting rates were concurrently related to demographic variables (socioeconomic status, race). Delay discounting of $1,000 of money predicted during treatment abstinence outcomes among adolescent marijuana abusers, over and above the effects of type of treatment received. Teens who show higher levels of discounting of the future may be an important subgroup to identify at treatment onset. Youth with a greater tendency to discount the future may require different intervention strategies that address their impulsivity (e.g., targeting executive function or inhibitory control) and/or different schedules of reinforcement to address their degree of preference for immediate rewards.

Single- and cross-commodity discounting among cocaine addicts: the commodity and its temporal location determine discounting rate.

RATIONALE: Intertemporal choice has provided important insights into understanding addiction, predicted drug-dependence status, and outcomes of treatment interventions. However, such analyses have largely been based on the choice of a single commodity available either immediately or later (e.g., money now vs. money later). In real life, important choices for those with addiction depend on making decisions across commodities, such as between drug and non-drug reinforcers. To date, no published study has systematically evaluated intertemporal choice using all combinations of a drug and a non-drug commodity. OBJECTIVES: In this study, we examine the interaction between intertemporal choice and commodity type in the decision-making process of cocaine-dependent individuals. METHODS: This study of 47 treatment-seeking cocaine addicts analyzes intertemporal choices of two commodities (equated amounts of cocaine and money), specifically between cocaine now vs. cocaine later (C-C), money now vs. money later (M-M), cocaine now vs. money later (C-M), and money now vs. cocaine later (M-C). RESULTS: Cocaine addicts discounted significantly more in the C-C condition than in M-M (P = 0.032), consistent with previous reports. Importantly, the two cross-commodity discounting conditions produced different results. Discounting in C-M was intermediate to the C-C and M-M rates, while the greatest degree of discounting occurred in M-C. CONCLUSIONS: These data indicate that the menu of commodities offered alter discounting rates in intertemporal choice and that the greatest rate is obtained when the drug is the later available commodity. Implications for understanding intertemporal choices and addiction are addressed.

Real and hypothetical rewards.

Laboratory studies of choice and decision making among real monetary rewards typically use smaller real rewards than those common in real life. When laboratory rewards are large, they are almost always hypothetical. In applying laboratory results meaningfully to real-life situations, it is important to know the extent to which choices among hypothetical rewards correspond to choices among real rewards and whether variation of the magnitude of hypothetical rewards affects behavior in meaningful ways. The present study compared real and hypothetical monetary rewards in two experiments. In Experiment 1, participants played a temporal discounting game that incorporates the logic of a repeated prisoner's-dilemma (PD) type game versus tit-for-tat; choice of one alternative ("defection" in PD terminology) resulted in a small-immediate reward; choice of the other alternative ("cooperation" in PD terminology) resulted in a larger reward delayed until the following trial. The larger-delayed reward was greater for half of the groups than for the other half. Rewards also differed in type across groups: multiples of real nickels, hypothetical nickels or hypothetical hundred-dollar bills. All groups significantly increased choice of the larger delayed reward over the 40 trials of the experiment. Over the last 10 trials, cooperation was significantly higher when the difference between larger and smaller hypothetical rewards was greater. Reward type (real or hypothetical) made no significant difference in cooperation. In Experiment 2, real and hypothetical rewards were compared in social discounting - the decrease in value to the giver of a reward as social distance increases to the receiver of the reward. Social discount rates were well described by a hyperbolic function. Discounting rates for real and hypothetical rewards did not significantly differ. These results add to the evidence that results of experiments with hypothetical rewards validly apply in everyday life.

Pre- and postnatal bisphenol A treatment results in persistent deficits in the sexual behavior of male rats, but not female rats, in adulthood.

Perinatal administration of the endocrine disruptor bisphenol A (BPA) reportedly inhibits the sexual behavior of sexually naïve adult male rats. In order to evaluate the effects of BPA administration during early development on later reproductive behavior, we administered one of five doses of bisphenol A daily to pregnant female rats throughout gestation and lactation, and quantified the appetitive and consummatory sexual behaviors of the resultant male and female offspring over multiple sexual encounters in adulthood. Males receiving low dose perinatal BPA (50 µg/kg bw/day) showed persistent deficits in sexual behavior in adulthood. Males receiving the highest dose (5 mg/kg bw/day), however, were indistinguishable from controls with respect to consummatory sexual behaviors but showed decreased latencies to engage in those behaviors when sexually naïve, with significant non-linear, or U-shaped, dose-response relationships observed on the first and last day of testing. Adult female sexual behavior was not affected by early BPA administration at any dose tested. These results are consistent with previous reports that BPA exerts behavioral effects especially at low doses, and further indicates that BPA can cause lasting impairment of sexual behavior in males, but does not alter the normal development of female appetitive or consummatory sexual behaviors. To our knowledge, this is the first report indicating that adult sexual performance is impaired in sexually experienced animals following perinatal exposure to bisphenol A.

The behavioral economics of drug dependence: towards the consilience of economics and behavioral neuroscience.

In this chapter, we review the research in this growing field by first discussing the concepts related to price and consumption (demand), its applications to the study of drug consumption and drug seeking, and the impact of other commodities on drug consumption. We then review the discounting of future commodities and events among the addicted, review the most recent research examining the neural correlates of discounting, and describe and review the new theory of addiction that results from that research. We conclude by addressing the next research steps that these advances engender.

Hypothetical intertemporal choice and real economic behavior: delay discounting predicts voucher redemptions during contingency-management procedures.

Delay discounting rates are predictive of drug use status, the likelihood of becoming abstinent, and a variety of health behaviors. Rates of delay discounting may also be related to other relevant behaviors associated with addiction, such as the frequency at which individuals redeem contingency management voucher earnings. This study examined the discounting rates of 152 participants in a buprenorphine treatment program for opioid abuse. Participants received up to 12 weeks of buprenorphine treatment combined with contingency management. Participant's drug use was measured via urine specimens submitted three times a week. Successive negative urine specimens were reinforced with increasing amounts of money. After each negative urine specimen, a participant could either redeem his or her earnings or accumulate it in an account. Analysis of the frequency of redemptions showed that participants with higher rates of delay discounting at study intake redeemed their earnings significantly more often than participants with lower rates of discounting. Age and income also predicted redemption rates. We suggest that delay discounting rates can be used to predict redemption behaviors in a contingency management treatment program and that these findings are consistent with the recent theory of the competing neurobehavioral decision systems.

A Geometrically Exact Model for Externally Loaded Concentric-Tube Continuum Robots.

Continuum robots, which are composed of multiple concentric, precurved elastic tubes, can provide dexterity at diameters equivalent to standard surgical needles. Recent mechanics-based models of these "active cannulas" are able to accurately describe the curve of the robot in free space, given the preformed tube curves and the linear and angular positions of the tube bases. However, in practical applications, where the active cannula must interact with its environment or apply controlled forces, a model that accounts for deformation under external loading is required. In this paper, we apply geometrically exact rod theory to produce a forward kinematic model that accurately describes large deflections due to a general collection of externally applied point and/or distributed wrench loads. This model accommodates arbitrarily many tubes, with each having a general preshaped curve. It also describes the independent torsional deformation of the individual tubes. Experimental results are provided for both point and distributed loads. Average tip error under load was 2.91 mm (1.5%-3% of total robot length), which is similar to the accuracy of existing free-space models.

Temporal horizon: modulation by smoking status and gender.

Recently, delay discounting has been argued to be conceptually consistent with the notion of temporal horizon [Bickel, W.K., Yi, R., Kowal, B.P., Gatchalian, K.M., 2008. Cigarette smokers discount past and future rewards symmetrically and more than controls: is discounting a measure of impulsivity? Drug Alcohol Depend. 96, 256-262]. Temporal horizon refers to the temporal distance over which behavioral events or objects can influence behavior. Here we examine the results on two putative measures of temporal horizon, future time perspective (FTP) and delay discounting, collected over three separate studies (n=227), to determine the influence of smoking and gender on temporal horizon. By comparing the results on these temporal horizon measures we address our population of interest: women who smoke. One of the measures of FTP indicates that smoking women have a shorter temporal horizon than their nonsmoking counterparts. Additionally, the story completion measures of FTP are positively correlated with delay discounting. In contrast, results of delay discounting measures showed no difference between smoking women and nonsmoking women, while results of delay discounting measures indicated smoking men have a shorter temporal horizon than non-smoking men. Additionally, the results of the FTP story completion measure indicated that lower third income earners had a shortened temporal horizon compared to upper third income earners. A possible explanation for these results is explored, and the implications of the modulation of temporal horizon by gender and smoking are discussed.

Delay, probability, and social discounting in a public goods game.

A human social discount function measures the value to a person of a reward to another person at a given social distance. Just as delay discounting is a hyperbolic function of delay, and probability discounting is a hyperbolic function of odds-against, social discounting is a hyperbolic function of social distance. Experiment 1 obtained individual social, delay, and probability discount functions for a hypothetical $75 reward; participants also indicated how much of an initial $100 endowment they would contribute to a common investment in a public good. Steepness of discounting correlated, across participants, among all three discount dimensions. However, only social and probability discounting were correlated with the public-good contribution; high public-good contributors were more altruistic and also less risk averse than low contributors. Experiment 2 obtained social discount functions with hypothetical $75 rewards and delay discount functions with hypothetical $1,000 rewards, as well as public-good contributions. The results replicated those of Experiment 1; steepness of the two forms of discounting correlated with each other across participants but only social discounting correlated with the public-good contribution. Most participants in Experiment 2 predicted that the average contribution would be lower than their own contribution.

Altruism among relatives and non-relatives.

Hamilton's [Hamilton, W.D., 1964. The genetical evolution of social behavior, I, II. J. Theor. Biol. 7, 1-52] kin-selection theory predicts that altruism will be greater with greater genetic overlap (degree of kinship) between giver and receiver. Kin may be identified in terms of social distance-the closer you feel to someone else, (a) the greater your genetic overlap with them should be, and (b) the more altruistic you should be toward them. The present experiment determined the amount of their own (hypothetical) monetary reward undergraduates were willing to forgo in order to give $75 to other people at various social distances. We found that (a) genetic relationship and (b) altruism varied inversely with social distance; the closer you feel to someone else, the closer their relation to you is likely to be, and the more altruistic you are likely to be toward them. However, even at the same social distance, participants were willing to forgo significantly more money for the benefit of relatives than for the benefit of non-relatives. These results are consistent with kin-selection theory and imply that altruism is determined by factors in addition to social distance.

Spatial memory performance in androgen insensitive male rats.

Masculinization of the developing rodent brain critically depends on the process of aromatization of circulating testosterone (T) to its estrogenic metabolite 17beta-estradiol, which subsequently interacts with estrogen receptors to permanently masculinize the brain. However, it remains unclear what role other androgenic mechanisms may play in the process of masculinization. A novel way of examining this is through the study of male rats that express the tfm mutation of the androgen receptor (AR) gene; such males are fully androgen insensitive and manifest a female phenotype due to a failure of AR-mediated masculinization of peripheral structures. Because tfm-affected males develop secretory testes and have near-normal T titers during development, aromatization would be expected to proceed normally, and brain mechanisms may be developmentally masculinized despite the feminized periphery. We compared tfm-affected males (X(tfm)Y) with normal males and females in the Morris Water Maze, a task in which males typically perform better than females. Performance of tfm-affected males was intermediate between that of normal males and females. While an overall male superiority was found in the task, the X(tfm)Y group reached male-typical escape latencies faster than females. Furthermore, in the X(tfm)Y group, the granule cell layer of the dentate gyrus was significantly larger than in females. These results support the suggestion that that AR mediated mechanisms contribute to the masculinization of spatial behaviours and hippocampal morphology, and this may be independent of estrogenic processes.