Adolescents and androgens, receptors and rewards

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Abstract

Adolescence is associated with increases in pleasure-seeking behaviors, which, in turn, are shaped by the pubertal activation of the hypothalamo-pituitary-gonadal axis. In animal models of naturally rewarding behaviors, such as sex, testicular androgens contribute to the development and expression of the behavior in males. To effect behavioral maturation, the brain undergoes significant remodeling during adolescence, and many of the changes are likewise sensitive to androgens, presumably acting through androgen receptors (AR). Given the delicate interaction of gonadal hormones and brain development, it is no surprise that disruption of hormone levels during this sensitive period significantly alters adolescent and adult behaviors. In male hamsters, exposure to testosterone during adolescence is required for normal expression of adult sexual behavior. Males deprived of androgens during puberty display sustained deficits in mating. Conversely, androgens alone are not sufficient to induce mating in prepubertal males, even though brain AR are present before puberty. In this context, wide-spread use of anabolic-androgenic steroids (AAS) during adolescence is a significant concern. AAS abuse has the potential to alter both the timing and the levels of androgens in adolescent males. In hamsters, adolescent AAS exposure increases aggression, and causes lasting changes in neurotransmitter systems. In addition, AAS are themselves reinforcing, as demonstrated by self-administration of testosterone and other AAS. However, recent evidence suggests that the reinforcing effects of androgens may not require classical AR. Therefore, further examination of interactions between androgens and rewarding behaviors in the adolescent brain is required for a better understanding of AAS abuse.

Section snippets

Overview

Adolescence awakens the brain to both pleasure and risk. In human teenagers, this frequently takes the form of experimentation with drugs and sex. In the United States, the median age for first intercourse in males is 16.4 years, and 65% have had intercourse by 12th grade (Kaiser Family Foundation, 2005). Likewise, this population has the highest rates of illicit drug use in the United States. According to the 2004 National Survey on Drug Use and Health, 38% of men ages 18–25 used an illicit

Adolescence as a sensitive period for brain development

Ultimately, the brain is both a trigger and a target for androgen action during adolescence. In young boys (< 12 years) and young hamsters (< 28 days of age), circulating androgens and gonadotropins are at basal levels. As secretion of luteinizing hormone from the anterior pituitary gland rises in response to hypothalamic gonadotropin-releasing hormone, circulating testosterone concentrations increase significantly. This occurs by Tanner stage II/III (14 years) in boys, and by 28 days of age in

Androgens and neural circuits for motivated behavior

Because adolescence is a transient and dynamic phase of development, it would be difficult to evaluate the adolescent brain and behavior in isolation. Instead, to appreciate the unique character of adolescence, it is helpful to contrast it with the brain and behavior of mature adults. Thus, with the focus of this paper on male sexual behavior and reward, it is important here to introduce the neural circuits for copulation and sexual motivation in adult males, including the role of gonadal

Steroid-dependent organization of behavior during adolescence

The traditional view of hormone action on adolescent behavior is based on activational effects of steroid hormones, which refer to the ability of steroids to facilitate behavior in specific social contexts by action within target cells in the neural circuits underlying behavior. Activational effects are transient in the sense that they come and go with the presence and absence of hormone, and they are typically associated with the expression of adult behavior. In contrast, organizational

Prepubertal behavioral responses to steroids

One of the enduring puzzles of adolescent behavioral development is why activation of reproductive behavior in response to steroid exposure is attenuated in prepubertal male hamsters. If low levels of androgens before puberty limit the expression of male sexual behavior in prepubertal males, then supplementing endogenous androgens in prepubertal males should elicit mating. This turns out not to be the case (Meek et al., 1997, Romeo et al., 2001, Romeo et al., 2002b), in spite of the fact that

Pharmacologic androgens

The preceding data suggest that endogenous gonadal steroids enhance motivated behaviors during adolescence. Now, what happens if one self-administers androgens at levels up to 100× normal physiologic concentrations? This is the problem of anabolic-androgenic steroid (AAS) abuse (reviewed in Brower, 2002, Clark and Henderson, 2003). A brief digression is appropriate here: all AAS are derivatives of testosterone, all AAS have a carbon skeleton with 4 fused rings, most have 19 carbons. AAS are

Reinforcing effects of androgens

Mating and fighting are each rewarding (at least if you win the fight). Male rats will press a lever repeatedly in order to copulate with a female (Everitt and Stacey, 1987). Similarly, male mice and female hamsters will form a conditioned place preference (CPP) for locations where they have previously won fights (Martinez et al., 1995, Meisel and Joppa, 1994). If AAS can enhance rewarding social behaviors above levels normally observed in gonad-intact males, it is logical to expect that

Summary

Here we review the evidence that androgens are potent mediators of adult motivated behaviors, and further, that the timing of androgen exposure during development programs androgen-dependent motivated behavior in adulthood. Anabolic steroids are fast becoming a favored drug of abuse by adolescents in the US. While AAS may not have the addictive potency of cocaine or heroin, we are just beginning to understand the potential for androgen reinforcement and addiction. In particular, as youth sports

Acknowledgments

We thank Eleni Antzoulatos, Cortney Ballard, Lucy Chu, Kelly Peters, Jennifer Triemstra, Jane Venier, Lisa Rogers, and Pamela Montalto for their assistance with these studies. This work supported by grants from the NIH (DA12843 to RIW, MH68764 to CLS, and MH070125 to KMS).

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