Reinforcing aspects of androgens

doi:10.1016/j.physbeh.2004.08.012

Physiology & Behavior

Volume 83, Issue 2, 15 November 2004, Pages 279-289

https://doi.org/10.1016/j.physbeh.2004.08.012 Get rights and content

Abstract

Are androgens reinforcing? Androgenic–anabolic steroids (AAS) are drugs of abuse. They are taken in large quantities by athletes and others to increase performance, often with negative long-term health consequences. As a result, in 1991, testosterone was declared a controlled substance. Recently, Brower [K.J. Brower, Anabolic steroid abuse and dependence. Curr. Psychiatry Rep. 4 (2002) 377–387.] proposed a two-stage model of AAS dependence. Users initiate steroid use for their anabolic effects on muscle growth. With continued exposure, dependence on the psychoactive effects of AAS develops. However, it is difficult in humans to separate direct psychoactive effects of AAS from the user's psychological dependence on the anabolic effects of AAS. Thus, studies in laboratory animals are useful to explore androgen reinforcement. Testosterone induces a conditioned place preference in rats and mice, and is voluntarily consumed through oral, intravenous, and intracerebroventricular self-administration in hamsters. Active, gonad-intact male and female hamsters will deliver 1 μg/μl testosterone into the lateral ventricles. Indeed, some individuals self-administer testosterone intracerebroventricularly to the point of death. Male rats develop a conditioned place preference to testosterone injections into the nucleus accumbens, an effect blocked by dopamine receptor antagonists. These data suggest that androgen reinforcement is mediated by the brain. Moreover, testosterone appears to act through the mesolimbic dopamine system, a common substrate for drugs of abuse. Nonetheless, androgen reinforcement is not comparable to that of cocaine or heroin. Instead, testosterone resembles other mild reinforcers, such as caffeine, nicotine, or benzodiazepines. The potential for androgen addiction remains to be determined.

Section snippets

Biological context: why are androgens reinforcing?

In a natural environment, testosterone secretion is intimately related to reinforcing social behaviors, including mating and aggression [1], [2]. While castrated males do not mate and show little offensive aggression, testosterone replacement restores both sexual and agonistic behaviors. Although testosterone and other gonadal steroids facilitate social behavior, the converse is also true. That is, steroid secretion can be modified by social interactions. Successful expression of mating or

Who is taking steroids?

Through their androgenic, anabolic, and psychotropic actions, androgens enhance performance, both athletic achievement and “competition” in nonathletic social situations [8]. Not surprisingly, AAS are abused, both by athletes and casual users. Although AAS were banned from Olympic competition in 1975, steroid abuse continues. In unannounced drug tests at national competitions, up to 50% of athletes tested positive for AAS [9]. In response to widespread abuse, testosterone was declared a

Steroids and experimental models of reward: limitations of human studies

While it is clear that AAS are abused, with many of the same negative consequences for health and society as abuse of addictive drugs, defining the potential for AAS addiction in humans has been problematic because it is difficult in humans to separate direct psychoactive effects of AAS from the user's psychological dependence on the anabolic effects of AAS. Thus, studies in laboratory animals are useful to explore androgen reinforcement. Several experimental models have been developed to study

Modifying androgen self-administration

To establish the potential for androgen reinforcement, our initial studies focused on gonad-intact adult male rats and hamsters because the majority of human AAS abusers are gonad-intact adult men. Individuals with low endogenous testosterone, including women, adolescents, and older men, are less likely to use AAS [40]. This suggests the possibility that endogenous androgens may enhance sensitivity to testosterone self-administration. However, many other factors, including undesirable

Comparison with other drugs

Based on the foregoing studies, it is evident that androgen reinforcement is not comparable to that of cocaine or heroin. Instead, it is likely that steroid reinforcement is similar to that of other mild reinforcers, such as caffeine, nicotine, or benzodiazepines. In this regard, rats in an operant chamber respond vigorously for iv heroin (28 μg: 9 responses/30 min) [52] or cocaine (62.5 μg: 130 responses/4 h) [53]. By contrast, whether by oral [38], iv, or icv self-administration [39], rats

Testosterone metabolites, steroid receptors, and the medial preoptic area (MPOA)

The brain is both the initial trigger for steroid production and also a principal target for steroid hormones. At the present time, the specific steroid signals, receptors, and brain sites of action for testosterone reinforcement are unknown. The reinforcing effects of testosterone may be androgenic, may be mediated by aromatization to estrogen, or may be sensitive to both androgens and estrogens. For many steroid-sensitive social behaviors in males, estrogen aromatized locally from

Behavioral consequences of androgen abuse

From a public health perspective, there is concern that AAS may have a negative impact not only on steroid users, but also on those around them. Through anecdotal reports of violent behavior in AAS users, “roid rage” is widely accepted in the popular media: a search on Google yielded 5200 results. However, few studies in humans have determined if androgens at pharmacologic doses cause uncontrolled aggression. From a clinical trial of nonathletes receiving 600 mg of testosterone enanthate per

Fatal consequences of androgen abuse

Many AAS users are aware of the negative cosmetic side effects of high-dose steroid use, including acne and balding, gynecomastia (“bitch tits”), and testicular atrophy in men, and clitoromegaly, facial hair, and lowering of the voice in women [12], [13], [16], [94], [95]. In addition to causing infertility in both sexes, AAS use at pharmacologic doses can produce serious health consequences, including myocardial infarction, cardiomyopathy, stroke, behavioral disturbances, and hepatic tumors

Acknowledgements

I thank Luke Johnson, Lucy Lee, Anita Nagypal, Jerelyn Osoria, Kelly Peters, and Jennifer Triemstra for assistance with these studies. This work supported by a grant from the NIH (DA12843).

References (105)

S. Niikura et al.
A causative factor of copulatory disorder in rats following social stress
J. Urol.
(2002)
J.X. Zhang et al.
Scent, social status, and reproductive condition in rat-like hamsters (Cricetulus triton)
Physiol. Behav.
(2001)
J.E. Sturmi et al.
Anabolic agents
Clin. Sports Medicine
(1998)
S. Jacob et al.
Psychological effects of musky compounds: comparison of androstadienone with androstenol and muscone
Horm. Behav.
(2002)
R. DeBeun et al.
Testosterone as appetitive and discriminative stimulus in rats: sex- and dose-dependent effects
Physiol. Behav.
(1992)
M.T. Arnedo et al.
Rewarding properties of testosterone in intact male mice: a pilot study
Pharmacol. Biochem. Behav.
(2000)
J. Miele et al.
Estradiol benzoate can function as an unconditioned stimulus in a conditioned taste aversion paradigm
Horm. Behav.
(1988)
E.P. Bless et al.
The effects of gonadal steroids on brain stimulation reward in female rats
Behav. Brain Res.
(1997)
A.S. Clark et al.
Anabolic–androgenic steroids and brain reward
Pharmacol. Biochem. Behav.
(1996)
V. DeRoche et al.
Rats orally self-administer corticosterone
Brain Res.
(1993)

B.A. Gosnell et al.

The relationship between saccharin and alcohol intake in rats

Alcohol

(1992)

J.R. Ganchrow et al.

Consummatory responses to taste stimuli in rats selected for high and low rates of self-stimulation

Physiol. Behav.

(1981)

J.D. Sinclair et al.

Taste preferences in rat lines selected for low and high alcohol consumption

Alcohol

(1992)

R.I. Wood

Oral testosterone self-administration in male hamsters: dose-response, voluntary exercise, and individual differences

Horm. Behav.

(2002)

S. Bhasin

The dose-dependent effects of testosterone on sexual function and on muscle mass and function

Mayo Clin. Proc.

(2000)

M.D. Jensen

Androgen effect on body composition and fat metabolism

Mayo Clin. Proc.

(2000)

S. Dai et al.

Heroin self-administration by rats: influence of dose and physical dependence

Pharmacol. Biochem. Behav.

(1989)

R.J. Briscoe et al.

Reinforcing effects of caffeine, ephedrine, and their binary combination in rats

Pharmacol. Biochem. Behav.

(1998)

T. Naruse et al.

Intravenous self-administration of diazepam in rats

Eur. J. Pharmacol.

(1987)

A.M. Manzardo et al.

Rats prefer cocaine over nicotine in a two-lever self-administration choice test

Brain Res.

(2002)

F. Celotti et al.

Steroid metabolism in the mammalian brain: 5alpha-reduction and aromatization

Brain Res. Bull.

(1997)

B.E. King et al.

Affective properties of intra-medial preoptic area injections of testosterone in male rats

Neurosci. Lett.

(1999)

A. Bonci et al.

The dopamine-containing neuron: maestro or simple musician in the orchestra of addiction?

Trends Pharmacol. Sci.

(2003)

J.P. Schroeder et al.

Role of dopamine receptor subtypes in the acquisition of a testosterone conditioned place preference in rats

Neurosci. Lett.

(2000)

C.A. Frye et al.

Progestins can have a membrane-mediated action in rat midbrain for facilitation of sexual receptivity

Horm. Behav.

(1996)

J.L. Aikey et al.

Testosterone rapidly reduces anxiety in male house mice (Mus musculus)

Horm. Behav.

(2002)

M.Y. McGinnis et al.

Physical provocation potentiates aggression in male rats receiving anabolic androgenic steroids

Horm. Behav.

(2002)

M.E. Breuer et al.

Aggression in male rats receiving anabolic androgenic steroids: effects of social and environmental provocation

Horm. Behav.

(2001)

M.J. Feinberg et al.

The effect of anabolic–androgenic steroids on sexual behavior and reproductive tissues in male rats

Physiol. Behav.

(1997)

R.H. Melloni et al.

Anabolic–androgenic steroid exposure during adolescence and aggressive behavior in golden hamsters

Physiol. Behav.

(1997)

J.M. Grimes et al.

Serotonin modulates offensive attack in adolescent anabolic steroid-treated hamsters

Pharmacol. Biochem. Behav.

(2002)

R.J. Harrison et al.

Chronic anabolic–androgenic steroid treatment during adolescence increases anterior hypothalamic vasopressin and aggression in intact hamsters

Psychoneuroendocrinology

(2000)

A.S. Clark et al.

Stanozolol, oxymetholone, and testosterone cypionate effects on the rat estrous cycle

Physiol. Behav.

(1998)

M.E. Blasberg et al.

Anabolic–androgenic steroid effects on sexual receptivity in ovariectomized rats

Horm. Behav.

(1997)

M.E. Blasberg et al.

The effects of 17 alpha-methyltestosterone, methandrostenolone, and nandrolone decanoate on the rat estrous cycle

Physiol. Behav.

(1997)

M.Y. McGinnis et al.

Effects of withdrawal from anabolic androgenic steroids on aggression in adult male rats

Physiol. Behav.

(2002)

M.L. Sullivan et al.

The cardiac toxicity of anabolic steroids

Prog. Cardiovasc. Dis.

(1998)

H.I. Siegel

Male sexual behavior

H.I. Siegel

Aggressive behavior

E.P. Monaghan et al.

Hormones and aggressive behavior

F. Macrides et al.

Effects of exposure to vaginal odor and receptive females on plasma testosterone in the male hamster

Neuroendocrinology

(1974)

A. Mazur et al.

Testosterone and dominance in men

Behav. Brain Sci.

(1998)

P.J. Goldstein

Anabolic steroids: an ethnographic approach

C.E. Yesalis et al.

Incidence of the nonmedical use of anabolic–androgenic steroids

K.E. Friedl

Reappraisal of the health risks associated with the use of high doses of oral and injectable androgenic steroids

K.J. Brower et al.

Evidence for physical and psychological dependence on anabolic androgenic steroids in eight weight lifters

Am. J. Psychiatry

(1990)

...

S. Gallaway

The steroid bible

(1997)

...

S.B. Karch

Karch's pathology of drug abuse

(2002)

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It is somewhat surprising that we see reactive aggression scores are highest when cortisol is low and change in testosterone is high, but this association does not extend to the proactive aggressive behaviors that are more closely allied with the status striving dominance that is thought to be the direct results of the interaction of high testosterone and low cortisol according to the DHH. While the theoretical significance of this interaction is somewhat undermined by its relatively weak strength of association in initial analyses (p = .042), it is possible the interaction indicates that the effect on reactive aggression of decreases in fear, punishment sensitivity, and anxiety occurring at lower levels of cortisol (Brown et al., 1996; Roelofs et al., 2009; Schulkin et al., 2005; Shields et al., 2015; van Honk et al., 2003) are increased through increased attention to social threat and reward salience/risk tolerance that have been shown to accompany the administration of exogenous testosterone (Radke et al., 2015; Welker et al., 2015; Wood, 2004). In addition to conditional evidence for the association between the interaction of testosterone and cortisol and reactive aggression, the current results also provided fairly consistent evidence for a negative association between cortisol and reactive aggression among women.
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Reinforcing aspects of androgens

Abstract

Section snippets

Biological context: why are androgens reinforcing?

Who is taking steroids?

Steroids and experimental models of reward: limitations of human studies

Modifying androgen self-administration

Comparison with other drugs

Testosterone metabolites, steroid receptors, and the medial preoptic area (MPOA)

Behavioral consequences of androgen abuse

Fatal consequences of androgen abuse

Acknowledgements

J. Urol.

Physiol. Behav.

Clin. Sports Medicine

Horm. Behav.

Physiol. Behav.

Pharmacol. Biochem. Behav.

Horm. Behav.

Behav. Brain Res.

Pharmacol. Biochem. Behav.

Brain Res.

Alcohol

Physiol. Behav.

Alcohol

Horm. Behav.

Mayo Clin. Proc.

Mayo Clin. Proc.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Brain Res.

Brain Res. Bull.

Neurosci. Lett.

Trends Pharmacol. Sci.

Neurosci. Lett.

Horm. Behav.

Horm. Behav.

Horm. Behav.

Horm. Behav.

Physiol. Behav.

Physiol. Behav.

Pharmacol. Biochem. Behav.

Psychoneuroendocrinology

Physiol. Behav.

Horm. Behav.

Physiol. Behav.

Physiol. Behav.

Prog. Cardiovasc. Dis.

Male sexual behavior

Aggressive behavior

Hormones and aggressive behavior

Effects of exposure to vaginal odor and receptive females on plasma testosterone in the male hamster

Neuroendocrinology

Testosterone and dominance in men

Behav. Brain Sci.

Anabolic steroids: an ethnographic approach

Incidence of the nonmedical use of anabolic–androgenic steroids

Reappraisal of the health risks associated with the use of high doses of oral and injectable androgenic steroids

Evidence for physical and psychological dependence on anabolic androgenic steroids in eight weight lifters

Am. J. Psychiatry

The steroid bible

Karch's pathology of drug abuse