Neurobiology of Anabolic-Androgenic Steroid Abuse
Summary and Keywords
Anabolic-androgenic steroids (AAS) are both performance-enhancing substances and drugs of abuse. Although AAS are banned in competitive sports, they are widely used by both elite and rank-and-file athletes. All AAS are derived from testosterone, the principle endogenous androgen produced by the testes of adult men. While AAS increase muscular strength and athletic performance, they also have serious consequences for health and behavior. AAS are implicated in maladaptive behavioral and cognitive changes such as increased risk-taking and altered decision-making. However, effects of AAS on cognition are not well understood. Studies of human AAS users are limited by an inability to control for pre-existing psychopathology and behavioral differences. Furthermore, in order to understand AAS effects on behavior, it is important to discover how AAS impact the brain. Animal models of AAS abuse parallel human studies to uncover effects on cognition, decision-making, and underlying neurobiological mechanisms. In operant discounting tests, rats treated with chronic high-dose testosterone are less sensitive to effort, punishment, and delay but are more sensitive to uncertainty. Likewise, they demonstrate impaired cognitive flexibility when tested for set-shifting and reversal learning. It appears that AAS induce many of these cognitive changes via effects on the mesocorticolimbic dopamine system, particularly through the dopamine D1- and D2-like receptors in subnuclei of the nucleus accumbens. AAS also have rewarding effects mediated by similar neural circuits. In preclinical studies, animals will voluntarily self-administer AAS. Human users may develop dependence. These findings highlight the vulnerability of brain circuits controlling cognition and reward to androgens at high doses.
Anabolic-Androgenic Steroid Abuse: The Scope of the Problem
The abuse of anabolic-androgenic steroids (AAS) is strongly associated with elite athletes, who use AAS for their anabolic (muscle-building) properties to improve athletic performance. According to the American College of Sports Medicine (2006), “The gains in muscular strength achieved through steroid use . . . improve performance and seem to increase aerobic power.” As a result, AAS have been banned from Olympic competition since 1976 and account for 50% of all “adverse analytical findings” in testing conducted by the World Anti-Doping Agency (2015; Figure 1). In 1990, the Anabolic Steroid Control Act made possession and distribution of AAS for nonmedical purposes a felony in the United States and classified AAS as Schedule III substances (Pope et al., 2013). Schedule III drugs have a currently accepted medical use, but abuse may lead to physical or psychological dependence (Drug Enforcement Administration, n.d.). Other Schedule III drugs include Tylenol with Codeine®, buprenorphine, and ketamine.
While users defend AAS as a “healthy lifestyle choice” (Gwartney, 2005), emerging evidence highlights a range of adverse health effects from chronic AAS abuse, including cardiovascular, hepatic, reproductive, and psychiatric dysfunction (Pope et al., 2013). Adverse effects of chronic exposure have been slow to accumulate because AAS use did not become widespread in the United States until the 1980s and 1990s. Although misuse of AAS is widely acknowledged, the potential risks are not. This is not because AAS have been shown to be safe but because AAS are understudied. Furthermore, the dangers of AAS abuse are not limited to the medical consequences of high-dose steroids themselves but result from risk-taking in nonsocial (drinking and driving [Middleman, Faulkner, Woods, Emans, & Durant, 1995]) and social (aggression, violence [Skårberg, Nyberg, & Engström, 2010]; risky sex [Ip, Yadao, Shah, & Lau, 2016]) contexts. In particular, AAS users have higher mortality rates than the general population, often due to suicide, homicide, accidents caused by reckless behavior, or complications of polydrug abuse (Thiblin, Lindquist, & Rajs, 2000).
This review focuses on cognitive changes and neurobiologic mechanisms of AAS abuse in humans and animal models, as well as AAS reward and dependence. Compared with other illicit drugs, our understanding of the neurobiology of AAS abuse is extremely limited. A large body of research has mapped hypothalamic sites for testosterone modulation of social behavior, including mating and aggression (Hull, Wood, & McKenna, 2006; Melloni & Ricci, 2010). However, at pharmacologic doses, the brain mechanisms of androgen action are not necessarily the same. In this regard, brain targets mediating cognitive effects of AAS include the mesocorticolimbic dopamine (DA) system, where DA cells in the ventral tegmental area (VTA) project rostrally to the nucleus accumbens (Acb) and prefrontal cortex (PFC; Orsini, Moorman, Young, Setlow, & Floresco, 2015).
Who Is Taking Steroids? What Are They Taking?
While the media focus on steroid use among elite athletes and on steroid detection to ensure “fairness” in sport, the use of AAS is far more widespread, and potential risks have become evident only since the 1990s (Pope et al., 2013). As many as 3 million Americans have used AAS. AAS are in high schools, fitness centers, and “rejuvenation” clinics. A typical AAS user is a young man in his late teens or early 20s. Among U.S. high school students, 4% to 6% of boys have used AAS versus 1% to 2% of girls (Centers for Disease Control and Prevention, 2012; Johnston, O’Malley, Bachman, & Schulenberg, 2013). This is comparable to the rates of crack cocaine or heroin use (Johnston et al., 2013). It is estimated that AAS use among men in their 20s is even higher (Pope et al., 2014).
Despite the varieties of AAS (nandrolone, boldenone, dianabol), all AAS are derived from testosterone, but most AAS users do not limit themselves to a single dose or type of steroid. Instead, users combine different steroids (“stacking”) in cycles of increasing and decreasing concentrations (“pyramiding”). They take steroids orally, transdermally, or by intramuscular (IM) injection (Pope et al., 2013). AAS stacks include nonsteroidal drugs to counteract side effects (gynecomastia, acne, baldness). Analgesics such as opioids treat pain and injury due to intense exercise, stimulants like amphetamine counter fatigue, and nutritional supplements and masking agents hide evidence of AAS use in drug testing (Sagoe et al., 2015). Human users also engage in extreme behavioral routines including excessive exercise and strict dieting regimens.
Animal Models and Limitations of Human Studies
Psychological evaluations of human users have implicated AAS in impaired decision-making stemming from feelings of invincibility (Pope & Katz, 1990). In terms of psychiatric effects, AAS can cause major mood disorders in susceptible individuals, including mania and hypomania during AAS use and depression during AAS withdrawal (Pope et al., 2013). Heightened aggression (so-called ’roid rage) is another common feature of AAS abuse. Notably, AAS have been implicated in several recent mass shootings. Anders Breivik, who committed the 2011 bombing in Olso, Norway, purposefully used AAS to increase his aggression (Pope & Kanayama, 2015). Additionally, the medical examiner in the recent Orlando, Florida, attack reported that the shooter Omar Mateen showed physical signs of long-term AAS use (Hamblin, 2016).
These reports highlight potential dangers of AAS abuse, but studies in humans have limitations. AAS use in humans is complicated by the user’s motivation for increased strength and muscle mass (Brower, Blow, Young, & Hill, 1991). Users are unusually covert about their use of steroids and are unlikely to disclose this information to physicians (Pope et al., 2014). However, animal studies can explore consequences of AAS in an experimental context where appearance and athletic performance are irrelevant. Animal studies eliminate potential confounds such as polydrug abuse and pre-existing behavioral tendencies to specifically determine androgen effects on health and behavior. Furthermore, it is unethical to treat human volunteers with the massive doses of AAS relevant to human users—precluding the possibility of randomized controlled human trials.
Although animal models cannot capture all aspects of AAS abuse, studies in animals complement field studies of illicit human steroid users. As a model for AAS abuse in humans, animal studies use rodents (most often rats and hamsters) treated chronically with high-dose AAS by daily injection subcutaneous beginning in adolescence (c. 35 days). Although human users also administer AAS transdermally and by IM injection, IM injections are painful, and transdermal delivery is unfeasible in furry animals. In addition, rodents will voluntarily self-administer AAS orally, and by intravenous (IV) or intracerebroventricular (ICV) injection (Wood, 2008).
AAS Stimulate Sexual and Aggressive Behavior (’Roid Rage)
Because the brain is both stimulus and target for endogenous testosterone produced in the testes, it is not surprising that exogenous testosterone and other AAS mimic and amplify testosterone’s effects on androgen-sensitive reproductive behaviors, including sex and aggression. The stimulatory effects of AAS on mating and aggression and brain mechanisms of action have been recently reviewed elsewhere (Cunningham, Lumia, & McGinnis, 2013; Melloni & Ricci, 2010; Oberlander & Henderson, 2012).
In surveys of current users and in prospective studies of human volunteers, increased aggression is the most consistent behavioral effect of AAS (Pope et al., 2013). This has given rise to the image of ’roid rage: a sudden and exaggerated response to a minimal provocation (think “Incredible Hulk”). ’Roid rage is recognized in popular media, in bodybuilding circles (Gwartney, 2005; Summers, 2003), and in clinical literature (Pope et al., 2013). Human aggression has been classified as hostile (impulsive, with intent to injure) or instrumental (premeditated, with intent for personal benefit; Ramirez & Andreu, 2006). Endogenous testosterone in humans correlates with power motivation and risk-taking in economic and social domains (reviewed in Wood & Stanton, 2012), which would reflect instrumental aggression. In a functional magnetic resonance imaging (fMRI) study of the Ultimatum Game, a social economic decision-making task, high testosterone levels correlated with both reduced activity in the orbitofrontal cortex (OFC) and with “aggressive” responses to unfair offers—rejection of the offers, resulting in no monetary gain for either player (Mehta & Beer, 2010). Likewise, animal studies show that AAS-induced aggression is not indiscriminate and unprovoked (Oberlander & Henderson, 2012). Instead, when presented with an opportunity for agonistic behavior, AAS treatment increases the likelihood that aggression will occur, but the aggressive response does not reflect a loss of control. Thus AAS-induced aggression is more nuanced than as depicted in the popular image of ’roid rage.
Clinical investigations of sexual response in human volunteers receiving injections of AAS have observed positive mood including sexual arousal and desire (Pope et al., 2013). Compared with non-users, human AAS users report increased sex drive (Moss, Panzak, & Tarter, 1993) and increases in risky sexual behaviors (e.g., increased numbers of partners, infrequent condom usage [Midgley et al., 2000], as well as unprotected anal intercourse among HIV-positive gay men recruited from British gyms [Bolding, Sherr, & Elford, 2002]). Among American high school students, AAS use correlated with not using a condom and a history of sexually transmitted disease (Middleman et al., 1995). AAS have also been implicated in inappropriate sexual behavior (Choi & Pope, 1994) and sexual aggression in adolescents (Borowsky, 1997). Similarly, AAS increase male mating behavior in animals, including reduced latency to initiate mating and increased efficiency of sexual performance (Farrell & McGinnis, 2004).
AAS Alter Cognitive Function
To understand the basis for AAS-enhanced enhanced sexual and aggressive behavior, recent studies have explored how AAS modify cognitive function, including memory, cognitive flexibility, and decision-making. Not surprisingly, AAS impact the mesocorticolimbic DA system, which is central to many of these processes.
Memory deficits have been demonstrated with chronic AAS use. Human users have diminished visuospatial memory compared to non-users, and the level of impairment is correlated with lifetime AAS use (Kanayama, Kean, Hudson, & Pope, 2013). Along with visuospatial memory deficits, AAS users show increased amygdala volume but decreased connectivity with cortical brain areas involved in cognitive control (Kaufman et al., 2015). Likewise in nonlaboratory settings, AAS users report deficits in prospective and retrospective memory and executive function (Heffernan, Battersby, Bishop, & O’Neill, 2015). In animal studies, spatial memory in the Morris water maze task is impaired in rats treated with high-dose testosterone (Magnusson et al., 2009; Pieretti et al., 2013), and exercise does not overcome this deficit (Tanehkar et al., 2013).
AAS effects on memory are not surprising, considering that CA1 of the hippocampus has abundant androgen receptors (Xiao & Jordan, 2002). In this regard, pubertal exposure to AAS increases dendritic spine density in CA1 (Cunningham, Claiborne, & McGinnis, 2007). The increased spine density persists weeks after treatment cessation, suggesting long-term effects of AAS on neural anatomy. There is the additional possibility of AAS-induced hippocampal cell death. AAS have been shown to promote death of dopaminergic neurons (Cunningham, Giuffrida, & Roberts, 2009) and neuronal cells in vitro (Basile et al., 2013; Caraci et al., 2011). Finally, since AAS abuse upregulates the adrenal axis (Blanco, Peltz, Staley, & Kim, 2002) and the dentate gyrus is responsive to corticosteroids (Snyder, Soumier, Brewer, Pickel, & Cameron, 2011), there is potential for damage from AAS mediated through the hypothalamo-pituitary-adrenal axis.
Our laboratory has recently demonstrated a decrease in cognitive flexibility in response to AAS (Wallin & Wood, 2015). Such deficits often result from an increase in perseverative behavior, the inability to cease use of a response strategy when it is no longer relevant. Perseveration has been associated with high levels of testosterone in both humans and animals. In a foraging paradigm, male chicks treated with testosterone continually peck grains of only one preferred color, while vehicle-treated chicks peck both grain colors (Andrew & Rogers, 1972). In humans, adolescent males exhibiting external signs of high testosterone are better at performing simple repetitive tasks than their peers with low testosterone, independent of cognitive ability (Broverman, Broverman, Vogel, Palmer, & Klaiber, 1964).
In human and animal studies, cognitive flexibility can be measured with set-shifting and reversal learning tasks. In humans, the Wisconsin Card Sorting Task tests set-shifting by asking subjects to match cards based on changing rules (e.g., color or shape). Although this task has not yet been tested in AAS users, we applied an operant model of set-shifting developed by Floresco, Block, and Tse (2008), where rats choose between two levers based on changing rules (i.e., cue light vs. direction; Figure 2A). Testosterone-treated rats required at least 50% more trials to adjust successfully to the task new rules for both set-shifting and reversal learning (Wallin & Wood, 2015; Figure 2B) but showed no general learning deficit. This implies that AAS diminish cognitive flexibility and impair function of the PFC (for set-shifting) and OFC (for reversal learning). Set-shifting behavior is dependent upon DA D1-like receptors in the nucleus Acb (Haluk & Floresco, 2009), which are reduced by AAS (Kindlundh et al., 2001).
If AAS impair aspects of memory and cognitive flexibility, it stands to reason that decision-making may also be affected. Recently, our laboratory used operant discounting tasks to assess AAS effects on decision-making. In humans and animals, the subject has a choice between large and small rewards, where the large reward is discounted (made less desirable) by some cost. Perhaps the most well-known example of delay discounting is the Stanford marshmallow experiment, which asked young children to choose between one marshmallow provided immediately or two marshmallows given after waiting for 15 minutes (Mischel, Ebbesen, & Zeiss, 1972). Preschoolers’ ability to delay gratification and wait for the large reward correlated with better outcomes later in life, including higher levels of education, better SAT scores, and lower body mass index (Caleza, Yañez-Vico, Mendoza, & Iglesias-Linares, 2016; Shoda, Mischel, & Peake, 1990). In other human studies, alterations in delay and probability discounting have been shown in drug addicts and pathological gamblers (Kirby, Petry, & Bickel, 1999; Miedl, Peters, & Büchel, 2012).
The operant discounting task for rats is illustrated in Figure 3A. Two retractable levers offer large (three to four sugar pellets) or small (one pellet) rewards, where the large reward is associated with effort, delay, uncertainty, or punishment. In animals, the effects of stimulants on decision-making behavior have been well characterized. Amphetamine generally increases preference for large rewards in spite of various costs (with the exception of physical punishment; Floresco, Zhang, & Enomoto, 2009; Orsini et al., 2015; Simon et al., 2011). Depressants such as alcohol increase impulsive choice in delay discounting and increase risky choice in probability discounting, while having no effect on punishment discounting (Mitchell, Vokes, Blankenship, Simon, & Setlow, 2011; Setlow, Mendez, Mitchell, & Simon, 2009). Previous animal research has also characterized the neural substrates underlying decision-making in discounting paradigms. Lesions and inactivation studies show that different aspects of decision-making—such as choice behavior, reward sensitivity, and loss sensitivity—depend on discrete brain regions and circuitry (St. Onge & Floresco, 2010; St. Onge, Stopper, Zahm, & Floresco, 2012; Stopper & Floresco, 2011). Thus determining AAS effects on decision-making in discounting tasks allows us to make inferences about underlying brain changes.
• Effort: In humans and animals, AAS increase willingness to expend physical effort. Human users engage in high-intensity exercise to maximize anabolic gains (Pope et al., 2013). This is consistent with our recent finding that testosterone reduces sensitivity to effort discounting (Wallin et al., 2015). Rats were required to press a lever repeatedly (up to 15 times) to obtain a large reward (three pellets); the small reward lever required only a single press to obtain one pellet. Vehicle- and testosterone-treated rats strongly preferred the large reward lever when response requirements for the two levers were equal (one press) across all blocks (Fig. 3B). This demonstrates that the rats do not simply reach satiety. However, as response requirements increased across blocks of trials, preference for the large reward lever in vehicle-treated rats decreased to ~53% but remained significantly higher (77%) in testosterone-treated rats (Fig. 3C).
• Punishment: AAS users not only expend tremendous effort to achieve their anabolic goals; they also subject themselves to pain and discomfort in training. Pain is a significant risk in many cost-benefit decisions. In surveys of human users, AAS users are more likely to drink and drive, carry a weapon, and not wear a helmet or seat belt (Middleman et al., 1995). Deaths among AAS users show high rates of homicide, suicide, and drug overdose (Thiblin et al., 2000). To determine if AAS reduce the response to punishment, we tested discounting behavior in testosterone-treated rats where the large reward lever was associated increased risk of mild footshock (1.2 mA/kg; Cooper, Goings, Kim, & Wood, 2014). As with effort discounting, preference for the large reward lever decreased in all rats as risk of footshock increased (Fig. 3D). However, testosterone-treated rats were less risk-averse than vehicle-treated controls. At 100% risk, vehicle-treated rats averaged 44% preference, while testosterone-treated rats responded on the large reward lever in 59% of trials. These results suggest that AAS reduce sensitivity to punishment, even though earlier studies show that AAS do not dampen pain sensitivity (Tsutsui, Wood, & Craft, 2011). On the other hand, in view of AAS actions via opioidergic mechanisms (see the Neurobiology of Androgen Reward section), there is potential for AAS to alter the response to pain via opioidergic mechanisms. This remains to be determined.
• Impatience (impulsive choice): We hypothesized that AAS would increase impatience, and this was evaluated by delay discounting (Wood et al., 2013). A response on the large reward lever delivers pellets after a brief delay (up to 45 seconds). With a 45-second delay, vehicle-treated rats chose the large reward lever on only 25% of trials (Fig. 3E). Somewhat surprisingly, testosterone-treated rats selected the large reward lever on 45% of trials, suggesting that AAS increased tolerance for reward delay.
• Uncertainty: In our studies of effort, punishment, and delay discounting, AAS consistently increased responding for the large reward. However, when tested with probability discounting, where a response on the large reward lever delivers pellets with diminished likelihood, AAS reduced tolerance for uncertainty (Wallin et al., 2015). At 25% probability, testosterone-treated rats chose the large reward lever on only 33% of trials, compared with 51% in vehicle-treated rats (Fig. 3F). Thus far, this is the only discounting task where AAS reduce preference for the large discounted reward lever, suggesting that AAS increase tolerance for costs, as long as reward is guaranteed.
• Complex decision-making (Iowa Gambling Task [IGT]): Discounting tasks have simple strategies that require consideration of only one variable. In real life, decisions are seldom one-dimensional. Instead, we integrate multiple variables to make choices that maximize reward. Good economic decision-making is a crucial aspect of daily life, and the IGT is thought to model real-life decision-making (Bechara, Damasio, Damasio, & Anderson, 1994). Subjects choose cards from among four decks, two of which are advantageous and yield higher payoffs than the disadvantageous decks. In humans, high levels of endogenous testosterone correlate with economic risk-taking in the stock market (Coates & Herbert, 2008) and with poor decision-making on the IGT (Stanton, Liening, & Schultheiss, 2011). Similarly, AAS use correlates with impaired judgment and increased risk-taking (Middleman et al., 1995; Midgley et al., 2000; Substance Abuse and Mental Health Services Administration Office of the Assistant Secretary, 1996).
Previous studies have shown that rats are capable of “playing the odds” and making advantageous choices in a rat version of the IGT (Zeeb, Robbins, & Winstanley, 2008; Zeeb & Winstanley, 2011), where rats choose among four levers that differ in reward magnitude, uncertainty, and delay. Furthermore, pharmacological manipulations of the DA and serotonergic systems impair decision-making on the rat IGT, leading to preference for disadvantageous levers. Our study modified the payoffs from each lever to enable comparison of lever choice where one variable (reward magnitude, probability, or delay) was held constant (Wallin-Miller, Li, Kelishani, & Wood, 2018; Fig. 4A). Although rats could earn nearly twice as many pellets from a consistent response on one of two advantageous levers (up to 208 pellets/session), they preferred the disadvantageous lever that delivered four pellets per trial (122 pellets/session). However, compared with vehicle-treated rats, testosterone-treated rats showed a stronger preference for the disadvantageous four-pellet lever and a weaker preference for levers associated with lower value rewards (Fig. 4B).
To summarize, several key features emerge from discounting tasks. AAS do not cause impulsivity with consistent preference for small, low-cost rewards, nor do they cause a risky “win-at-all-costs” strategy that always favors the large reward. Instead, there is a selective effect of AAS, where steroid-treated rats are less sensitive to effort (Wallin et al., 2015), punishment (Cooper et al., 2014), and delay (Wood et al., 2013) but are more sensitive to uncertainty (Wallin et al., 2015). These findings highlight that AAS effects on decision-making in humans may be somewhat subtle because they are context dependent. This does not mean that AAS are safe but that effects on aggression and sexual behavior may be more likely to manifest under certain circumstances (e.g., loss aversion in situations involving uncertainty).
Neurobiology of Testosterone and Decision-Making
It is likely that the effects of androgens on motivation and decision-making involve the mesolimbic DA system. The mesolimbic DA system is central to motivation and reward but also regulates decision-making through connections with PFC (Orsini et al., 2015). DA dysfunction is implicated in impaired decision-making. Patients with neurological disorders involving DA, such as schizophrenia and Parkinson’s disease, exhibit abnormal choice behavior and impulse control (Mehler-Wex et al., 2006).
Already, we know that both testosterone and Acb DA are essential for mating and fighting. DA is released into Acb with sex (Pfaus et al., 1990) and aggression (van Erp & Miczek, 2000). Furthermore, testosterone is required for DA release that accompanies (and presumably drives) male mating (Hull, Du, Lorrain, & Matuszewich, 1995; Putnam, Du, Sato, & Hull, 2001). However, it is also important to note that DA is not the only neurochemical system sensitive to AAS. AAS influence aggression via modulation of the serotonergic system (Melloni & Ricci, 2010). AAS decrease serotonergic function in the hypothalamus, amygdala, and nucleus Acb by inducing long-lasting decreases in serotonin innervation, release, and receptor density (Salas-Ramirez, Montalto, & Sisk, 2010; Zotti et al., 2014). AAS also influence the function of arginine vasopressin, glutamate, and GABA (Cunningham et al., 2013).
Nonetheless, the interaction of AAS and DA is still unclear. As measured by in vivo microdialysis, testosterone per se does not induce Acb DA release (Triemstra, Sato, & Wood, 2008). Furthermore, testosterone modifies expression of social behaviors (mating, fighting) but does not itself cause behavior. Instead, studies have shown that AAS reduce cocaine- or amphetamine-induced DA release in Acb (Kailanto, Kankaanpaa, & Seppala, 2011; Kurling, Kankaanpaa, & Seppala, 2008), most likely mediated through AAS-induced alterations in DA D1-like (D1R) and D2-like (D2R) receptors in Acb subnuclei. AAS decrease D2R density in the shell region of Acb (AcbSh) and increase D2R density in the core region (AcbC). AAS also decrease D1R density in both subregions of Acb (Kindlundh et al., 2001).
As illustrated in Figure 5, AAS and DA each have site- and task-specific effects on discounting costs. Using selective inactivation of Acb subnuclei, effort discounting is localized to AcbC, while AcbSh regulates probability discounting (Ghods-Sharifi & Floresco, 2010; Stopper & Floresco, 2011). For probability discounting, testosterone reduces preference for the large reward lever, as described for decision-making and uncertainty previously (Wallin et al., 2015). Other labs have demonstrated that systemic treatment with either the D2R antagonist eticlopride hydrochloride or the D1R antagonist SCH23390 hydrobromide (SCH) also reduce large reward preference with probability discounting (Floresco, Tse, & Ghods-Sharifi, 2008; St. Onge & Floresco, 2009; St. Onge, Abhari, & Floresco, 2011; Stopper, Khayambashi, & Floresco, 2013). Systemic treatment with agonists of D1R (SKF81297 [SKF]) or D2R (quinpirole) have the opposite effect (St. Onge & Floresco, 2009). These pharmacologic manipulations align with the observation that the long-acting AAS nandrolone decanoate decreases D1R and D2R in AcbSh (Kindlundh et al., 2001; Fig. 5B). Accordingly, it seems likely that AAS increase sensitivity to uncertainty during probability discounting by reducing DA receptors in AcbSh (Fig. 5C). In support of this argument, low doses of SKF or quinpirole during probability discounting selectively restored preference for the large reward lever in testosterone-treated males to the level of vehicle controls (Wallin-Miller, Kreutz, Li, & Wood, 2018; Fig. 6).
The opposite is true for effort discounting. Testosterone increases rats’ willingness to expend physical effort to obtain a large reward (Wallin et al., 2015). In other studies, systemic treatment with the D2R antagonist eticlopride hydrochloride and to a lesser extent the D1R antagonist SCH also reduce large reward preference (Floresco, Tse, & Ghods-Sharifi, 2008; Nowend, Arizzi, Carlson, & Salamone, 2001). Since AAS increase D2R in AcbC (Kindlundh et al., 2001), it is logical that AAS increase the willingness to work for a large reward through increased D2R in AcbC. The links with D1R are somewhat more difficult to predict: systemic SCH stimulates a modest decrease in preference for the large reward during effort discounting (Floresco, Tse, & Ghods-Sharifi, 2008), yet nandrolone reduces D1R in AcbC (Kindlundh et al., 2001). This discrepancy is as yet unexplained, and the specific targets of AAS for effort-based decision-making remain unresolved.
In addition to modulating neurotransmitter systems, AAS affect brain structure at the gross and microscopic levels. A recent brain imaging study found a negative correlation between AAS use and both brain volume and cortical thickness (Bjørnebekk et al., 2017). In a related study measuring resting-state functional brain connectivity by fMRI, AAS users had reduced connectivity between brain regions involved in emotional and cognitive regulation, including between the amygdala and default-mode network (Westlye, Kaufmann, Alnæs, Hullstein, & Bjørnebekk, 2016). At the microscopic level, AAS in rats reduce dendritic spine density on medium spiny neurons (MSN) in Acb (Wallin-Miller, Li, Kelishani, & Wood, 2016). Nearly every drug of abuse has been shown to induce structural plasticity in Acb (reviewed in Robinson & Kolb, 2004; Russo, Dietz, Dumitriu, Malenka, & Nestler, 2010). However, different classes of addictive drugs can exert opposite effects on MSN spine density. For instance, stimulants such as cocaine and amphetamine increase MSN spine density (Li, Kolb, & Robinson, 2003), while opiates like morphine decrease spine density (Robinson, Gorny, Savage, & Kolb, 2002). In our recent study (Wallin-Miller et al., 2016), high-dose testosterone significantly decreased spine density in AcbSh (Fig. 7). Even so, testosterone did not significantly affect total spine number, dendritic length, or arborization measured by Sholl analysis. These results provide a potential mechanism for AAS to modify cognition and decision-making behavior. In this regard, MSN spines integrate ascending DA projections from VTA with excitatory glutamatergic inputs from PFC, amygdala, and hippocampus and provide a neural substrate for behavioral changes in decision-making and addiction (Russo et al., 2010).
AAS Are Rewarding
Reinforcing Effects of Androgens
AAS users try to distance themselves from users of street drugs, arguing that, “Unlike, say, crack addicts, the men who take steroids are basically healthy, clean-living people” (McDougall, 2004). However, clinical research suggests that a significant fraction of long-term users develop dependence (Grönbladh, Nylander, & Hallberg, 2016). In the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), AAS dependency is in the category of “other substance-related disorder.” Unlike other drugs of abuse, AAS do not produce a short-term “high,” and users are not initially motivated by their reinforcing effects. However, with prolonged AAS exposure, some individuals experience withdrawal symptoms (depression, anhedonia, hypogonadism) when they attempt to stop using (Kanayama, Brower, Wood, Hudson, & Pope, 2009).
Our laboratory pioneered androgen self-administration in rats and hamsters to model reinforcing effects of AAS abuse. We have demonstrated androgen self-administration orally, IV, and ICV (Wood, 2008), supporting the hypothesis that androgens are reinforcing via effects on the brain. Moreover, androgens may cause dependence, as evidenced by tolerance (Peters & Wood, 2004b), withdrawal (Peters & Wood, 2004a), and fatal overdose during self-administration (Peters & Wood, 2004b). Many aspects of androgen self-administration in animals parallel human AAS use (reviewed in Wood, 2008). AAS abuse is greatest in the late teens, when endogenous androgen production peaks. Likewise, we found that high circulating androgens increase sensitivity to exogenous androgens. In addition, most human users begin with oral androgens and progress to injectable steroids. Similarly, hamsters show greater self-administration of injectable androgens versus orally active AAS. In both humans and hamsters, there is a strong association of AAS and exercise, and steroids may increase sexual activity. Last, although AAS use is uncommon in women, female hamsters self-administer testosterone.
Hormonal Mechanisms for Androgen Reward
Initially, we investigated the hormonal signals and neural mechanisms for the reinforcing effects of AAS. Animals will self-administer testosterone, the nonaromatizable androgen dihydrotestosterone (DHT), or estrogen; they show conditioned place preference (CPP) in response to testosterone, DHT, or 3αdiol, a DHT metabolite (reviewed in Wood, 2008). Together, these results suggest that either androgens or estrogens have potential to influence brain systems for reward and decision-making. This implies that AAS may act through classical androgen (AR) or estrogen receptors (ER), or through non-genomic mechanisms (Balthazart, Choleris, & Remage-Healey, 2018). There is substantial overlap in the brain distribution of AR, and ER, including both α and β forms of the ER (Hull et al., 2006).
A large body of research has mapped brain sites for testosterone modulation of mating and aggression. For agonistic behavior, AAS bind to AR in the anterior hypothalamus (Melloni & Ricci, 2010). Similarly, the medial preoptic area has abundant AR and ER and is key for expression of male sexual behavior (Hull et al., 2006). However, injections of testosterone into medial preoptic area fail to induce CPP in rats (King, Packard, & Alexander, 1999). Instead, testosterone injected into Acb can induce CPP (Packard, Cornell, & Alexander, 1997). Since the mesolimbic DA system has relatively few classical steroid receptors (Kritzer, 1997), it is likely that the effects of AAS on Acb are transduced through non-genomic receptors. This was tested with ICY self-administration of DHT coupled to bovine serum albumin and self-administration in Tfm mutant rats, which lack functional AR. From the results of these studies, it appears that classical AR are not required for androgen reinforcement (Sato, Johansen, Jordan, & Wood, 2010).
Neurobiology of Androgen Reward
Many drugs of abuse also act in the mesolimbic DA system to increase DA release (amphetamines) or inhibit DA reuptake (cocaine; Cooper, Robison, & Mazei-Robison, 2017). Already there is evidence that AAS impact Acb DA. Male rats form CPP in response to intra-Acb infusion of testosterone (Packard et al., 1997). Conversely, systemic or intra-Acb treatment with D1R and D2R antagonists blocks testosterone-induced CPP (Packard, Schroeder, & Alexander, 1998; Schroeder & Packard, 2000). Last, high-dose testosterone stimulates Fos not only in brain circuits for male sexual behavior but also in VTA (DiMeo & Wood, 2006). Nonetheless, as measured by in vivo microdialysis, testosterone does not acutely stimulate Acb DA release (Triemstra et al., 2008). Perhaps this is not unexpected. The time-course of testosterone reward is slow (Johnson & Wood, 2001), compared with cocaine or other addictive drugs.
On the other hand, androgen reward may be mediated by opioidergic as well as DA mechanisms. Over the course of our self-administration studies, we found that several animals died. Upon further examination, testosterone self-administration ICY causes autonomic depression, similar to opioid overdose (Peters & Wood, 2004b). This is blocked by the opioid antagonist naltrexone. In other studies, nandrolone enhances morphine-induced hypothermia through κ opioid receptors (Celerier et al., 2003). Likewise, testosterone enhances antinociceptive effects of the κ agonist U50,488 (Stoffel, Ulibarri, Folk, Rice, & Craft, 2005). This is consistent with nandrolone-induced opioid receptor binding in brain (Johansson, Hallberg, Kindlundh, & Nyberg, 2000).
Furthermore, emerging evidence suggests that AAS users do abuse other drugs, particularly opioids (Sagoe et al., 2015). AAS and opioids are linked most often through the common bond of exercise. Most AAS users engage in high-intensity exercise to maximize anabolic gains. With injury and overtraining, the combination of AAS and opiates enables the user to continue training despite muscle and joint pain. Among bodybuilders, nalbuphine hydrochloride (Nubain) is popular (Wines et al., 1999) and is associated with other substance misuse. Inevitably, some individuals develop opioid dependence. AAS may interact with heroin in accidental drug overdose (Thiblin et al., 2000).
In 1989, Kashkin and Kleber hypothesized that AAS dependence might involve opioidergic mechanisms, in which AAS potentiate endogenous opioid activity, and AAS withdrawal leads to an acute hyperadrenergic syndrome (reviewed in Grönbladh et al., 2016). In 2002, Arvary and Pope suggested that AAS could act as a gateway drug to opioid dependence (reviewed in Pope et al., 2013). In a survey of 223 men entering drug treatment, AAS use was considerably higher (25%) among opioid users, compared with men using other drugs (5%; Kanayama, Cohane, Weiss, & Pope, 2003). A recent study from New Zealand found that 50% of dependent AAS users met DSM-IV criteria for a lifetime history of opioid abuse or dependence, as compared to 19% of nondependent AAS users and 7% of nonusers (see Kanayama et al., 2009).
Questions remain regarding the mechanisms through which AAS impair cognitive function. First, we do not know the timing and duration of AAS effects: How rapidly do behavioral changes emerge, and how long do they persist when steroids are discontinued? Rapid actions (hours/days) could implicate involvement of nongenomic steroid receptors in Acb (Sato et al., 2010). Slower changes in behavior (days/weeks) would be consistent with actions of AAS on classical genomic receptors. In this regard, testosterone decreased dendritic spine density in Acb after eight weeks of chronic treatment, as described in the Neurobiology of Testosterone and Decision-Making section. However, in a small pilot study, we found no effect on dendritic spines after only two weeks of testosterone exposure (unpublished findings). This suggests that structural effects of AAS on MSN in Acb may take several weeks to emerge.
Although some users experience negative symptoms of withdrawal when AAS use is discontinued, we do not know how long cognitive alterations may persist after cessation of AAS use. This is particularly relevant because most AAS users are young adults, and it is possible that AAS abuse may alter brain development to cause enduring cognitive differences. In this regard, Cunningham et al. (2007) found that AAS-induced changes in hippocampal dendritic spine density persisted for weeks after drug treatment ended. If so, there is the additional possibility that early AAS use could accelerate age-related cognitive decline and neural degeneration. Pharmacologic investigations may also reveal manipulations (such as dopaminergic agents) that can rescue cognitive function after (or even during) AAS abuse. This could lead to medical treatments to improve the well-being of current and former AAS users.
Furthermore, we cannot differentiate whether AAS effects on cognition are mediated via androgen or estrogen receptors. Testosterone can be converted in the brain to androgenic or estrogenic metabolites. Likewise, human AAS users commonly abuse both aromatizable and non-aromatizable androgens (Pope et al., 2013). Thus AAS may exert their influence over behavior and brain function by androgenic and/or estrogenic mechanisms. Future studies could investigate the effects of non-aromatizable androgens (such as DHT) and estrogens on decision-making in male rats. In this regard, Uban, Rummel, Floresco, and Galea (2011) found that estradiol increased large reward preference during effort discounting in ovariectomized female rats. Although we cannot definitively identify the mechanism of AAS action on cognition, our studies of AAS self-administration suggest that the reinforcing effects are related to androgenic potency (Ballard & Wood, 2005). This suggests that AAS may be transduced through the mesolimbic DA system via androgenic mechanisms.
Last, additional behavioral investigations will add to our understanding of AAS effects on cognition. In humans and animals, AAS increase willingness to expend physical effort. Human users engage in high-intensity exercise to maximize anabolic gains (Pope et al., 2013). This is consistent with our recent finding that testosterone reduces sensitivity to effort discounting (Wallin et al., 2015). Nonetheless, it remains unclear how these findings relate to decision-making and risk-taking in modern society. In the early 21st century, the majority of decisions that determine neuroeconomic success involve cognitive effort, including attention and executive function, rather than physical effort (Cocker, Hosking, Benoit, & Winstanley, 2012). Furthermore, different neural substrates may underlie physical and cognitive effort. Specifically, cognitive effort decision-making is less sensitive to DA manipulations (Hosking, Floresco, & Winstanley, 2015). However, cognitive effort is dependent on normal function of the PFC (Hosking, Cocker, & Winstanley, 2014). Determining AAS effects on cognitive effort discounting will be important for understanding behavioral deficits of human users and for highlighting the potential of these drugs to interfere with performance in the workplace and the classroom.
Recent human and animal studies reveal previously unknown cognitive and behavioral effects of AAS. These findings contrast with common misconceptions regarding AAS abuse. In particular, the public and media often focus on AAS use by famous athletes, highlighting the problem of fairness in professional sports. However, AAS impairment of cognition and behavior is a more substantial problem for public health and may contribute to the increased incidence of such psychiatric disturbances in human AAS users (Pope et al., 2013; Thiblin et al., 2000). AAS use by young athletes in high school and college is particularly disturbing, as adolescents’ developing brains render them more prone to the cognitive and behavioral deficits identified here (Blakemore & Choudhury, 2006), and accidental injury is the leading cause of death in adolescents and young adults (Centers for Disease Control and Prevention, 2016).
Along with altered decision-making, AAS causes corresponding alterations in the mesocorticolimbic DA system. Elucidating AAS influence over behavior and its neural substrates will facilitate better medical interventions for AAS abusers. Understanding AAS effects on the mesolimbic DA system may even lead to the development of pharmacologic treatments for the cognitive and behavioral effects of AAS. However, the most significant potential impact of this work is to highlight previously unknown dangers of AAS use. Although clinicians may recognize the physiological side effects of AAS, they may not be attuned to behavioral side effects. Furthermore, there is a need to inform policymakers, medical practitioners, and public health authorities about the consequences of AAS use on brain and behavior.
We thank Grace Li, Jordyn Chesley, Diana Kelishani, Frida Kreutz, and Soheila Zoriyat Khah for assistance with animal studies of decision-making. This work was supported by the National Institutes of Health (NIH R01-DA029613 to RIW).
American College of Sports Medicine. (2006). Position statement: Senate hearing on the abuse of anabolic steroids and their precursors by adolescent athletes. Indianapolis, IN: Author.Find this resource:
Andrew, R. J., & Rogers, L. J. (1972). Testosterone, search behaviour and persistence. Nature, 237, 343–346.Find this resource:
Ballard, C. L., & Wood, R. I. (2005). Male hamsters self-administer commonly abused androgens. Behavioural Neuroscience, 119, 752–758.Find this resource:
Balthazart, J., Choleris, E., & Remage-Healey, L. (2018). Steroids and the brain: 50 years of research, conceptual shifts and the ascent of non-classical and membrane-initiated actions. Hormones and Behavior, 99, 1–8.Find this resource:
Basile, J. R., Binmadi, N. O., Zhou, H., Yang, Y. H., Paoli, A., & Proia, P. (2013). Supraphysiological doses of performance enhancing anabolic-androgenic steroids exert direct toxic effects on neuron-like cells. Frontiers in Cellular Neuroscience, 7, 69.Find this resource:
Bechara, A., Damasio, A. R., Damasio, H., & Anderson, S. W. (1994). Insensitivity to future consequences following damage to human prefrontal cortex. Cognition, 50, 7–15.Find this resource:
Blakemore, S. J., & Choudhury, S. (2006). Development of the adolescent brain: Implications for executive function and social cognition. Journal of Child Psychology and Psychiatry, 47, 296–312.Find this resource:
Blanco, C. E., Peltz. A., Staley, R., & Kim. F. (2002). Effects of pharmacologic androgen treatment duration on glucocorticoid receptor alpha immunoreactivity of lumbosacral motor neurons in the male rat. Neuroscience, 115, 941–949.Find this resource:
Bolding, G., Sherr, L., & Elford, J. (2002). Use of anabolic steroids and associated health risks among gay men attending London gyms. Addiction, 97, 195–203.Find this resource:
Bjørnebekk, A., Walhovd, K. B., Jørstad, M. L., Due-Tønnessen, P., Hullstein, I. R., & Fjell, A. M. (2017). Structural brain imaging of long-term anabolic-androgenic steroid users and nonusing weightlifters. Biological Psychiatry, 82(4), 294–302.Find this resource:
Borowsky, I. W. (1997). Adolescent sexual aggression: Risk and protective factors. Pediatrics, 100(6), e7.Find this resource:
Broverman, D. M., Broverman, I. K., Vogel, W., Palmer, R. D., & Klaiber, E. L. (1964). The automatization cognitive style and physical development. Child Development, 35, 1343–1359.Find this resource:
Brower, K. J., Blow, F. C., Young, J. P., & Hill, E. M. (1991). Symptoms and correlates of anabolic-androgenic steroid dependence. British Journal of Addiction, 86, 759–768.Find this resource:
Caleza, C., Yañez-Vico, R. M., Mendoza, A., & Iglesias-Linares, A. (2016). Childhood obesity and delayed gratification behavior: A systematic review of experimental studies. The Journal of Pediatrics, 169, 201–207.Find this resource:
Caraci, F., Pistarà, V., Corsaro, A., Tomasello, F., Giuffrida, M. L., Sortino, M. A., . . . Copani, A. (2011). Neurotoxic properties of the anabolic androgenic steroids nandrolone and methandrostenolone in primary neuronal cultures. Journal of Neuroscience Research, 89, 592–600.Find this resource:
Celerier, E., Yazdi, M. T., Castane, A., Ghozland, S., Nyberg, F., & Maldonado, R. (2003). Effects of nandrolone on acute morphine responses, tolerance and dependence in mice. European Journal of Pharmacology, 465, 69–81.Find this resource:
Centers for Disease Control and Prevention. (2012). Youth risk behavior surveillance—United States, 2011. MMWR, 61(4), 23.Find this resource:
Centers for Disease Control and Prevention. (2016). Adolescent health. Atlanta, GA: Author.Find this resource:
Choi, P. Y., & Pope, H.G. Jr. (1994). Violence toward women and illicit androgenic-anabolic steroid use. Annals of Clinical Psychiatry, 6, 21–25.Find this resource:
Coates, J. M., & Herbert, J. (2008). Endogenous steroids and financial risk taking on a London trading floor. Proceedings of the National Academy of Sciences of the United States of America, 105, 6167–6172.Find this resource:
Cocker, P. J., Hosking, J. G., Benoit, J., & Winstanley, C. A. (2012). Sensitivity to cognitive effort mediates psychostimulant effects on a novel rodent cost/benefit decision-making task. Neuropsychopharmacology, 37(8), 1825–1837.Find this resource:
Cooper, S. E., Goings, S. P., Kim, J. Y., & Wood, R. I. (2014). Testosterone effects on risk tolerance and motor impulsivity in male rats. Psychoneuroendocrinology, 40, 201–212.Find this resource:
Cooper, S., Robison, A. J., & Mazei-Robison, M. S. (2017). Reward circuitry in addiction. Neurotherapeutics, 14(3), 687–697.Find this resource:
Cunningham, R. L., Claiborne, B. J., & McGinnis, M. Y. (2007). Pubertal exposure to anabolic androgenic steroids increases spine densities on neurons in the limbic system of male rats. Neuroscience, 150(3), 609–615.Find this resource:
Cunningham, R. L., Giuffrida, A., & Roberts, J. L. (2009). Androgens induce dopaminergic neurotoxicity via caspase-3-dependent activation of protein kinase C delta. Endocrinology, 150(12), 5539–5548.Find this resource:
Cunningham, R. L., Lumia, A. R., & McGinnis, M. Y. (2013). Androgenic anabolic steroid exposure during adolescence: Ramifications for brain development and behavior. Hormones and Behavior, 64(2), 350–356.Find this resource:
DiMeo, A. N., & Wood, R. I. (2006). Anabolic steroids activate Fos in forebrain and brainstem. Psychoneuroendocrinology, 31, 237–249.Find this resource:
Drug Enforcement Administration. (n.d.). Controlled substance schedules. Springfield, VA: Author.Find this resource:
Farrell, S. F., & McGinnis, M. Y. (2004). Long-term effects of pubertal anabolic-androgenic steroid exposure on reproductive and aggressive behaviors in male rats. Hormones and Behavior, 46(2), 193–203.Find this resource:
Floresco, S. B., Block, A. E., & Tse, M. T. (2008). Inactivation of the medial prefrontal cortex of the rat impairs strategy set-shifting, but not reversal learning, using a novel, automated procedure. Behavioural Brain Research, 190(1), 85–96.Find this resource:
Floresco, S. B., Tse, M. T., & Ghods-Sharifi, S. (2008). Dopaminergic and glutamatergic regulation of effort-and delay-based decision making. Neuropsychopharmacology, 33(8), 1966–1979.Find this resource:
Floresco, S. B., Zhang, Y., & Enomoto, T. (2009). Neural circuits subserving behavioral flexibility and their relevance to schizophrenia. Behavioural Brain Research, 204(2), 396–409.Find this resource:
Ghods-Sharifi, S., & Floresco, S. B. (2010). Differential effects on effort discounting induced by inactivations of the nucleus accumbens core or shell. Behavioural Neuroscience, 124(2),179–191.Find this resource:
Grönbladh, A., Nylander, E., & Hallberg, M. (2016). The neurobiology and addiction potential of anabolic androgenic steroids and the effects of growth hormone. Brain Research Bulletin, 126(Pt. 1), 127–137.Find this resource:
Gwartney, D. (2005). Steroid addiction: Fact or fallacy? Muscular Development.Find this resource:
Haluk, D. M., & Floresco, S. B. (2009). Ventral striatal dopamine modulation of different forms of behavioral flexibility. Neuropsychopharmacology, 34(8), 2041–2052.Find this resource:
Hamblin, J. (2016, June 16). Toxic masculinity and murder: Can we talk about men? The Atlantic.Find this resource:
Heffernan, T. M., Battersby, L., Bishop, P., & O’Neill, T. S. (2015). Everyday memory deficits associated with anabolic-androgenic steroid use in regular gymnasium users. The Open Psychiatry Journal, 9, 1–6.Find this resource:
Hosking, J. G., Cocker, P. J., & Winstanley, C. A. (2014). Dissociable contributions of anterior cingulate cortex and basolateral amygdala on a rodent cost/benefit decision-making task of cognitive effort. Neuropsychopharmacology, 39(7), 1558–1567.Find this resource:
Hosking, J. G., Floresco, S. B., & Winstanley, C. A. (2015). Dopamine antagonism decreases willingness to expend physical, but not cognitive, effort: A comparison of two rodent cost/benefit decision-making tasks. Neuropsychopharmacology, 40(4), 1005–1015.Find this resource:
Hull, E. M., Du, J., Lorrain, D. S., & Matuszewich, L. (1995). Extracellular dopamine in the medial preoptic area: Implications for sexual motivation and hormonal control of copulation. The Journal of Neuroscience, 15(11), 7465–7471.Find this resource:
Hull, E. M., Wood, R. I., & McKenna, K. E. (2006). Male sexual behavior. In J. D. Neill (Ed.), The physiology of reproduction (3rd ed., pp. 1729–1824). New York, NY: Raven Press.Find this resource:
Ip, E. J., Yadao, M. A., Shah, B. M., & Lau, B. (2016). Infectious disease, injection practices, and risky sexual behavior among anabolic steroid users. AIDS Care, 28(3), 294–299.Find this resource:
Johansson, P., Hallberg, M., Kindlundh, A., & Nyberg, F. (2000). The effect on opioid peptides in the rat brain, after chronic treatment with the anabolic androgenic steroid, nandrolone decanoate. Brain Research Bulletin, 51, 413–418.Find this resource:
Johnson, L. R., & Wood, R. I. (2001). Oral testosterone self-administration in male hamsters. Neuroendocrinology, 73, 285–292.Find this resource:
Johnston, L. D., O’Malley, P. M., Bachman, J. G., & Schulenberg, J. E. (2013). Monitoring the future: National results on drug use: 2012 overview, key findings on adolescent drug use. Ann Arbor: Institute for Social Research, University of Michigan.Find this resource:
Kailanto, S., Kankaanpaa, A., & Seppala, T. (2011). Subchronic steroid administration induces long lasting changes in neurochemical and behavioral response to cocaine in rats. Steroids, 76(12), 1310–1316.Find this resource:
Kanayama, G., Cohane, G. H., Weiss, R. D., & Pope, H. G. (2003). Past anabolic-androgenic steroid use among men admitted for substance abuse treatment: An underrecognized problem? Journal of Clinical Psychiatry, 64, 156–160.Find this resource:
Kanayama, G., Brower, K. J., Wood, R. I., Hudson, J. I., & Pope, H. G. Jr. (2009). Issues for DSM-V: Clarifying the diagnostic criteria for anabolic-androgenic steroid dependence. American Journal of Psychiatry, 166(6), 642–645.Find this resource:
Kanayama, G., Kean, J., Hudson, J. I., & Pope, H. G. Jr. (2013). Cognitive deficits in long-term anabolic-androgenic steroid users. Drug and Alcohol Dependence, 130(1–3), 208–214.Find this resource:
Kaufman, M. J., Janes, A. C., Hudson, J. I., Brennan, B. P., Kanayama, G., Kerrigan, A. R., . . . Pope, H. G. Jr. (2015). Brain and cognition abnormalities in long-term anabolic-androgenic steroid users. Drug and Alcohol Dependence, 152, 47–56.Find this resource:
Kindlundh, A. M., Lindblom, J., Bergström, L., & Nyberg, F. (2001). The anabolic-androgenic steroid nandrolone decanoate affects the density of dopamine receptors in the male rat brain. European Journal of Neuroscience, 13(2), 291–296.Find this resource:
King, B. E., Packard, M. G., & Alexander, G. M. (1999). Affective properties of intra-medial preoptic area injections of testosterone in male rats. Neuroscience Letters, 269, 149–152.Find this resource:
Kirby, K. N., Petry, N. M., & Bickel, W. K. (1999). Heroin addicts have higher discount rates for delayed rewards than non-drug-using controls. Journal of Experimental Psychology: General, 128(1), 78–87.Find this resource:
Kritzer, M. F. (1997). Selective colocalization of immunoreactivity for intracellular gonadal hormone receptors and tyrosine hydroxylase in the ventral tegmental area, substantia nigra, and retrorubral fields in the rat. Journal of Comparative Neurology, 379, 247–260.Find this resource:
Kurling, S., Kankaanpaa, A., & Seppala, T. (2008). Sub-chronic nandrolone treatment modifies neurochemical and behavioral effects of amphetamine and 3,4-methylenedioxymethamphetamine (MDMA) in rats. Behavioural Brain Research, 189(1), 191–201.Find this resource:
Li, Y., Kolb, B., & Robinson, T. E. (2003). The location of persistent amphetamine-induced changes in the density of dendritic spines on medium spiny neurons in the nucleus accumbens and caudate-putamen. Neuropsychopharmacology, 28(6), 1082–1085.Find this resource:
Magnusson, K., Hånell, A., Bazov, I., Clausen, F., Zhou, Q., & Nyberg, F. (2009). Nandrolone decanoate administration elevates hippocampal prodynorphin mRNA expression and impairs Morris water maze performance in male rats. Neuroscience Letters, 467(3), 189–193.Find this resource:
McDougall, C. (2004, December 6). Cracking down on steroid use. Men's Health.Find this resource:
Mehler-Wex, C., Riederer, P., & Gerlach, M. (2006). Dopaminergic dysbalance in distinct basal ganglia neurocircuits: Implications for the pathophysiology of Parkinson’s disease, schizophrenia and attention deficit hyperactivity disorder. Neurotoxicity Research, 10(3–4), 167–179.Find this resource:
Mehta, P. H., & Beer, J. (2010). Neural mechanisms of the testosterone–aggression relation: The role of orbitofrontal cortex. Journal of Cognitive Neuroscience, 22(10), 2357–2368.Find this resource:
Melloni, R. H., & Ricci, L. A. (2010). Adolescent anabolic/androgenic steroids and the neurobiology of offensive aggression: A hypothalamic neural model of aggression based on findings in pubertal Syrian hamsters. Hormones and Behavior, 58(1), 177–191.Find this resource:
Middleman, A. B., Faulkner, A. H., Woods, E. R., Emans, S. J., & Durant, R. H. (1995). High-risk behaviors among high school students in Massachusetts who use anabolic steroids. Pediatrics, 96(2 Pt. 1), 268–272.Find this resource:
Midgley, S. J., Heather, N., Best, D., Henderson, D., McCarthy, S., & Davies, J. B. (2000). Risk behaviours for HIV and hepatitis infection among anabolic-androgenic steroid users. AIDS Care, 12(2), 163–170.Find this resource:
Miedl, S. F., Peters, J., & Büchel, C. (2012). Altered neural reward representations in pathological gamblers revealed by delay and probability discounting. Archives of General Psychiatry, 69(2), 177–186.Find this resource:
Mischel, W., Ebbesen, E. B., & Zeiss, A. R. (1972). Cognitive and attentional mechanisms in delay of gratification. Journal of Personality and Social Psychology, 21(2), 204–218.Find this resource:
Mitchell, M. R., Vokes, C. M., Blankenship, A. L., Simon, N. W., & Setlow, B. (2011). Effects of acute administration of nicotine, amphetamine, diazepam, morphine, and ethanol on risky decision-making in rats. Psychopharmacology, 218(4), 703–712.Find this resource:
Moss, H. B., Panzak, G. L., & Tarter, R. E. (1993). Sexual functioning of male anabolic steroid users. Archives of Sexual Behavior, 22, 1–12.Find this resource:
Nowend, K. L., Arizzi, M., Carlson, B. B., & Salamone, J. D. (2001). D1 or D2 antagonism in nucleus accumbens core or dorsomedial shell suppresses lever pressing for food but leads to compensatory increases in chow consumption. Pharmacology, Biochemistry and Behavior, 69(3–4), 373–382.Find this resource:
Oberlander, J. G., & Henderson, L. P. (2012). The Sturm und Drang of anabolic steroid use: Angst, anxiety, and aggression. Trends in Neuroscience, 35(6), 382–392.Find this resource:
Orsini, C. A., Moorman, D. E., Young, J. W., Setlow, B., & Floresco, S. B. (2015). Neural mechanisms regulating different forms of risk-related decision-making: Insights from animal models. Neuroscience and Biobehavioral Reviews, 58, 147–167.Find this resource:
Packard, M. G., Cornell, A. H., & Alexander, G. M. (1997). Rewarding affective properties of intra-nucleus accumbens injections of testosterone. Behavioural Neuroscience, 111, 219–224.Find this resource:
Packard, M. G., Schroeder, J. P., & Alexander, G. M. (1998). Expression of testosterone conditioned place preference is blocked by peripheral or intra-accumbens injection of alpha-flupenthixol. Hormones and Behavior, 34(1), 39–47.Find this resource:
Peters, K. D., & Wood, R. I. (2004a). Anabolic-androgenic steroid addiction involves androgen and opioid receptors. Program No. 997.6. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience.Find this resource:
Peters, K. D., & Wood, R. I. (2004b). Androgen overdose: Behavioral and physiologic effects of testosterone infusion. Neuroscience, 130, 971–981.Find this resource:
Pfaus, J. G., Damsma, G., Nomikos, G. G., Wenkstern, D. G., Blaha, C.D., Phillips, A.G., & Fibiger, H. C. (1990). Sexual behavior enhances central dopamine transmission in the male rat. Brain Research, 530(2), 345–348.Find this resource:
Pieretti, S., Mastriota, M., Tucci, P., Battaglia, G., Trabace, L., Nicoletti, F., & Scaccianoce, S. (2013). Brain nerve growth factor unbalance induced by anabolic androgenic steroids in rats. Medicine in the Science of Sports and Exercise, 45(1), 29–35.Find this resource:
Pope, H. G. Jr., Kanayama, G., Athey, A., Ryan, E., Hudson, J. I., & Baggish, A. (2014). The lifetime prevalence of anabolic-androgenic steroid use and dependence in Americans: Current best estimates. American Journal of Addiction, 23(4), 371–377.Find this resource:
Pope, H. G., & Kanayama, G. (2015). Treatment of anabolic-androgenic steroid related disorders. In N. el-Guebaly, G. Carra, & M. Galanter (Eds.), Textbook of addiction treatment: International perspectives 2015 (pp. 621–636). Milan, Italy: Springer-Verlag.Find this resource:
Pope, H. G. Jr., & Katz, D. L. (1990). Homicide and near-homicide by anabolic steroid users. Journal of Clinical Psychiatry, 51, 28–31.Find this resource:
Pope, H. G. Jr., Wood, R. I., Rogol, A., Nyberg, F., Bowers, L., & Bhasin, S. (2013). Adverse health consequences of performance-enhancing drugs: An Endocrine Society scientific statement. Endocrine Reviews, 35(3), 341–375.Find this resource:
Putnam, S. K., Du, J., Sato, S., & Hull, E. M. (2001). Testosterone restoration of copulatory behavior correlates with medial preoptic dopamine release in castrated male rats. Hormones and Behavior, 39(3), 216–224.Find this resource:
Ramirez, J. M., & Andreu, J. M. (2006). Aggression, and some related psychological constructs (anger, hostility, and impulsivity). Some comments from a research project. Neuroscience and Biobehavioral Reviews, 30, 276–291.Find this resource:
Robinson, T. E., Gorny, G., Savage, V. R., & Kolb, B. (2002). Widespread but regionally specific effects of experimenter-versus self-administered morphine on dendritic spines in the nucleus accumbens, hippocampus, and neocortex of adult rats. Synapse, 46(4), 271–279.Find this resource:
Robinson, T. E., & Kolb, B. (2004). Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology, 47, 33–46.Find this resource:
Russo, S. J., Dietz, D. M., Dumitriu, D., Malenka, R. C., & Nestler, E. J. (2010). The addicted synapse: Mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends in Neuroscience, 33(6), 267–276.Find this resource:
Sagoe, D., McVeigh, J., Bjørnebekk, A., Essilfie, M. S., Andreassen, C. S., & Pallesen, S. (2015). Polypharmacy among anabolic-androgenic steroid users: A descriptive metasynthesis. Substance Abuse Treatment, Prevention, and Policy, 10, 12.Find this resource:
Salas-Ramirez, K. Y., Montalto, P. R., & Sisk, C. L. (2010). Anabolic steroids have long-lasting effects on male social behaviors. Behavioural Brain Research, 208(2), 328–335.Find this resource:
Substance Abuse and Mental Health Services Administration Office of the Assistant Secretary. (1996). 1994 national household survey on drug abuse, main findings 1994. DHHS Publication No. (SMA) 96–3085. Rockville, MD: Author.Find this resource:
Sato, S. M., Johansen, J., Jordan, C. L., & Wood, R. I. (2010). Membrane, not nuclear, androgen receptor mediates androgen reinforcement. Psychoneuroendocrinology, 35(7), 1063–1073.Find this resource:
Schroeder, J. P., & Packard, M. G. (2000). Role of dopamine receptor subtypes in the acquisition of a testosterone conditioned place preference in rats. Neuroscience Letters, 282, 17–20.Find this resource:
Setlow, B., Mendez, I. A., Mitchell, M. R., & Simon, N. W. (2009). Effects of chronic administration of drugs of abuse on impulsive choice (delay discounting) in animal models. Behavioural Pharmacology, 20(5–6), 380–389.Find this resource:
Shoda, Y., Mischel, W., & Peake, P. K. (1990). Predicting adolescent cognitive and self-regulatory competencies from preschool delay of gratification: Identifying diagnostic conditions. Developmental Psychology, 26(6), 978–986.Find this resource:
Simon, N. W., Montgomery, K. S., Beas, B. S., Mitchell, M. R., LaSarge, C. L., Mendez, I. A., . . . Bizon, J. L. (2011). Dopaminergic modulation of risky decision-making. Journal of Neuroscience, 31(48), 17460–17470.Find this resource:
Skårberg, K., Nyberg, F., & Engström, I. (2010). Is there an association between the use of anabolic-androgenic steroids and criminality? European Addiction Research, 16(4), 213–239.Find this resource:
Snyder, J. S., Soumier, A., Brewer, M., Pickel, J., & Cameron, H. A. (2011). Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature, 476(7361), 458–461.Find this resource:
St. Onge, J. R., & Floresco, S. B. (2009). Dopaminergic modulation of risk-based decision making. Neuropsychopharmacology, 34(3), 681–697.Find this resource:
St. Onge, J. R., & Floresco, S. B. (2010). Prefrontal cortical contribution to risk-based decision making. Cerebral Cortex, 20(8), 1816–1828.Find this resource:
St. Onge, J. R., Abhari, H., & Floresco, S. B. (2011). Dissociable contributions by prefrontal D1 and D2 receptors to risk-based decision making. Journal of Neuroscience, 31(23), 8625–8633.Find this resource:
St. Onge, J. R., Stopper, C. M., Zahm, D. S., & Floresco, S. B. (2012). Separate prefrontal-subcortical circuits mediate different components of risk-based decision making. Journal of Neuroscience, 32(8), 2886–2899.Find this resource:
Stanton, S. J., Liening, S. H., & Schultheiss, O. C. (2011). Testosterone is positively associated with risk taking in the Iowa Gambling Task. Hormones and Behavior, 59, 252–256.Find this resource:
Stoffel, E. C., Ulibarri, C. M., Folk, J. E., Rice, K. C., & Craft, R. M. (2005). Gonadal hormone modulation of mu, kappa, and delta opioid antinociception in male and female rats. Journal of Pain, 6, 261–274.Find this resource:
Stopper, C. M., & Floresco, S. B. (2011). Contributions of the nucleus accumbens and its subregions to different aspects of risk-based decision making. Cognitive, Affective, & Behavioral Neuroscience, 11(1), 97–112.Find this resource:
Stopper, C. M., Khayambashi, S., & Floresco, S. B. (2013). Receptor-specific modulation of risk-based decision making by nucleus accumbens dopamine. Neuropsychopharmacology, 38(5), 715–728.Find this resource:
Summers, J. (2003). Steroids 101. Aurora, CO: Anabolics.com.Find this resource:
Tanehkar, F., Rashidy-Pour, A., Vafaei, A. A., Sameni, H. R., Haghighi, S., Miladi-Gorji, H., . . . Bavarsad, K. (2013). Voluntary exercise does not ameliorate spatial learning and memory deficits induced by chronic administration of nandrolone decanoate in rats. Hormones and Behavior, 63(1), 158–165.Find this resource:
Thiblin, I., Lindquist, O., & Rajs, J. (2000). Cause and manner of death among users of anabolic androgenic steroids. Journal of Forensic Science, 45, 16–23.Find this resource:
Triemstra, J. L., Sato, S. M., & Wood, R. I. (2008). Testosterone-induced dopamine release in nucleus accumbens of male Syrian hamsters. Psychoneuroendocrinology, 33(3), 386–394.Find this resource:
Tsutsui, K. T., Wood, R. I., & Craft, R. M. (2011). Anabolic-androgenic steroid effects on nociception and morphine antinociception in male rats. Pharmacology Biochemistry and Behavior, 99(3), 500–508.Find this resource:
Uban, K. A., Rummel, J., Floresco, S. B., & Galea, L. A. (2011). Estradiol modulates effort-based decision making in female rats. Neuropsychopharmacology, 37(2), 390–401.Find this resource:
van Erp, A. M., & Miczek, K. A. (2000). Aggressive behavior, increased accumbal dopamine, and decreased cortical serotonin in rats. Journal of Neuroscience, 20(24), 9320–9325.Find this resource:
Wallin, K. G., & Wood, R. I. (2015). Anabolic-androgenic steroids impair set-shifting and reversal learning in male rats. European Neuropsychopharmacology, 25(4), 583–590.Find this resource:
Wallin, K. G., Alves, J. M., & Wood, R. I. (2015). Anabolic-androgenic steroids and decision making: Probability and effort discounting in male rats. Psychoneuroendocrinology, 57, 84–92.Find this resource:
Wallin-Miller, K. G., Li, G. R., Kelishani, D., & Wood, R. I. (2016). Anabolic-androgenic steroids decrease dendritic spine density the nucleus accumbens of male rats. Neuroscience, 330, 72–78.Find this resource:
Wallin-Miller, K. G., Kreutz, F., Li, G., & Wood, R. I. (2018). Anabolic-androgenic steroids (AAS) increase sensitivity to uncertainty by inhibition of dopamine D1 and D2 receptors. Psychopharmacology, 235(4), 959–969Find this resource:
Wallin-Miller, K. G., Li, G., Kelishani, D., & Wood, R. I. (2018). Anabolic-androgenic steroids alter decision making in a balanced rodent model of the Iowa Gambling Task. Behavioral Neuroscience, 132(3), 152–160Find this resource:
Westlye, L. T., Kaufmann, T., Alnæs, D., Hullstein, I. R., & Bjørnebekk, A. (2016). Brain connectivity aberrations in anabolic-androgenic steroid users. Neuroimage Clinic, 13, 62–69.Find this resource:
Wines, Jr., J. D., Gruber, A. J., Pope, Jr., H. G., & Lukas, S. E. (1999). Nalbuphine hydrochloride dependence in anabolic steroid users. American Journal of Addiction, 8, 161–164.Find this resource:
Wood, R. I. (2008). Anabolic steroid dependence? Insights from animals and humans. Frontiers in Neuroendocrinology, 29(4), 490–506.Find this resource:
Wood, R. I., Armstrong, A., Fridkin, V., Shah, V., Najafi, A., & Jakowec, M. (2013). ’Roid rage in rats? Testosterone effects on aggressive motivation, impulsivity and tyrosine hydroxylase. Physiology and Behavior, 110, 6–12.Find this resource:
Wood, R. I., & Stanton, S. J. (2012). Testosterone in sport: Current perspectives. Hormones and Behavior, 61(1), 147–155.Find this resource:
World Anti-Doping Agency. (2015). 2015 anti-doping testing figures. Montreal, QC: Author.Find this resource:
Xiao, L., & Jordan, C. L. (2002). Sex differences, laterality, and hormonal regulation of androgen receptor immunoreactivity in rat hippocampus. Hormones and Behavior, 42(3), 327–336.Find this resource:
Zeeb, F., Robbins, T. W., & Winstanley, C. A. (2008). Serotonergic and dopaminergic modulation of gambling behavior as assessed using a novel rat gambling task. Neuropsychopharmacology, 34, 2329–2343.Find this resource:
Zeeb, F. D., & Winstanley, C. A. (2011). Lesions of the basolateral amygdala and orbitofrontal cortex differentially affect acquisition and performance of a rodent gambling task. The Journal of Neuroscience, 31(6), 2197–2204.Find this resource:
Zotti, M., Tucci, P., Colaianna, M., Morgese, M. G., Mhillaj, E., Schiavone, S., . . . Trabace, L. (2014). Chronic nandrolone administration induces dysfunction of the reward pathway in rats. Steroids, 79, 7–13.Find this resource: