As professional baseball players have been finding out, steroid use draws a lot of scrutiny. And it's not just in pro sports. Given the surge in steroid abuse, especially among young people, neuroscientists are racing to find out whether and how these drugs affect the nervous system. At the University of Southern California's Keck School of Medicine, neuroscientists Cortney Ballard, PhD, and Ruth Wood, PhD, investigated for the first time how hamsters handled four popular anabolic steroids and got a clear answer: The nervous system can find some of these drugs reinforcing.
The findings, published in the June Behavioral Neuroscience (Vol. 119, No. 3), also show that it's not just the drug. It's the form of the drug. The injectable anabolic androgenic steroids (AASs) appear to be more reinforcing than oral AASs.
"This highly significant study...helps form the groundwork for the identification and characterization of AASs as classically rewarding substances," says Richard Melloni Jr., PhD, a behavioral neuroscientist at Northeastern University. Because rodents' nervous systems are like people's, researchers say they can comfortably transfer their conclusions to humans. Testing drug reinforcement in animals also allows scientists to eliminate the impact of social factors on drug use.
Nancy Pilotte, PhD, chief of the Functional Neuroscience Research Branch at the National Institute on Drug Abuse (NIDA), which helped to fund the study, describes it as a good first step in understanding how these drugs act on the brain. The research, she says, is crucial in figuring out whether their use can result in addiction, which NIDA views as a chronic relapsing brain disease in which people will take a drug often and repeatedly in the face of negative consequences. Says Pilotte, "We know these drugs are abused; now we're exploring whether they're addictive."
Evidence that steroids affect the nervous system augments the findings of neurobiologist Marilyn Y. McGinnis, PhD, of the University of Texas at San Antonio, that long-term AAS exposure boosts aggression in rats, particularly in response to mild provocation. McGinnis says that if anabolic steroids are rewarding, "this factor may contribute to the increasing and long-term use of these drugs in humans."
AASs have been classified as controlled substances since 1991, yet their potential for dependence remains largely unknown. "AASs are not mysterious, just understudied," says Wood. As abuse--their use for nonmedical purposes--has risen, doctors have begun to report possible cases of physical and psychological dependence. According to Ballard and Wood, more than 1 million Americans have taken these synthetic hormones, mostly to build muscle.
Melloni notes that steroids--also known as roids, juice, hype, weight trainers, gym candy or pumpers--have been "typically not thought of as classically rewarding substances like many other drugs of abuse, and so they are not considered as potentially dangerous by the American psyche."
Pilotte points out that people don't take AASs for themselves, as they might with cocaine or heroin, but rather for what they produce. The new revelation about reinforcement raises new questions because, as Wood notes, "Initially, most athletes and clinicians simply assumed that AASs acted systemically, but had little impact on the central nervous system."
Known health hazards include mood swings, hallucinations and paranoia; liver damage; high blood pressure; and increased risk of heart disease, stroke and some types of cancer. There are sex-specific dangers and, from sharing injection needles, the risks of HIV and hepatitis. The Centers for Disease Control and Prevention estimate that upwards of 3 percent of high schoolers have used steroids, a rate comparable to that of crack cocaine or heroin use.
Steroid abuse, especially by adolescents and young adults, can promote aggressive behaviors and may be followed by serious depression when their use is discontinued, says Pilotte. Still, abuse may be reinforced by a culture that reveres athleticism and stresses body image. In response, most pro sports leagues have banned steroid use because of the unfair impact on competition. To assess enforcement, the U.S. House of Representatives has held public hearings on steroid use among athletes and opened subcommittee hearings in May to discuss a proposed Drug Free Sports Act. For effective regulation and consumer education, policy- makers need to understand the full impact of these drugs on human health, say experts.
The four most commonly used AASs differ in their method of administration (oral versus injection), duration of action (long versus short) and potential for metabolic breakdown to estrogen or DHT, a potent androgen called dihydrotestosterone. They are:
Nandrolone, a popular injectable with a longer metabolic breakdown.
Drostanolone, a fast-acting injectable derived from DHT.
Oxymethalone, taken orally.
Stanozolol, also taken orally and popular among females because of its low androgenic potency.
Ballard and Wood hypothesized that although all these steroids are reinforcing, the male Syrian hamsters on which they have conducted other sex-hormone studies would respond the most to potent, fast-acting injectable androgens compared with lower-potency steroids with longer half-lives.
To gauge which type of steroid the hamsters would come to want the most once they had a "taste," the researchers randomly assigned the subjects into 12 groups of eight hamsters. Reward power was tested at three different concentrations: 0.1, 1.0 and 2.0 micrograms per microliter each in solution.
Ballard and Wood implanted tiny stainless-steel pipes, or cannulae, into the animals' skulls to deliver steroid infusions into brain cavities filled with cerebrospinal fluid, which allows for maximum diffusion without tissue damage. This process is called icv, for intracerebroventricular infusion. After the hamsters recovered, the researchers placed each one for four hours in a conditioning chamber that had two nose-poke holes, one-inch circles cut into the wall. A nose poking into the "active" hole broke an infrared beam positioned just on the other side, which triggered a computer to turn on a syringe pump to deliver an icv infusion. Ballard and Wood also recorded nose pokes into the "inactive" hole, which had no effect.
The researchers gave the hamsters an opening 1.0 microliter dose of the AAS solution. Then they measured what happened over the next four hours: How often did each hamster poke the active versus the inactive hole? Given that a poke into the active hole would earn the hamster another microliter of the drug, and the inactive hole would net no injection, what would leave them wanting more?
Potency and reinforcement
Each type of steroid presented a different pattern of results, but there was a clear dividing line between the injectables and the orally administered drugs. For the injectables, the hamsters poked the active hole significantly more times than they poked the inactive hole. Giving the hamsters the highly potent injectable drostanolone at the lowest dose had no impact. However, at the two higher concentrations, hamsters averaged twice as many responses on the active nose-poke as on the inactive nose-poke.
For the long-acting injectable nandrolone, responses on the active nose-poke increased with increasing concentrations of the drug, at least at the two higher levels (the lowest level didn't garner a reaction). At the higher concentrations, seven of the eight hamsters preferred the active nose-poke.
The picture was different for the potent oral androgen oxymethalone: The hamsters did not develop a significant preference for the active nose-poke at any dose. And the oral drug stanozolol, which also failed to induce any significant preference for the active nose-poke, produced the lowest amount of operant responding.
Thus, the authors report that the injectable androgens may be more reinforcing than the orally active steroids. However, Wood cautions that this doesn't make orally active androgens safer: First, as Melloni notes, "AAS abusers typically graduate from oral use to the [more rewarding] injectable forms." Second, oral steroids have their own serious side effects, such as liver damage.
Game not over
The findings sound a warning that steroids pack an even more powerful punch than we knew. And all steroids are not the same: Ballard and Wood note that just as these drugs "differ in their potency, half-life, metabolism and mode of administration...the properties of different anabolic steroids also affect their reward potential." The differences may lie in how these drugs are metabolized and in their androgenic potency, the intensity with which they affect masculinization.
Further research is needed, experts say. For one, Wood and her colleagues want to find the specific brain site where steroids act. She hopes that if research uncovers more about AAS reinforcement, such as permanent changes in brain and behavior, "those who may be tempted to try steroids will be more cautious, particularly high school students for whom AASs--in addition to the other hazards--can limit adult height."
Pilotte would like to see the findings replicated with closer attention to the different ways that humans get steroids into the bloodstream. Additionally, Melloni hopes that new knowledge about steroids, "will better assist us in the development of rational pharmacologic and therapeutic treatment strategies for long-term AAS users."
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