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Androgen Dependence in Hamsters: Overdose, Tolerance and Potential Opioidergic Mechanisms
K. D. Peters, R. I. Wood
Neuroscience (2004)
doi:10.1016/j.neuroscience.2004.09.063
When steroid use is discontinued, many
AAS users experience withdrawal symptoms characterized
by a hyperadrenergic state resembling opioid withdrawal. Other studies suggest
that AAS may possess euphorigenic effects. While these data suggest that AAS are
rewarding independent of their anabolic effects, defining
the potential for AAS addiction in humans has been difficult.
This study used i.c.v. testosterone selfadministration
and controlled infusions of testosterone or
vehicle in hamsters to explore central mechanisms of androgen
overdose.
A total of 42 hamsters have been tested for i.c.v. testosterone
self-administration in our laboratory. Of these, 10
(24%) died during testing. None of the deaths occurred in
the operant chambers. Instead, hamsters often died during
the night, several hours after removal from the operant
chamber.
Deaths correlated with peak daily
intake of testosterone. Of the hamsters that self-administered
a peak intake of <20 mug/day, there was 100% survival (10/10).
Survival decreased to 86% (19/22) when daily testosterone
intake peaked at 20–60 mug/day. Only 30% (three of 10) survived
when daily testosterone intake exceeded 60 mug/day.
Deaths are not due to volume or vehicle because i.c.v. infusions
of 80 ml vehicle had no effect. Testosterone overdose
resembles opiate intoxication.
When male hamsters received
infusions of 40 mug testosterone, locomotion (25.1 +/- 18.8 gridcrossings/
10 min), respiration (72.7 +/- 5.4 breaths/min) and
body temperature (33.5 +/- 0.4 °C) were significantly reduced,
compared with males receiving vehicle infusions (186.1 +/- 8.1
crossings/10 min, 117.6 +/- 1.0 breaths/min, 35.9 +/- 0.1 °C,
P<0.05).
However, males developed tolerance to continued
daily testosterone infusion. After 15 days, locomotion
(170.2 +/- 6.3 crossings), respiration (118.4 +/- 1.3 breaths/min),
and body temperature (35.3 +/- 0.3 °C) in testosterone-infused
males were equivalent to that in vehicle controls (P>0.05).
The depressive effects of testosterone infusion are blocked
by the opioid antagonist, naltrexone.
With naltrexone pretreatment
(10 mg/kg s.c.), locomotion (183.7 +/- 1.8 crossings/
10 min), respiration (116.9 +/- 0.3 breaths/min), and body
temperature (36.1 +/- 0.4 °C) during testosterone infusion were
equivalent to vehicle controls.
Likewise, naltrexone prevents
the reinforcing effects of i.c.v. testosterone selfadministration.
These results indicate that testosterone at
high doses causes central autonomic depression, which may
be a factor in deaths during self-administration. As well, the
depressive effects of large quantities of testosterone may be
mediated, at least in part, by an opioidergic mechanism.
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De curven geven aan hoe vaak de proefdieren zichzelf met testosteron injecteren. De lijn met de zwarte bolletjes staat
voor het aantal injecties met actieve stof, de doorzichtige bolletjes voor injecties zonder testosteron. In het grijze
gebied krijgen de hamsters de morfineblokker, in het open veld niet meer. Duidelijk is hoe de dieren dan pas de smaak van
het anabole hormoon te pakken krijgen.
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The power of potent steroids
If anabolic steroids are rewarding, "this factor may contribute to the increasing and long-term use of these drugs in humans"
APA Online
Volume 36, No. 7 July/August 2005
BY RACHEL ADELSON
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."
Risky business
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.
Drug testing
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."
[Link]
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[Definitie:] "An ergogenic aid is any substance or phenomenon that enhances performance."
(Wilmore and Costill) 
