Pubdate: Wed, 04 Apr 2007
Source: Journal of the American Medical Association (US)
Section: 2007; 297: 1419-1421
Copyright: 2007 American Medical Association.
Contact:  http://jama.ama-assn.org/
Details: http://www.mapinc.org/media/219
Author: Bridget M. Kuehn
Bookmark: http://www.mapinc.org/coke.htm (Cocaine)
Bookmark: http://www.mapinc.org/heroin.htm (Heroin)
Bookmark: http://www.mapinc.org/meth.htm (Methamphetamine)
Bookmark: http://www.mapinc.org/rehab.htm (Treatment)

BRAIN SCANS, GENES PROVIDE ADDICTION CLUES

Scientists using advanced brain imaging and genetic testing to probe 
the physiological basis of addiction are gleaning new insights into 
these disorders and how to treat them.

A symposium sponsored by Brookhaven National Laboratory (Upton, NY), 
held in conjunction with the American Association for the Advancement 
of Science's annual meeting in San Francisco in February, highlighted 
several advances in addiction science made over the past year. 
Researchers presented findings from brain imaging studies revealing 
the importance of memory and drug-related cues in addiction, the role 
of monoamine oxidase-inhibiting compounds in cigarette smoking, the 
damage to inhibitory controls caused by methamphetamine use, as well 
as results from studies suggesting that genomics could be used to 
better tailor addiction therapies.

Craving Key

Dopamine, a neurotransmitter associated with pleasurable feelings, 
plays an important role in reinforcing the use of addictive 
substances. Many studies have demonstrated that addictive drugs 
increase endogenous dopamine levels in the nucleus accumbens of the 
brain. This phenomenon, which also occurs in the brain of someone 
engaged in eating or other activities necessary for survival, is one 
of the most powerful mechanisms driving behavior, explained Nora D. 
Volkow, MD, director of the National Institute on Drug Abuse.

Harder to explain is another key component of addiction: the intense 
craving or desire that addicted individuals experience when they are 
exposed to drug-associated cues, such as persons with whom they used 
the drug, places where they used the drugs, and drug paraphernalia. 
Now, however, brain imaging techniques are giving scientists a window 
on what happens in an individual's brain during craving.

To probe this response, Volkow and her colleagues at Brookhaven 
National Laboratory used positron emission tomography (PET) scans to 
obtain an indirect measurement of dopamine levels in the brains of 18 
cocaine-addicted individuals under two conditions: while watching 
videos of people buying and using cocaine and also while watching 
videos featuring nature scenes (Volkow et al. J Neurosci. 2006;26:6583-6588).

To gauge dopamine levels, the scientists injected each individual 
with a radiotracer that binds dopamine receptors in the brain and 
used PET to measure the signal produced by the receptor-bound 
radiotracers. Endogenous dopamine competes with the radiotracer to 
bind dopamine receptors, so as the brain releases molecules of 
endogenous dopamine and they bind to receptors, fewer molecules of 
the radiotracer are able to bind, and the signal weakens.

When the individuals viewed the cocaine-related video, their dopamine 
levels increased significantly compared with the levels released 
while they watched nature videos. The scientists noted the effect 
particularly in the ventral striatum, suggesting this region may play 
a key role in drug craving. Levels of craving reported by the 
participants also correlated with the levels of dopamine increase. 
Similar increases in dopamine levels in the ventral striatum have 
been documented in individuals exposed to food cues, suggesting that 
addiction hijacks the same pathways that make eating rewarding.

Targeted Treatments

New research also suggests that it may soon be possible to use 
genetics or other factors to target existing treatments to the 
individuals who may benefit the most from them. One existing drug 
that may be most effective when used in a targeted fashion is naltrexone.

The US Food and Drug Administration (FDA) approved oral naltrexone 
for the treatment of heroin addiction in 1984. Naltrexone blocks 
heroin from binding to opioid receptors and prevents individuals from 
experiencing the high associated with heroin use. Currently, it is 
used almost exclusively to treat physicians, nurses, and pharmacists 
with opioid addictions, said Charles O'Brien, MD, PhD, director of 
the Center for Studies of Addiction at the University of Pennsylvania 
in Philadelphia, at the symposium. A variety of factors, such as the 
need to take a daily pill and occasional adverse effects, such as 
nausea, have limited its use. In June, the FDA approved a lower-dose 
monthly injectable form of the drug. This formulation circumvents the 
liver and prevents nausea, and it also offers the benefit of less 
frequent administration.

The drug also has been used to treat alcoholism, but studies suggest 
it is most effective in individuals who have a strong family history 
of alcoholism, who experience euphoria when using alcohol, and who 
experience strong cravings (Monterosso JR et al. Am J Addict. 
2001;10:258-268). These findings suggest that there may be a genetic 
basis for a patient's response to naltrexone.

Further evidence that some patients are predisposed to respond to 
naltrexone treatment came from a 2003 study of 141 patients randomly 
assigned to receive naltrexone (n = 82) or placebo (n = 59). The 
study found that patients with a variant of the gene encoding the 
u-opioid receptor were more likely to benefit from the drug (Oslin DW 
et al. Neuropsychopharmacology. 2003;28:1546-1552). During 12 weeks 
of treatment, patients with 1 or 2 copies of the Asp40 allele who 
were treated with naltrexone had a significantly lower rate of 
relapse or stayed abstinent longer if they did relapse than did those 
with 2 copies of the Asn40 allele. A second group of scientists 
reported at the American College of Neuropsychopharmacology meeting 
in December that they had replicated these findings in patients 
participating in the Combining Medications and Behavioral 
Interventions (COMBINE) trial, O'Brien said.

The findings may have broader implications for physicians trying to 
select the best treatments for their patients. "Once we begin to 
correlate genotype with medication response, then physicians will be 
able to do a much better job of selecting the right medication from 
the beginning," O'Brien said.

Mood-Boosting Cigarettes

While much research on smoking has focused on the effects of 
nicotine, cigarette smoke contains 4000 chemical compounds, some of 
which also reinforce smoking behavior. This may explain why nicotine 
replacement therapies are often ineffective alone. In particular, 
some chemicals in cigarette smoke inhibit monoamine oxidase (MAO), an 
enzyme that breaks down neurotransmitters. Such inhibition may 
produce antidepressant effects, as MAO inhibitors are used to treat 
depression, said Joanna Fowler, PhD, director of the Center for 
Translational Neuroimaging at Brookhaven National Laboratory.

Using PET, Fowler and colleagues found that compared with controls, 
smokers have 40% lower levels of MAO in their brains and 35% to 45% 
lower levels in other organs, such as the heart, lungs, kidney, and 
spleen (Fowler JS et al. Nature. 1996;379:733-736, Fowler JS et al. 
Proc Natl Acad Sci U S A. 2003;100:11600-11605). "We don't know the 
physiological implications, but we think it may account for the 
increased rate of smoking in diseases like depression," Fowler said.

The lower MAO levels also may account for smokers' lower risk for 
Parkinson disease. Fowler explained that when MAO breaks down 
neurotransmitters, it creates hydrogen peroxide, a source of damaging 
free radicals that may contribute to Parkinson disease; smokers with 
lower levels of MAO may thus have lower levels of free radicals.

Other groups are conducting clinical trials to determine whether 
certain MAO inhibitors may be useful in smoking cessation. A 
preliminary 8-week randomized placebo-controlled trial of selegiline 
hydrochloride showed promising results (George TP et al. Biol 
Psychiatry. 2003;53:136-143). Nine of 20 patients randomly assigned 
to receive selegiline hydrochloride were abstinent at 1 week vs only 
3 of 20 patients given placebo, and 6 of the patients taking the drug 
were abstinent during the last 4 weeks of the trial compared with 1 
patient in the placebo group. The scientists are currently conducting 
a larger trial, Fowler said.

Scientists have also recently isolated MAO-inhibiting chemicals in 
tobacco smoke (Khalil AA et al. Bioorg Med Chem. 2006;14:3392-3398). 
In this and previous studies, the scientists identified 
MAO-inhibiting effects of terpene trans-trans-farnesol in the rat 
brain and in human, baboon, monkey, dog, rat, and mouse livers. Such 
studies may lead to the development of smoking cessation treatments 
or neuroprotective agents.

Boosting Inhibition

Brain imaging studies also are providing evidence that 
methamphetamine use may cause functional and structural deficits that 
interfere with users' ability to control negative emotions.

Edythe D. London, PhD, of the Semel Institute of Neuroscience and 
Biobehavioral Science at the University of California in Los Angeles, 
and colleagues have used PET scans and radiolabeled glucose to 
monitor and compare brain activity in methamphetamine-addicted 
individuals who have abstained from the drug for 4 to 11 days with 
that of controls (London ED et al. Arch Gen Psychiatry. 
2004;61:73-84). They found abnormally low levels of activity (as 
measured by glucose metabolism) in the cerebral cortex that was 
related to symptoms of depression.

More recent findings by researchers from the University of California 
in Los Angeles provide more evidence that individuals who use 
methamphetamine lose the ability to control their negative emotional 
responses. Using functional magnetic resonance imaging, the 
scientists measured brain activity in methamphetamine-dependent 
individuals and controls as they viewed emotionally charged images. 
The methamphetamine-dependent individuals reported a weaker emotional 
response to the images than did controls, but their scans revealed 
more activity in the amygdala, a region involved in regulating 
emotion. When asked to suppress their emotional response to the 
images, healthy individuals showed activity in part of the prefrontal 
cortex, but methamphetamine-dependent individuals did not.

London said the findings suggest that methamphetamine use leads to a 
loss of function in parts of the brain that control emotion. This, 
she said, may explain why methamphetamine users often are involved 
with serious crimes and violence and why they have difficulty 
abstaining. "It could be that they misinterpret environmental stimuli 
and react in a strong way," she said.

She and her colleagues are now studying whether modafinil, a drug 
used to treat narcolepsy, might help in treating methamphetamine 
dependence. The drug has been shown to improve inhibitory control in 
healthy individuals and in those with attention-deficit/hyperactivity 
disorder. Such a means to control a problematic symptom of 
methamphetamine abuse may improve the effectiveness of existing 
therapies, such as behavioral therapy.
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MAP posted-by: Beth Wehrman