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.