June 16, 2005
Addiction Keeps Its Own Clock
The Clock gene, widely appreciated as a driver of circadian
rhythms, has now been shown to aid in regulating the brain's reward
circuitry, which is triggered by drugs of addiction, such as cocaine.
The findings from this study and others continue to build the case that
Clock is a key cog in the machinery that drives an ever widening
range of behaviors.
The researchers, including Howard Hughes Medical Institute
investigator Joseph S. Takahashi at Northwestern University, published
their findings June 13, 2005, in the early online edition of the
Proceedings of the National Academy of Sciences. Other
co-authors include Eric J. Nestler and colleagues from the University
of Texas Southwestern Medical Center, the University of Crete and the
Rosalind Franklin University of Medicine and Science in Chicago.
“Before, we would have assumed that the circadian clock was modulating such a process as the response to drugs, perhaps due to the influence of the time of day.”
Joseph S. Takahashi
Studies by Takahashi and other researchers have revealed that
Clock regulates other genes involved in the biological clock
machinery. Most biological clocks operate on a 24-hour, circadian
(Latin for "about a day") cycle that governs functions such as sleeping
and waking, rest and activity, fluid balance, body temperature, cardiac
output, oxygen consumption and endocrine gland secretion.
However, said Takahashi, there had also been intriguing connections
between circadian rhythms and the effects of drugs of addiction. For
example, drug addiction is associated with disruptions in sleep and
circadian rhythmicity. And animal studies have shown a circadian effect
of drug self-administration, which suggested that there may be a
connection between the brain's circadian and reward pathways.
More direct evidence of such a link has come from experiments with
fruit flues by Jay Hirsh and colleagues at the University of Virginia,
who found that mutant flies lacking some genes in the circadian pathway
showed altered behavioral responses to cocaine.
In the latest experiments, Takahashi and his colleagues studied the
effects of cocaine administration on mice that carry a mutant
Clock gene. In one experiment, they placed the
Clock-defective mice in a test chamber, in order to study how
cocaine affected their activity. However, he said, even the act of
placing the mutant animals in the new environment yielded interesting
results.
“When the Clock mutants were put into the test chamber,
the first surprising thing was that even before the cocaine was given,
they were more active in the novel environment than wild-type
controls,” said Takahashi. “We hadn't seen this before,
because we just measured Clock mutant mice in their home cages.
So, we were seeing a heightened response to novelty, we believe.”
After the researchers began to administer cocaine, they found that the
mutant mice responded with greater activity than did normal mice.
The researchers next gauged the level of reward the mice experienced
in response to cocaine by first teaching them to associate receiving
cocaine with being in one of two connected chambers. The subsequent
preference of the mice for a particular chamber was a measure of the
reward they received from the cocaine. These experiments revealed that
the mutant mice had a heightened reward response to cocaine, when
compared to normal mice.
The researchers also used Clock mutant mice to measure
effects of the Clock gene had on the brain's reward circuitry,
which is activated by the neurotransmitter dopamine. They found higher
electrophysiological activity of dopamine-triggered neurons in a major
reward area of the animals' brains. They also found that the mutant
mice showed higher levels of an enzyme that is key to dopamine
production in the area of the brain that processes reward response.
More broadly, they found that the mutant mice showed decreased activity
of a number of circadian genes known to be activated by
Clock.
“These findings suggest a very different and unexpected role
of these circadian genes from the traditional way we have thought about
their effects,” said Takahashi. “Before, we would have
assumed that the circadian clock was modulating such a process as the
response to drugs, perhaps due to the influence of the time of day. But
in this case, it looks as if the Clock gene itself is an
upstream regulator of the mechanism involving dopamine in a very
interesting part of the brain, where the reward pathway is
located.”
According to Takahashi, the latest findings add to previous studies
in his laboratory, in which it was found that Clock-defective
mutant mice show a metabolic disorder. The mice show weight gain,
elevated blood glucose and insulin insensitivity, he said.
“Our future studies will seek to understand whether behavioral
and metabolic alterations are a result of the effects of the
Clock gene itself, or of the genes it regulates,” said
Takahashi.
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Jennifer Michalowski
