MAPS: Glutamate Is More Essential To Addiction Than Dopamine

[Peter Webster <vignes@xxxxxxxxx>]

The Scientist 16[2]:16, Jan. 21, 2002

NEWS

Phenotype Offers New Perception on Cocaine

Researchers say glutamate is more essential to addiction than dopamine
By Tom Hollon

In cocaine research, dopamine and glutamate make a brilliant star and
supporting player, respectively. One takes center stage, the anointed
crowd-pleaser; the other, though a leading actor in other productions, is
so overshadowed that admiration of its performance is relegated to an
acquired taste. A quick PubMed search recently disclosed their perceived
importance: 3,628 abstracts on cocaine and dopamine, 178 for cocaine and
glutamate.

Now, however, perceptions may shift?not that dopamine descends from the
firmament, but that glutamate will sparkle as brightly. Recent knockout
mouse evidence1 from researchers led by François Conquet, CEO of Addex
Pharmaceuticals in Geneva, Switzerland, reveals that glutamate's role in
cocaine dependence is even more central than dopamine's.

The case for dopamine's centrality remains airtight. Cocaine binds the
dopamine transporter, blocking reuptake of dopamine into presynaptic
neurons. Blockade increases dopamine concentration in synapses, an event
responsible for cocaine's pleasurable effects and suggested as key to
developing drug dependence. But although loss of the transporter and
dopamine receptors in knockout mice may alter behavior toward cocaine,
always the drug remains addictive. When the dopamine transporter is lost,
for instance, mice may still become cocaine dependent through cocaine's
ability to bind the serotonin transporter. This is not necessarily
surprising, observes Peter Kalivas, of the Medical University of South
Carolina in Charleston, who is a leading investigator of the
glutamate-cocaine relationship. "The ability of an organism to predict
rewarding stimuli in the environment is absolutely critical to survival,"
says Kalivas, "so there probably is some redundancy."

Contrast this redundancy to what Conquet finds when metabotropic glutamate
receptor mGluR5 disappears: Without mGluR5, mice turn up noses and whiskers
to cocaine, even though their dopaminergic systems respond to cocaine as
usual. "These are the first knockout mice completely unresponsive to this
powerfully addictive drug," says Conquet, who engineered the knockout mice
when he was at GlaxoSmithKline in Lausanne, Switzerland. From this
phenotype emerges a new picture of dopamine and glutamate: Sustaining
cocaine-seeking behavior requires both neurotransmitters, while only
glutamate is indispensable for cocaine dependence.

The Consolation Prize

Glutamate, the main excitatory neurotransmitter, is associated with
learning and memory. Its receptors divide into ionotropic and metabotropic
forms important to this function. "Learning occurs in part from changes in
both ionotropic and metabotropic signals," Kalivas explains. "You adjust
both in order to change the way cells communicate." Ionotropic receptors
are also called ligandgated ion channels.

Ligand binding opens the channel so ions can pass through the cell
membrane. Generally these are ion channels first, receptors second,
controlling very quick changes in membrane current. In comparison,
metabotropic glutamate receptors bring slower changes; largely they
modulate signals from other neurotransmitters, acting through second
messenger systems. They belong to the seven-transmembrane, G-protein linked
superfamily of receptors. Conquet studies metabotropic receptors mGluR1 and
mGluR5, which act through the phospholipase C signaling pathway.

Conquet's discovery of mGluR5's role in cocaine addiction originates in his
second-place finish in a race to make mGluR5 knockout mice. Conquet was at
the time head of Glaxo's experimental pathology unit, where his job was to
make knockout mice deficient in various neuronal receptors. He lost to John
Roder, of the Hospital for Sick Children, in Toronto. By showing that
mGluR5 mutant mice perform poorly in the Morris water maze test and in
fear-related learning, Roder implicated mGluR5 in spatial learning and
memory.2 Roder's experiments suggest that mGluR5 is involved in long-term
potentiation (LTP) within the hippocampus. Scooped, Conquet had to ask
himself if Roder's description of the phenotype was complete. A possibility
Roder might have missed, Conquet decided, was how the mice would react to
cocaine.

The possibility of a connection between mGluR5 and cocaine appealed to
Conquet's sense of drug dependence as a form of learned behavior. He knew
that cocaine increases glutamate concentration in the nucleus accumbens, a
brain region associated with cocaine dependence and stimulation of
locomotor activity, and the location for the natural reward circuitry for
food, water, mating and maternal behavior. Kalivas and his associates have
demonstrated that mGluR5 receptors are down regulated following chronic
cocaine administration.3

Conquet turned for help to his colleague Christian Chiamulera, who works on
psychiatric drugs in a Glaxo laboratory in Verona, Italy. Willing to take a
flyer on a wild idea, but wanting to avoid weeks of work with nothing to
show for it, Chiamulera suggested a quick-and-dirty observation of cocaine
as a psychostimulant: Inject cocaine into the bellies of the knockouts,
then look for hyperactivity.

When Conquet watched the first injections, immediately he worried something
was wrong. Instead of frenzied exploration of their surroundings, the
mGluR5 knockouts lolled about as if nothing had happened. They verified in
fact that the mice had received walloping doses. To their excitement, wild
type mice on cocaine behaved as expected?no sleepwalkers or indolent
beachcombers here. These creatures were ready to jitterbug 'til dawn at
Mardi Gras. Conquet and Chiamulera were ready to join them. Chiamulera
would now follow up with more elaborate experiments. For a test that
approximates cocaine addiction in humans, Conquet brought in Mark
Epping-Jordan, another Glaxo scientist, to do cocaine self-administration
experiments.

Chiamulera confirmed his initial results. Wild type mice responded to
cocaine in a dose-dependent manner: The higher the dose, the more
hyperactive they became. Knockouts remained unperturbed regardless of dose.
Abolishing mGluR5 abolishes cocaine-induced hyperactivity.

Epping-Jordan began the self-administration experiments by first training
knockout and wild type mice to press a lever in order to get food. Both
groups learned lever pressing equally well. Then he substituted intravenous
cocaine for food and watched what happened. Wild type mice responded
enthusiastically to the new menu, and would press for cocaine a dozen or
more times an hour. MGluR5 mutants ignored cocaine at every dose; within a
few sessions they would learn levers no longer produced food and stop pressing.

It was possible that the connection between cocaine dependence and mGluR5
was indirect, that loss of mGluR5 during development altered molecules even
closer to control of dependence. Conquet's group examined the issue by
asking if 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective mGluR5
antagonist, reduced cocaine self-administration in normal mice. It did?In
dose-dependent fashion, MPEP decreased demand for cocaine by up to 50%. The
link, then, is direct and essential. "Somehow, glutamate transmission at
mGluR5 is critical for the animal to recognize the rewarding effects of
cocaine," says Kalivas. "The surprising thing is that it must be a
secondary effect, because cocaine does not act directly on glutamate
transmission. There is no binding by cocaine directly to any protein that
has to do with glutamate transmission."

Leaving Natural Reward Along

Loss of mGluR5 apparently leaves the dopaminergic system intact. Using
microdialysis to measure dopamine in freely moving mice, the researchers
found dopamine concentrations in the nucleus accumbens were the same for
mutant and normal mice, with or without cocaine. Levels of D1 and D2-class
dopamine receptors and dopamine transporters were also normal.

Most striking is that reward systems strongly influenced by
dopamine?nourishment, mating, and nursing?were also unaffected by loss of
mGluR5. Conquet emphasizes that no other knockout has behaved this way:
"This is the first time a mammal has been found insensitive to cocaine
while its other reward-based systems remain normal."

He continues, "Dopamine receptor knockouts fail to curb cocaine dependence
because mGluR5 is still working. They just affect general dopaminergic
activity," and with considerable "collateral damage". Experiments with
dopamine receptor agonists also indicate that dopamine does not lie at the
center of cocaine dependence: "People have shown that you can never induce
dependence from scratch with dopamine agonists. But you can maintain the
process with these compounds once dependence is ongoing, probably after
mGluR5 has turned the system on."

Kalivas now distinguishes dopamine and glutamate by their short and long
term effects. "The acute rewarding properties that keep people coming back
to the drug are mediated by dopamine," he says. "The 'Once an addict,
always an addict' kinds of folklore that really make an addict are probably
long-term changes in glutamate transmission." In retrospect, this isn't
surprising: "All of neuroscience has been pointing to glutamate
transmission as the critical player in the brain's ability to adapt to the
environment." Cocaine addiction is one such adaptation.

From Scientist to Entrepreneur

Conquet founded Addex only a few weeks ago, departing Glaxo for better
opportunities to continue his work. Following Glaxo's merger with
SmithKline, drugs against cocaine addiction seemed better markets for
smaller companies. Glaxo's larger size demands larger markets if the pharma
giant is to sustain itself. For a small firm like Addex, a new mGluR5
antagonist could be quite profitable. Why develop a new drug when MPEP
exists? Because MPEP dissolves very poorly and barely crosses the
blood-brain barrier, Conquet explains.

Conquet does not know if mGluR5 plays a role with ethanol and nicotine
addiction. Self-administration experiments have not been done. Partly he
hasn't had time, since he's busy starting Addex. Partly the mice haven't
had time, since other drugs of abuse, especially alcohol, require longer
training periods. Whether mGluR5 influences other so-called addictions, is
a question left for the distant future.

If Addex does find a good mGluR5 antagonist, therapeutic possibilities may
extend well beyond helping snorters and crackheads stay clean. Glutamate
may be implicated in numerous psychiatric disorders, according to Kalivas.
mGluR5 inhibitors have been suggested as possible treatments for Alzheimer
Disease, Parkinsonian akinesia, muscle rigidity, stroke, anxiety, and
inflammatory pain. But as always, Kalivas reminds, once a good drug
candidate is in hand, only running the clinical experiments will tell for sure.
Tom Hollon (thollon@xxxxxxxxxxxxx) is a freelance writer in Rockville, Md.

References
1. C. Chiamulera et al., "Reinforcing and locomotor stimulant effects of
cocaine are absent in mGluR5 null mutant mice," Nature Neuroscience,
4:873-4, September 2001.

2. Z. Jia et al, "Gene targeting reveals a role for the glutamate receptors
mGluR5 and GluR2 in learning and memory," Physiology and Behavior,
73:793-802, August 2001.

3. C.J. Swanson et al., "Repeated cocaine administration attenuates group I
metabotropic glutamate receptor-mediated glutamate release and behavioral
activation: a potential role for Homer," Journal of Neuroscience,
21:9043-52, Nov. 15, 2001.

© Copyright 2002, The Scientist, Inc. All rights reserved.
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