Common pathway found in early stages of addiciton to alcohol and many drugs

In a finding that reveals a link between alcoholism and drug addiction,
scientists have discovered that a key step leading to alcohol addiction can be
blocked by preventing alcohol from gaining access to nerves in the brain
involved in learning.

The discovery, in experiments with mice, suggests that the experience of
becoming increasingly stimulated by repeated use of a substance - a process
known as sensitization -
employs the same chemical pathway of learning whether the substance is alcohol,
cocaine, morphine or amphetamine. This strengthens the view that safely
blocking these drugs’ or alcohol’s access to the pathway could interrupt the
learning that reinforces addiction.

“Our research provides evidence that drugs able to block the sensitizing
effects of alcohol may be useful in the treatment of alcohol addiction,” says
Rosana Camarini, PhD, post-doctoral researcher at the Ernest Gallo Clinic and
Research Center at UC San Francisco and lead author on a paper reporting the
research finding. The key, she said, would be to find a molecule that blocks or
modulates access to the key brain receptors without blocking the receptor’s
normal function, crucial to learning.

The study is published in the March issue of the journal Alcoholism: Clinical
& Experimental Research. It was carried out by Camarini and colleagues at the
Federal University of Sao Paolo, Brazil.

“Sensitization is thought to lay the chemical and behavioral groundwork for
addiction,” says Clyde Hodge, PhD, assistant professor of neurology at UCSF and
Camarini’s advisor at the Gallo Center. “We know we’re on a promising track
when we find a molecular pathway that blocks this behavioral effect of
substances of abuse. The research encourages us to look at common underlying
systems of sensitization that would lead an animal or a human to want more of
the substance, whether it is a drug or alcohol.”

In the research by Camarini and colleagues at the Federal University of Sao
Paulo, Brazil, the scientists studied how mice responded to injections of
ethanol alone and also 21 days of injections of ethanol along with a substance
called MK-801. This substance, a “receptor antagonist,” blocks access to
receptors located on brain neurons which normally receive signals involved in
learning. The so-called NMDA (for N-methyl-D-aspartate) receptors are part of
what is known as the glutamate excitatory signaling system, one of several
signaling systems between neurons in the brain.

Earlier research by others has shown that blocking access to NMDA receptors
interferes with sensitization to cocaine, morphine, amphetamines and other
drugs. Camarini and her colleagues showed that blocking NMDA receptors also prevents
alcohol sensitization.

Sensitization is known to occur early in addiction, but it also plays a role
in relapses - the vulnerability of a recovered alcoholic or drug addict to
become dependent again upon exposure to a substance of abuse. The process of
sensitization is the reverse of tolerance - the growing insensitivity to
alcohol or a drug the more one is exposed to it. Both processes are part of
addiction.

The search for a drug to prevent addiction will have to go beyond MK-801,
Hodge pointed out, since the compound itself would probably be addictive. In
addition, uniformly blocking NMDA receptors might interfere with normal
learning. But as scientific consensus builds that NMDA receptors are key
players in the early steps of a wide range of addictions, momentum will
increase to search for drugs that can selectively block these receptors without
side effects, he said. 

Other receptors—notably those to the mood-modulating neurotransmitter
dopamine—have been implicated in the process of addiction, but they too play
sensitive roles that scientists are reluctant to block. If dopamine receptors
are blocked, the risk of developing Parkinson’s disease or bringing on episodes
of schizophrenia increases.

“The kind of basic research that Camarini and her colleagues have done should
help us develop drugs to modulate the sensitization process without side
effects or addiction,” Hodge hopes.

Camarini is intrigued by the learning component suggested by the role of the
NMDA receptors.

“It has been shown that receiving drugs in the same place and the same time
seems to contribute to drug abuse” she says. “This may be part of NMDA-mediated
learning of addiction, a process that we may be able to interrupt.”

She says that the next step would be to study alcohol sensitization in
relation to the setting in which the animals become stimulated by alcohol. In
this way she can clarify if NMDA receptors are critical to the process whereby
a familiar setting is associated with the experience of pleasure from alcohol.
If this proves to be true, she says, then blocking this component of learning
could contribute to treating addiction.

Colleagues in the research and co-authors with Carmarini on the paper are
Roberto Frussa-Filho, Maristela Goldnadel Monteiro and Helena Maria Calil, all
PhDs, professors and researchers at the Federal University of Sao Paulo.

The research was funded by Conselho Nacional de Desenvolvimento Cientifico e
Tecnologico (CNPq) and Associacao Fundo de Pesquisa a Psicofarmacologia (AFIP)
in Brazil.