OHSU Scientists Discover Mice Lacking Dopamine Receptor Are Supersensitive To Alcohol, Cocaine And Methamphetamine

September 18, 1997

Scientists at Oregon Health Sciences University have discovered that mice lacking a certain brain cell receptor for the chemical messenger dopamine are supersensitive to alcohol, cocaine and methamphetamine. Their findings appear in the September 19, 1997, issue of the journal Cell and detail the increased locomotor activity of mice who lack the D4 receptor.

"Branching nerve cells communicate with each other by secreting chemical messengers like dopamine that bind to receptors on neighboring nerve cells in a lock-and-key fashion," explains, David Grandy, Ph.D., OHSU scientist and senior author of the article. "Dopamine is one of the primary chemical messengers, or neurotransmitters, and plays numerous complex roles in both movement and emotional states. Disturbances in the dopamine system are known to be associated with human disorders such as Parkinson's disease, schizophrenia and addiction. Dopamine producing neurons continue to be the focus of research because of their widespread importance in regulating complex locomotor, emotional and motivational states."

Grandy further explains that dopamine producing neurons are involved in mediating some of the positive reinforcing properties shared by drugs of abuse such as alcohol, cocaine, methamphetamine and opiates.

"We examined mice that were genetically engineered to lack the D4 dopamine receptor to investigate the role of this receptor in mediating the effects of various drugs," says Grandy. "We discovered that mice given either alcohol, cocaine or methamphetamine displayed a dramatic increase in locomotor activity compared to normal mice. Prior to their treatment with these drugs, the mutant mice tended to be less active than normal mice. Following treatment their activity level increased greatly compared to normal mice.

"Based on the observation that mice lacking the D4 receptor show a supersensitivity to certain drugs of abuse, we speculate that the D4 receptor is implicated in modulating the effects of such drugs," says Grandy. "Consequently, the D4 receptor may be a new target for the treatment of drug abuse."

Grandy explains that humans show a wide variability in the gene that encodes the D4 receptor, and there are reports that some forms of the D4 gene may predispose an individual to drug taking and novelty seeking behaviors. The D4 receptor has been the focus of intense interest since its discovery in 1990 because of its high affinity for the antipsychotic drug clozapine, which is used to treat schizophrenia. Recently, several new D4-selective drugs that are similar to clozapine have been developed and are currently undergoing clinical trials for the treatment of schizophrenia. In addition to shedding light on the role that the D4 receptor plays in an organism*s response to drugs like alcohol, cocaine and methamphetamine, the new research reported by Grandy and his colleagues underscores the relevance of this receptor to antipsychotic drug development.
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Oregon Health & Science University

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