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How Morphine Breaks the Brain's Brakes May Be Key to Breaking Addiction

Study of rat brains identifies new culprit and possible therapeutic target for addiction
morphine drip



© ISTOCKPHOTO/STEFAN KLEIN
A single dose of morphine can block a process in the brain associated with learning and memory for as long as a full day after being ingested, according to a new study. The disruption causes a neuronal imbalance that researchers say could be the first step in the development of addiction. They add that therapies designed to prevent this from happening during drug use could one day help to thwart chemical dependency.

A team of Brown University scientists found that morphine disrupts an inhibitory mechanism in the ventral tegmental area (VTA), a cluster of neurons in the center of the brain responsible for processing naturally rewarding actions, such as eating and sexual activity. The resulting imbalance between excitation and inhibition allows the levels of the neurotransmitter dopamine, a pleasure chemical, to surge.

Morphine blocks a process called long-term potentiation (LTP), which strengthens the synapses (connections between neurons) to make the transfer of information between cells more efficient. Neuroscientists have identified this mechanism as a cellular process behind memory and learning.

In the current study, scientists focused on synapses between dopamine-containing neurons and those that contain GABA (gamma-aminobutyric acid), an inhibitory chemical. "The ability to have LTP at these synapses is probably a natural mechanism to balance excitation and inhibition," says senior study author Julie Kauer, "so the synapse won't get crazily excited."

When the synapse for glutamate (the main excitatory neurotransmitter in the brain) is activated, it triggers a chemical cascade that eventually causes neighboring inhibitory neurons to release GABA into the synapse between it and the dopamine neuron. If a GABA response is blocked—preventing LTP from taking place, as is the case when morphine is in the system—dopamine release is unabated, causing a pleasure sensation. The release of GABA is like "a natural brake on the system," explains Kauer, a Brown University professor of medical science. "When morphine is given 24 hours before, it is like that natural brake has been removed."

Researchers blocked the release of different chemicals in this neurotransmitter cascade a day after injecting rats with a single dose of morphine to determine whether LTP could be induced via electrical stimulation. The team traced the disturbance caused by morphine to an enzyme called guanylate cyclase. Kauer speculates that morphine either decreases guanylate cyclase to levels too low to activate the next chemical in the cascade, or deafens the enzyme to the chemical that signals it.

"[Kauer] has many steps in the LTP pathway," says Susan Volman, program director at the National Institute on Drug Abuse in Bethesda, Md.," but it's not the complete pathway." She adds, however, that "from a potential medication point of view … the guanylate cyclase is a possible target in this cascade, because that's the step at which the morphine seems to be interrupting the LTP."

Kauer suggests that a drug targeting guanylate cyclase could be offered along with morphine to lower the chances of addiction when it is prescribed for pain management. It could prevent addiction, she says, "without interfering with analgesic properties of the drug."

The research, published in the new issue of Nature, provides further evidence that the balance between excitatory and inhibitory drivers is upset by abuse of narcotics; previous studies have shown similar results from abuse of cocaine, nicotine and alcohol. It also confirms, Kauer says, that "the cellular underpinnings of synapses that allow us to learn are the same ones that allow addiction

"Addiction is like memory,'' she adds," in that it's very difficult to erase."

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