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NIDA. (1997, October 1). Is Morphine-Induced Shrinking of Neurons a Clue to Drug Dependence?. Retrieved from

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October 01, 1997
Neil Swan

A NIDA-funded study has shown that chronic administration of morphine to rats reduces by one-quarter the size of dopamine-producing cells in the rodents' brains. Dopamine is a neurotransmitter, a brain chemical that carries messages from one neuron, or nerve cell, to another and from one functional section of the brain to another. Increases in dopamine levels are related to feelings of elation or pleasure. Evidence that morphine shrinks dopamine-producing cells could be a clue to how long-term drug use actually changes brain structures or functions in ways associated with drug dependence.

The researchers, Dr. Eric J. Nestler and his colleagues at Yale University in New Haven, Connecticut, also have found a naturally occurring compound that can block morphine's action in reducing the size of these dopamine-producing neurons.

Photographs of neuronsAt left is a normal dopamine-producing neuron in the ventral tegmental area of a rat's brain. Repeated administration of morphine shrinks the neuron perceptibly, as shown in the center photo. However, when a natural brain compound called BDNF is administered along with morphine, no shrinkage occurs, as shown in the right photo. Researchers say this illustrates how BDNF can "rescue" the dopamine-producing neurons from alteration by morphine.

The Yale researchers examined the effects of chronic morphine administration on the rats' ventral tegmental area (VTA), one center of dopamine activity in the brain. They used a laboratory procedure to tag and then trace the size and shape of certain neurons. They found that chronic morphine administration reduced the size of the VTA dopamine-producing neurons by an average of 25 percent. Chronic use of morphine did not alter the size of other nerve cells in the VTA, and it did not affect the total number of neurons there, an indication that neurons were not killed. If, as Dr. Nestler suspects, the size reduction of dopamine-producing neurons is a long-lasting effect, it may have potentially significant and prolonged influences on brain function and, presumably, behavior, he suggests.

Researchers have speculated that morphine and other opiates intensively activate the VTA dopamine-producing neurons, which, after chronic exposure, adapt to try to compensate for the activation. Under this hypothesis, when morphine is then withheld, these compensatory alterations would contribute to deficient VTA neuronal function and possibly the negative state associated with drug withdrawal symptoms. Thus, shrinkage of dopamine-producing cells in response to chronic morphine administration could be evidence of compensatory action in the dopamine system that may be related to drug dependence and withdrawal, says Dr. Nestler.

Chronic morphine administration reduced the size of the dopamine neurons by an average of 25 percent.

Dr. Nestler and his coworkers were able to prevent morphine's shrinking of dopamine-producing cells by administering naltrexone, a compound that blocks the actions of opiates such as morphine. They also could block morphine-induced size reduction by using a natural compound called brain-derived neurotropic factor (BDNF). Dr. Nestler says this blocking action can "rescue" dopamine neurons from functional impairment relating to their reduction in size.

The fact that BDNF can block morphine's action on VTA dopamine-producing neurons suggests that it should be studied for potential development as an opiate treatment medication, he notes. The Yale research team is now conducting studies on a compound similar to BDNF - glial-derived neurotropic factor, or GDNF - which reportedly acts more specifically on dopamine-producing neurons.


  • Sklair-Tavron, L.; Shi, W.X.; Lane, S.B.; Harris, H.W.; Bunny, B.S.; and Nestler, E.J. Chronic morphine induces visible changes in the morphology of mesolimbic dopamine neurons. Proceedings of the National Academy of Sciences 93:11202-11207, 1996.