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NIDA. (2008, December 1). Methadone Reduces Rats' Cocaine Seeking. Retrieved from

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High-dose methadone undermines animals' motivation to acquire cocaine.

December 01, 2008

Methadone may prove to be an effective treatment for cocaine as well as opioid abuse, if the results of a recent study with rats, funded by NIDA and the Canadian Institutes of Health Research, can be replicated and applied to people. The animals' cocaine seeking dropped in response to methadone given in doses that produce blood levels equivalent to those therapeutically effective for opioid addiction. Methadone at more than twice that dose abolished cocaine seeking.

bar graph of time spent in cocaine associated compartment versus methadone dose - see caption Cocaine Seeking Diminished: In the absence of methadone, each rat in a group of eight spent, on average, more time in a compartment that it associated with cocaine than in one not associated with the drug. When implanted mini-pumps delivered high-dose methadone to the rats, there was no significant difference between the times spent in the two compartments.

"Methadone is the primary drug used to treat opiate dependence worldwide, yet there is still so much to find out about it," says Dr. Francesco Leri of the University of Guelph in Ontario, Canada. "My colleagues and I are exploring the effects of maintaining relatively stable doses of methadone over time in rats to discover all of the benefits and properties of this valuable medication."

Extinguishing Rats' Motivation

Clinical trials have shown that people who take high-dose methadone for heroin addiction and who are also addicted to cocaine decrease their abuse of both drugs. To Dr. Leri, that observation suggested that methadone might have unexploited potential as a medication to treat cocaine abuse in patients both with and without histories of opioid abuse. Accordingly, with colleagues at Concordia University in Montreal and Rockefeller University in New York, Dr. Leri set out to better understand methadone's effect on cocaine seeking.

The team first tested whether methadone would suppress the normal tendency of rats to seek cocaine once they have been repeatedly exposed to the stimulant. To prepare their animals for the test, the researchers put some on methadone (20 or 55 mg/kg/day) via implanted mini-pumps and gave others saline by the same route. During these regimens, for 2 weeks, the researchers trained the animals to associate one designated chamber with cocaine injections and another with saline injections. Daily for 3 days, they injected each animal once with cocaine (1, 5, or 20 mg/kg) and once with saline. Immediately after each cocaine injection, they placed the animal in the first chamber; after each saline injection, they placed it in the second chamber.

On the day of the test, the researchers placed each rat between the two chambers without giving it any cocaine or saline, and monitored where it went. Among the animals given the highest dose of cocaine, those that received no methadone showed a strong preference for the cocaine-associated chamber; those that received the lower methadone dose showed less preference; and those maintained on the higher methadone dose, no preference at all, indicating a total loss of motivation to seek cocaine (see graph).

Another experiment by Dr. Leri's team assessed methadone's impact on cocaine seeking by measuring how hard rats will work to obtain the drug intravenously. They first trained rats to press a lever for cocaine, then implanted mini-pumps: Eight animals received 30 mg/kg/day of methadone, while another six received only saline. The rats were allowed to self-administer cocaine, but the system was programmed to require progressively more presses before it would release each successive infusion. The eight methadone-treated animals gave up pressing the cocaine lever after six presses, on average, whereas the rats that did not receive methadone continued to press it more than 30 times to receive a single dose (see graph).

Some scientists have suggested that methadone-induced sluggishness saps individuals' initiative to seek cocaine. But Dr. Leri asserts that other behavioral tests by his team rule out this explanation. For example, methadone did not alter the animals' general activity, food consumption, or response to heat-generated pain.

"Overall, our results support the usefulness of high-dose methadone as a pharmacological tool to reduce severe cocaine abuse in opioid-dependent individuals and possibly in the management of addiction to only cocaine," Dr. Leri says.

Although the study found high-dose methadone to be effective in this regard, the highest doses of methadone tested in rats produced blood concentrations of the drug more than twice as high as those achieved in people undergoing standard methadone therapy. "To determine whether higher levels of methadone can be efficacious without producing adverse effects, we need clinical research on doses that are higher than customarily used in drug abusers," says Dr. Nancy Pilotte, of NIDA's Division of Basic Neuroscience and Behavioral Research.

Brain Correlates

Methadone helps heroin abusers abstain from opioids by partially stimulating the brain's mu-opioid receptors, an effect that keeps the symptoms of withdrawal at bay and also blocks the rewarding effects of other opioids. But it is not clear how methadone suppresses cocaine seeking. Methadone does not, for example, directly interact with the dopamine transporter, the brain protein that is primarily responsible for the cocaine high.

Dr. Leri suspects that the mu-opioid receptor, which is the site where methadone exerts its primary activity against opioid addiction, also plays a role in the medication's potentially therapeutic effect on cocaine addiction. In support of this idea, he and collaborators at Rockefeller University in New York City showed that cocaine increases production of the mu-opioid receptor in the nucleus accumbens, a key brain area involved in reward and addiction. Methadone, they also found, counteracts these increases.

bar graph - see caption Rats Receiving Methadone Expend Little Effort to Gain Cocaine: When rats were required to respond with more and more lever presses to receive cocaine, the six animals infused with an inactive substance dramatically increased their average number of responses, while the eight animals infused with methadone kept their responses at the same level as their earlier responses to continuously available cocaine.

In the experiments, rats exposed to three injections of 5 or 20 mg/kg doses of cocaine were found to have more mu-opioid receptor messenger RNA (mRNA)—an indicator of receptor production rates—than animals exposed to three injected doses of the drug at 1 mg/kg. These elevations were less pronounced, however, in rats that were being maintained on 20 mg/day of methadone at the time of the cocaine exposures. Moreover, rats exposed to cocaine while being maintained on 55 mg/kg/day of methadone had mu-opioid mRNA levels that were indistinguishable from those of rats that received no cocaine.

From these results, the researchers hypothesize that methadone probably blocks cocaine seeking by inhibiting cocaine-induced enhancement of muopioid receptor production. Other explanations may be possible, however, as enhancing receptor production is not methadone's only effect on brain chemistry. Among its other influences, it boosts the body's natural opioids, the endorphins. Dr. Mary Jeanne Kreek of Rockefeller University says, "We wonder whether people who are dependent on both heroin and cocaine respond well to methadone because methadone reduces the number of mu-opioid receptors in the reward system of their brains or whether they respond because cocaine depletes endorphins and methadone brings the endorphins back."

"Methadone and the mu-opioid antagonist, naltrexone, which blocks the mu receptor and its associated responses, can both be considered as treatments for cocaine abuse, as both decrease the availability of the mu-opiate receptor," says Dr. Pilotte. "Methadone may even be the better treatment as it does not force the client into an uncomfortable state of withdrawal as it decreases the incentive to take cocaine."


Leri, F., et al. High-dose methadone maintenance in rats: Effects on cocaine self-administration and behavioral side effects. Neuropsychopharmacology 32(11):2290-2300, 2007. [Full Text]

Leri, F., et al. Effects of high-dose methadone maintenance on cocaine place conditioning, cocaine selfadministration, and mu-opioid receptor mRNA expression in the rat brain. Neuropsychopharmacology 31(7):1462-1474, 2006. [Full Text]