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Home > Publications > NIDA Notes > Vol. 19, No. 5 > Research Findings

Dopamine Enhancement Underlies a Toluene Behavioral Effect
Research Findings
Vol. 19, No. 5 (January 2005)

By Carl Sherman, NIDA NOTES Contributing Writer

Overall drug abuse among teenagers has declined in the past several years, but inhalant abuse is on the rise. The National Survey on Drug Use and Health (NSDUH) for 2002 found that nearly 10 percent of youths aged 12 to 17 had misused inhalants to get high at least once in their lives. Nearly 2.6 million young people have put themselves at risk for toxic brain effects from glue, gasoline, and a wide variety of other household and workplace products. These fumes can strip the myelin insulation from nerve cells throughout the brain, sometimes inflicting severe brain damage.

The drug effects that cause people to take such risks have been difficult to pin down, largely because of the variety of different inhalants and their multiple effects in many parts of the brain. Recently, however, Drs. Art Riegel and Edward French at the University of Arizona in Tucson shed light on how one much-abused inhalant— toluene, a solvent contained in gasoline, spray paint, and glue—may motivate abuse. The NIDA-funded team demonstrated that toluene causes one of its typical behavioral effects in rats, locomotor stimulation—increased roaming—by enhancing dopamine activity in the brain's pleasure center, the nucleus accumbens (NAc). Other drugs that cause locomotor stimulation in this way also promote euphoria—a motivator for drug abuse—by the same mechanism.

To test whether toluene-induced locomotor stimulation might be related to dopamine activity, the researchers compared the drug's effects in rats with intact dopamine neurotransmission and others treated to block dopamine from reaching the NAc. They injected the latter group of rats with 6-hydroxydopamine (6-OHDA), a neurotoxin that inactivates dopamine-releasing nerve terminals. To ensure that any effects they might observe in these rats truly would be due to dopamine reduction in the NAc, the researchers administered the injections directly into the NAc and also gave the rats desipramine. Without this latter precaution, 6-OHDA would also have shut down the terminals that release another important neurotransmitter, norepinephrine.

Neurotoxin Test Shows a Role for Dopamine in Both Toluene-
And Amphetamine-Induced Behaviors
Neurotoxin Test Shows a Role for Dopamine in Both Toluene- and Amphetamine-Induced Behaviors

A dose of toluene increased locomotor stimulation in rats, just as a dose of amphetamine did. When the neurotoxin 6-OHDA, which inactivates dopaminergic neurons, was injected into the rats' nucleus accumbens, it attenuated locomotor stimulation in response to both substances, while a sham injection had no effect. These results suggest that the inhalant affects the brain much like a classic drug of abuse, through activity of the same neurotransmitter (dopamine) in the same part of the brain (nucleus accumbens).

Fourteen days after the 6-OHDA treatment, the researchers began injecting the experimental animals with three different drugs—toluene, amphetamine, and scopolamine—at 2-day intervals. Three groups of rats were used: the rats treated with 6-OHDA; a second group, which had received sham treatment with an inert substance; and untreated rats. As hypothesized, the sham-procedure rats and untreated rats showed locomotor stimulation when given toluene, amphetamine, or scopolamine. But in those pretreated with 6-OHDA, the locomotor response to toluene declined by 55 percent, nearly as much as did the response to amphetamine (67 percent), which is known to work through the dopamine system. The response to scopolamine, which induces locomotor stimulation through neurotransmitters other than dopamine, was unchanged. Postmortem examination confirmed that the neurotoxin had reduced the amount of dopamine in the NAc of the rats' brains.

"The findings put inhalants squarely in the same category as other drugs of abuse, suggesting that a similar mechanism of action is involved."

In a second experiment, rats were injected with LY379268, which activates glutamate receptors, abundant in the NAc, that inhibit the release of dopamine. Earlier experiments have shown LY379268 to lessen the dopamine-dependent behavioral effects of PCP (phencyclidine) and amphetamine. Here too, when the rats were treated with LY379268, locomotor stimulation in response to toluene was significantly reduced.

The results of both experiments were consistent with the hypothesis that increased dopamine activity in the NAc is behind toluene's locomotor stimulation effect, Dr. Riegel says. "Using two very different approaches, we came up with the same end result. The findings put inhalants squarely in the same category as other drugs of abuse, suggesting that a similar mechanism of action is involved."

Inhalant Abuse Rises, Awareness of Its Dangers Drops
Inhalant Abuse Rises, Awareness of Its Dangers Drops

Awareness that inhalant use can kill has decreased significantly among sixth- and eighth-graders, which may translate into an increasing number of inhalant-related injuries and deaths. NIDA Director Dr. Nora D. Volkow says deafness, blindness, tremors, and permanent personality changes are just some of the brain-related problems caused by inhalant abuse. "These substances, when inhaled, can cause deaths by multiple mechanisms by triggering arrhythmia of the heart, which can lead to cardiac arrest, or through asphyxiation."

That toluene-induced dopamine release in the NAc underlies locomotor stimulation suggests that the drug may cause addiction in very similar fashion to other drugs of abuse. "Locomotor stimulation is a good behavioral marker for the abuse potential of a drug," Dr. Riegel says. Previous animal studies have closely linked increased dopamine activity in the NAc and increased locomotion to the behavioral response of drug-seeking following exposure to cocaine, amphetamine, PCP, and nicotine. Along with increased roaming activity, the rats press a lever to obtain those drugs and favor the side of the cage in which the drug has been provided to them. Inactivating the dopamine-releasing nerve terminals in the NAc with a toxic substance attenuates both behavioral responses to the drugs.

Toluene's similarity to other drugs of abuse may be characteristic of other abused inhalants as well. "Toluene is the prototypical inhalant," explains Dr. Riegel, now with NIDA's Division of Intramural Research. "Toluene is itself abused, and it shows up in a wide variety of inhaled substances. Given the choice among two dozen colors of spray paint, abusers prefer gold and silver, which have the highest concentrations of toluene."

Dr. Riegel says that further research is indicated to clarify just what toluene does to neurons to increase dopamine release. A report on anatomical studies to elucidate such processes is currently in preparation.

On a practical level, the findings suggest that "we shouldn't be thinking of inhalants only in terms of their toxicity," says Dr. Riegel. "Because they activate the same areas of the brain as other important drugs of abuse, there is a strong likelihood that they are highly addictive substances and that some of the same strategies that work for other addictions may effectively combat inhalant abuse as well."


National Survey on Drug Use and Health. Inhalant use among youths: 2002 update. The NSDUH Report. March 18, 2004.

Riegel, A.C.; Ali, S.F.; and French, E.D. Toluene-induced locomotor activity is blocked by 6-hydroxydopamine lesions of the nucleus accumbens and the mGluR2/3 agonist LY379268. Neuropsychopharmacology 28(8):1440- 1447, 2003.


Volume 19, Number 5 (January 2005)

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