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National Institute on Drug Abuse - NIDA NOTES
Marijuana Research
Volume 10, Number 6
November/December 1995


Marijuana Antagonist Reveals Evidence of THC Dependence in Rats


By Neil Swan, NIDA NOTES Contributing Writer


For the first time, researchers have demonstrated that marijuana may cause drug dependency in animals. This findingwas made possible by the recent development of a potent marijuana antagonist - an agent that blocks many effects of the drug. The marijuana antagonist appears to act like an on-off switch, allowing researchers to control the effects of withdrawal from delta-9-tetrahydrocannabinol (THC), the principal psychoactive ingredient of marijuana.


Dr. Billy Martin found that when rats that are
adminstered the main psychoactive ingredient
in marijuana are then given doses of a compound
that blocks the action of this ingredient, the rats
"dramatically" exhibit classic rodent withdrawal
symptoms.
Dr.


Dr. Billy Martin, a NIDA-funded marijuana researcher at Virginia Commonwealth University's Medical College of Virginia, who conducted one of two initial studies, presented his findings at NIDA's National Conference on Marijuana Use: Prevention, Treatment, and Research last summer. During his research, rats were exposed to THC for 4 days, then given a dose of the THC antagonist SR 141716A, which was developed by French scientists last year. The rats immediately and "dramatically" exhibited classic rodent behavioral withdrawal symptoms, indicating that they were dependent on THC, Dr. Martin said.

Within 10 minutes after administration of the marijuana antagonist, the rats exhibited behavior that included "wet-dog shakes" and facial rubbing, which constitute "definite evidence of withdrawal" from the effects of THC, said Dr. Martin. This behavior mimics long-observed opiate withdrawal symptoms in rodents.

The shakes and rubbing were so striking and frequent that they could be quantified by trained observers. Other, less frequent withdrawal-like behaviors included head shakes, biting, drooping eyelids, retropulsion (backing away), ear twitching, chewing, licking, and arching the back, Dr. Martin said.

The wet-dog shakes were dose-dependent, meaning they became more pronounced as dose levels of the antagonist were increased in the THC-exposed animals.

Dr. Martin acknowledged that such behavior is not like any marijuana withdrawal syndrome in humans.

"The fact that people do seek treatment for marijuana dependence is evidence of marijuana withdrawal in humans, but, even among those seeking treatment, we do not see dramatic withdrawal symptoms," said Dr. Martin. "That's because the withdrawal process in humans is so long and drawn out, evidenced chiefly by mild distress or anxiety. But with the rats, using SR 141716A as an effective antagonist, we compress and accentuate that withdrawal process.

"The challenge for us now is to use these animal data to design human studies-to determine how small a dose of THC is needed to become dependent on marijuana," said Dr. Martin.

Dr. Martin, senior investigator Dr. Mario D. Aceto, and colleagues at the Department of Pharmacology and Toxicology of Virginia Commonwealth University have published the results of their research.

"We have been searching for a marijuana antagonist for many years," said Dr. Martin, who has been a marijuana researcher for 22 years.

Sources

Aceto, M.D.; Scates, S.M.; Lowe, J.A.; and Martin, B.R. Canna-binoid-precipitated withdrawal by a selective antagonist: SR 141716A. Eur. J. Pharmacol. 282(1-3):R1-R2, 1995.

Rinaldi-Carmona, M., et al. SR 141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS (Federation of European Biochemical Societies) Letters 350(2-3):240-244, 1994.

Tsou, K.; Patrick, S.; and Walker, M.J. Physical withdrawal in rats tolerant to delta-9-tetrahydrocannabinol precipitated by a cannabinoid receptor antagonist. Eur. J. Pharmacol. 280:R13-R15, 1995.

From NIDA NOTES, November/December, 1995


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