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Vol. 95, Issue 17, 10269-10273, August 18, 1998

Mesolimbic dopaminergic decline after cannabinoid withdrawal

Marco Diana*,, Miriam Melis, Anna Lisa Muntoni, and Gian Luigi Gessa

* Department of Drug Sciences University of Sassari, via Muroni 23/a 07100 Sassari, Italy; and Department of Neuroscience, "B.B. Brodie," University of Cagliari, via Porcell 4 09124, Cagliari, Italy

Communicated by Avram Goldstein, Stanford University, Stanford, CA, June 9, 1998 (received for review February 25, 1998)

The mesolimbic dopamine system has recently been implicated in the long-term aversive consequences of withdrawal from major drugs of abuse. In the present study we sought to determine whether mesolimbic dopamine neurons are involved in the neurobiologic mechanisms underlying withdrawal from chronic cannabinoid exposure. Rats were treated chronically with the major psychoactive ingredient of hashish and marijuana, 9-tetrahydrocannabinol (9-THC). Administration of the cannabinoid antagonist SR 141716A precipitated an intense behavioral withdrawal syndrome, whereas abrupt 9-THC suspension failed to produce overt signs of abstinence. In contrast, both groups showed a reduction in dopamine cells activity as indicated by extracellular single unit recordings from antidromically identified meso-accumbens dopamine neurons. The administration of 9-THC to spontaneously withdrawn rats restored neuronal activity. Conversely, SR 141716A produced a further decrease of spontaneous activity in cannabinoid-treated although it was ineffective in control rats. These data indicate that withdrawal from chronic cannabinoid administration is associated with reduced dopaminergic transmission in the limbic system, similar to that observed with other addictive drugs; these changes in neuronal plasticity may play a role in drug craving and relapse into drug addiction.

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Copyright 1998 by the National Academy of Sciences

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