Mesolimbic dopaminergic decline after cannabinoid withdrawal

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, Δ9-tetrahydrocannabinol (Δ9-THC).
Administration of the cannabinoid antagonist SR 141716A
precipitated an intense behavioral withdrawal syndrome,
whereas abrupt D9-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 mesoaccumbens
dopamine neurons. The administration of Δ9-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to spontaneously withdrawn rats restored neuronal activity.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.