Intermittent morphine treatment causes a protracted increase in cholinergic striatal neurotransmission measured ex vivo.

Considering the long-lasting neuroadaptations that occur in the brain after exposure to drugs of abuse, we found that the facilitatory effect of an EC50 concentration (0.1 microM) of the acetylcholinesterase inhibitor physostigmine, unlike that of the muscarinic receptor agonist oxotremorine, on K(+)-induced [3H]dopamine release from rat striatal slices was enhanced about 2-fold 1 month after cessation of intermittent morphine treatment. Similarly, the inhibitory effect of physostigmine on K(+)-induced [14C]acetylcholine release from the slices was enhanced subsequent to morphine treatment, whereas that of oxotremorine appeared to be unchanged. Therefore, intermittent morphine administration may cause a very long-lasting increase of muscarinic receptor activation by released endogenous acetylcholine in rat striatum, which may play a pivotal role in the enduring character of stimulus hyperresponsiveness after exposure to drugs of abuse.