Adaptive changes in M1 muscarinic receptors localized to specific rostral brain regions during and after morphine withdrawal

Morphine-dependent rats were allowed to undergo withdrawal by abrupt discon tinuation of the drug, The regional expression of brain M1 muscarinic recep tors was measured directly by autoradiographic determination with [H-3] pir enzepine, and indirectly by quantifying the relative levels of M1 mRNA enco ding the receptor protein. Patterns of receptor changes after morphine trea tment were in general agreement using the two methods. Frontal cortical sam ples derived from morphine-dependent rats exhibited a 28% increase in M1 re ceptor mRNA measured at the end of the infusion. At the peak of the withdra wal, M1 mRNA levels for dependent rats were much lower (33.4%) than those f or control rats. Hippocampal samples derived from morphine-dependent rats e xhibited no changes in M1 mRNA levels after the morphine infusion. During t he peak of withdrawal, however, hippocampal M1 mRNA levels were reduced (57 %) compared with levels for controls. The M1 mRNA levels remained at this r educed degree of expression even after withdrawal symptoms had subsided. Ad dition of diisopropylflurophophate (DFP) to the morphine infusion schedule inhibited the adaptive changes in M1 mRNA levels induced by morphine. Durin g the peak period of withdrawal, M1 mRNA levels in the hippocampus declined by only 18% as compared with 57% for the morphine control group. The adapt ive decrease in hippocampal M1 receptors after withdrawal subsided may refl ect prolonged heightened cholinergic activity in an area where such choline rgic innervation plays an important role in memory. (C) 2000 Elsevier Scien ce Ltd. All rights reserved.