Involvement of insular muscarinic cholinergic receptors in morphine-induced conditioned place preference in rats.

RATIONALE: Drug addiction represents a pathological usurpation of neural processes involved in learning and memory. Retrieval of drug-related memories can result in drug craving and relapse. Recently, the insula was identified as part of the neuronal circuit responsible for the processing of drug memory; however, its precise role remains unclear.
OBJECTIVE: To investigate the involvement of insular muscarinic acetylcholine receptors (mAChRs) in the processing of drug memory.
METHOD: The morphine-induced conditioned place preference (CPP) was used to assess drug memory. All rats were first trained with morphine to establish the CPP. Sub-groups of these rats were used for contextual cue-induced CPP reinstatement. Other sub-groups of rats underwent extinction of the CPP, and 5 m/kg morphine was used for priming-induced CPP reinstatement. Microinjection of mAChR antagonists or agonists into the insula was performed prior to the CPP tests in order to evaluate their effect on CPP expression.
RESULTS: Insular microinjections of the nonselective mAChR antagonist, scopolamine, and the M₁ antagonist, pirenzepine, significantly inhibited CPP expression in both contextual cue- and priming-induced CPP reinstatement; the M₁ agonist, MCN-A-343, and the M₄ antagonist, tropicamide, enhanced CPP expression. The M₄ agonist, LY2033298, inhibited CPP expression. The M₂ antagonist, methoctramine, and M₃ antagonist, 4-DAMP, had no effect on CPP expression.
CONCLUSION: Our results demonstrate that insular mAChRs play a role in the processing of drug memory. M₁ and M₄ mAChRs work paradoxically; M₁ activation and M₄ inhibition attenuate the expression of drug memory, while M₁ inhibition and M₄ activation augment the expression of drug memory.