Behavioral effects of morphine and cocaine in M1 muscarinic acetylcholine receptor-deficient mice.

RATIONALE: Muscarinic acetylcholine receptors (M1-M5) modulate the activity of the central nervous system and an array of physiological functions. Recent evidence has also implicated muscarinic receptors in behavioral effects of drugs of abuse such as morphine and cocaine. However, the genetic similarity between muscarinic receptors and the coexpression of multiple subtypes in most cells has impeded the development of selective antagonists and the determination of the role of each muscarinic receptor subtype in morphine's and cocaine's behavioral effects.

OBJECTIVE

The present studies employ mice deficient in the M1 receptor subtype (M1 KO) to assess morphine antinociception (2.5, 5.0, 10, or 20 mg/kg) and the conditioned rewarding effects of morphine and cocaine (2.5, 5.0, or 10 mg/kg).

METHODS

M1 KO and their wild-type (WT) littermates were tested using a 56 degrees C hotplate assay and a conditioned place preference procedure. Parallel studies using the M1 receptor antagonist, pirenzepine, were also conducted in the background strain C57BL6 mice.

RESULTS

The results demonstrate that M1 KO mice display a greater antinociceptive effect of morphine in the hotplate assay; however, the effects of morphine as well as cocaine were attenuated in the conditioned place preference procedure. Comparable results were obtained with the pharmacological antagonism of the M1 receptor by pirenzepine.

CONCLUSIONS

These results suggest a modulatory role of the M1 muscarinic receptor in opioid antinociception and conditioned drug reward, and demonstrate the utility of M1 receptor knockout models for the determination of the role of the M1 subtype in the behavioral effects of morphine and cocaine.