Antagonist of M1 muscarinic acetylcholine receptor prevents neurotoxicity induced by amphetamine via nitric oxide pathway.

The psychostimulant amphetamine (AMPH) has been found to induce striatal acetylcholine release and neurotoxic processes via nitric oxide (NO) and lipid peroxidation (LPO). Our purpose was to determine whether blocking striatal muscarinic (M1) receptors by the selective M1 antagonist toxin 7 (MT 7; bilaterally, 2 microg per side) might attenuate the effects of AMPH (4 x 5 mg/kg, i.p.). Systemic AMPH administration increased NO and LPO in the striatal tissue. Stimulation of M1 receptors by i.c.v. injection of M1 agonist McN-A-343 (200 microg) caused a similar enhancement of NO and LPO. Pretreatment with the MT7 prevented the AMPH-induced NO generation and greatly reduced the LPO caused by the psychostimulant. These results show that M1 acetylcholine receptors are critically involved in neurotoxic processes induced by AMPH via NO and LPO.