Effect of M1- and M2-muscarinic drugs on striatal dopamine release and metabolism: an in vivo microdialysis study comparing normal and 6-hydroxydopamine-lesioned rats

Abstract

Microdialysis was used to study the effect of M1 and M2 selective agonists and antagonists on striatal dopamine release and metabolism. Microdialysis probes were implanted, under anesthesia, in the left and the right striatum of the normal rats and in the normal and denervated striatum of the nigral 6-hydroxydopamine-lesioned rats. Dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined by liquid chromatography and electrochemical detection. The different drugs were infused through the dialysis probe during 40 min. Pirenzepine (5 μM), a selective M1 antagonist, produced a significant decrease in DA release in the normal and the 6-hydrodopamine-lesioned rats, with no significant difference between both groups. Methoctramine, a selective M2 antagonist, produced a dose-dependent increase in DA release between 20 and 200 μM in the normal rats, with no significant effect on DOPAC and HVA. Infusing 75 μM methocramine produced a significant increase in DA release with a more pronounced effect in the intact animals compared to the 6-hydroxydopamine-lesioned animals. The non-selective agonist carbachol produced a decrease in dopamine release after infusion of 50 μM (M2 effect) and an increase in dopamine release after infusion of 50 mM (M1 effect) in the normal rats. Infusing 50 μM carbachol in the denervated striatum, produced a slight increase in DA release. Our data suggest that presynaptic M1-muscarinic receptors enhance and M2-muscarinic receptors inhibit DA release in the striatum of the rat; and that 3 weeks after 6-hydroxydopamine lesioning there may be a normalisation of the number of M1-receptors with a loss of M2-receptors at the denervated side.