Activation of the mesocorticolimbic dopaminergic system by stimulation of muscarinic cholinergic receptors in the ventral tegmental area

Objective: To investigate the function of muscarinic receptors in the ventral tegmental area in vivo, the release of endogenous monoamines was simultaneously measured in the somatodendritic (ventral tegmental area) and terminal (frontal cortex and nucleus accumbens) regions of the mesocorticolimbic dopaminergic system in rats, using dual probe microdialysis. Methods: Rats were implanted with dual microdialysis probes ipsilaterally into the ventral tegmental area (VTA) and nucleus accumbens (NAC) or frontal cortex (FC). Results: Intrategmental infusion of the muscarinic a,agonist oxotremorine M (OXO M, 0.1 and 1 mM) increased extracellular levels of dopamine and serotonin, but not noradrenaline, in the VTA to a maximum of 200% over baseline in both urethane-anaesthetized and unanaesthetized rats. In freely moving animals, this effect was accompanied by strong motor agitation. Both VTA dopamine and serotonin levels dropped to 60% or less of baseline when the perfusion medium was replaced by a calcium-free medium containing OXO M. In the NAC and FC, a similar increase in extracellular dopamine, but not serotonin and noradrenaline, was observed during OXO M infusion in the VTA. The removal of calcium during OXO M infusion in the VTA did not cause a decrease in NAC dopamine levels. Activation of serotonin and dopamine release by OXO M in the VTA and FC was dramatically reduced or prevented by the coinfusion of the muscarinic antagonist N-methylscopolamine (0.1 mM). Conclusion: These data demonstrate that VTA dopamine cells possess functional muscarinic receptors whose activation stimulates the release of dopamine in the VTA, NAC and FC. These results also suggest that muscarinic receptors may modulate the synaptic release of serotonin in the VTA.