Midbrain muscarinic receptor mechanisms underlying regulation of mesoaccumbens and nigrostriatal dopaminergic transmission in the rat

Anthony D. Miller, Charles D. Blaha*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

65 Citations (Scopus)

Abstract

Laterodorsal (LDT) and pedunculopontine (PPT) tegmental nuclei in the mesopontine project cholinergic inputs to the midbrain ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), respectively, to directly and indirectly influence the activity of dopamine neuronal cells via actions on muscarinic and nicotinic receptors. The present study investigated the role of midbrain muscarinic receptors in the functional modulation of VTA and SNc dopamine cell activity as reflected by alterations in, respectively, nucleus accumbens (NAc) and striatal dopamine efflux. In vivo chronoamperometry was used to measure changes in basal dopamine efflux via stearate-graphite paste electrodes implanted unilaterally in the NAc or striatum of urethane- anaesthetized rats, following blockade or activation of, respectively, VTA or SNc muscarinic receptors. Intra-VTA or -SNc infusion of the muscarinic antagonist scopolamine (200 μg/μL) reduced, respectively, NAc and striatal dopamine efflux while infusion of the muscarinic and nicotinic agonist carbachol (0.5 μg/μL) or the prototypical muscarinic agonist muscarine (0.5 μg/μL) increased NAc and striatal dopamine efflux. Transient decreases in dopamine efflux preceded these increases selectively in the striatum, suggesting a reduction in excitatory or increase in inhibitory drive to the SNc by preferential activation of M3 muscarinic receptors on GABA interneurons and glutamatergic inputs. This was confirmed by showing that selective blockade of M3 receptors with p-F-HHSiD (0.5 μg/μL) increased striatal, but not NAc, dopamine efflux. Together, these findings suggest that midbrain muscarinic receptors, probably M5 subtypes on VTA and SNc dopamine neurons, contribute to the tonic excitatory regulation of forebrain basal dopamine transmission whereas presynaptic M3 receptors serve to counter excessive excitation of nigral dopamine cell activity.

Original languageEnglish
Pages (from-to)1837-1846
Number of pages10
JournalEuropean Journal of Neuroscience
Volume21
Issue number7
DOIs
Publication statusPublished - Apr 2005

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