ar-r-17779 and xanomeline

The nucleus accumbens receives limbic inputs from a number of brain regions, including the ventral subiculum. In rats, activation of the ventral subiculum following microinjection of N-methyl-D-aspartate (NMDA) or carbachol increases locomotor activity, whilst ventral subiculum application of NMDA also increases dopamine efflux in the ipsilateral nucleus accumbens. Microdialysis experiments were therefore conducted to ascertain the consequences for dopamine release in the nucleus accumbens following ventral subiculum administration of carbachol, and to explore the acetylcholine receptor subtype(s) that might be involved. We report that, in anaesthetised rats, ventral subiculum administration of carbachol increased dopamine levels in the nucleus accumbens. The response was attenuated by co-administration with atropine, whilst administration of nicotine and the alpha-7 nicotinic acetylcholine receptor agonist AR-R17779 (spiro[1-azabicyclo[2,2,2]octane-3,5'-oxazolidine]-2'-one monohydrochloride) failed to evoke a response. Oxotremorine-M produced a dose-dependent increase in dopamine efflux confirming sensitivity to muscarinic receptor stimulation. However, the ventral subiculum was insensitive to xanomeline and pilocarpine, muscarinic M(1) receptor-preferring agonists, but sensitive to BuTAC ([5R-[exo]-6-[butylthio]-1,2,5-thiadiazol-3-yl]-1-azabicyclo[3.2.1])octane), a muscarinic M(2)/M(4) receptor agonist. The dopamine response to oxotremorine-M was significantly attenuated, although not abolished by co-administration with the M(2)/M(4) receptor antagonist methoctramine, and studies combining oxotremorine-M with (-)-bicuculline, indicated a dual action in the ventral subiculum that was dependent and independent of reduced GABA neurotransmission. The data presented indicates that activation of the ventral subiculum by carbachol increases dopamine efflux in the nucleus accumbens by stimulation of muscarinic receptors, and that the ventral subiculum-nucleus accumbens projection system is sensitive to muscarinic M(2)/M(4) receptor stimulation.

Topics: Animals; Atropine; Bicuculline; Bridged-Ring Compounds; Carbachol; Cholinergic Agonists; Diamines; Dopamine; Hippocampus; Male; Microdialysis; Muscarinic Agonists; Muscarinic Antagonists; Nicotine; Nucleus Accumbens; Oxotremorine; Pilocarpine; Pyridines; Rats; Receptors, Muscarinic; Spiro Compounds; Thiadiazoles; Tropanes