Reduction in acetylcholine release in the hippocampus of dopamine D5 receptor-deficient mice.
Activation of the dopamine D1-like receptor stimulates acetylcholine (ACh) release in the hippocampus, apparently through the molecularly defined d5 receptor. In the present study, we used a transgenic mouse completely deprived of functional d5 receptor (d5-/-) to confirm the role and elucidate the possible function of the d5 receptor subtype on hippocampal cholinergic neurotransmission. ACh release was measured using in vivo microdialysis in the mouse dorsal hippocampus of 4 months old homozygous (d5-/-), heterozygous (d5+/-), and the wild-type (d5+/+) littermates. Using the no net flux technique, a significant reduction in basal hippocampal ACh level was found in the d5-/- compared to d5+/- and d5+/+ mice. Moreover, the administration of SKF 38393, a D1-like receptor agonist, systemically (2.0 and 10.0 mg/kg ip), or locally through the dialysis probe (10 and 50 microM), produced a dose-dependent enhancement of ACh release in the d5+/+, a moderate stimulation in the d5+/- but had no effect in the d5-/- mice. Quantitative receptor autoradiography revealed significant increases in M1-like but not in M2-like muscarinic receptor binding sites in the hippocampal formation. These results confirm and extend the role of the d5 receptor in the modulation of hippocampal ACh release and provide evidence for long-term alteration of hippocampal cholinergic neurotransmission resulting from the absence of the d5 receptors including chronically reduced ACh release and change in M1-like receptor levels.
Laplante
François
F
Douglas Hospital Research Centre, LaSalle, Verdun, QC, Canada.
Sibley
David R
DR
Quirion
Rémi
R
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D018491:Dopamine Agonists / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D043643:Receptor, Muscarinic M1 / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D050641:Receptors, Dopamine D5
D018491:Dopamine Agonists; C493606:Drd5 protein, mouse; D043643:Receptor, Muscarinic M1; D017447:Receptors, Dopamine D1; D050641:Receptors, Dopamine D5; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000109:Acetylcholine