title: Dopamine D₂ and acetylcholine α7 nicotinic receptors have subcellular distributions favoring mediation of convergent signaling in the mouse ventral tegmental area.
abstract: Alpha7 nicotinic acetylcholine receptors (α7nAChRs) mediate nicotine-induced burst-firing of dopamine neurons in the ventral tegmental area (VTA), a limbic brain region critically involved in reward and in dopamine D2 receptor (D2R)-related cortical dysfunctions associated with psychosis. The known presence of α7nAChRs and Gi-coupled D2Rs in dopamine neurons of the VTA suggests that these receptors are targeted to at least some of the same neurons in this brain region. To test this hypothesis, we used electron microscopic immunolabeling of antisera against peptide sequences of α7nACh and D2 receptors in the mouse VTA. Dual D2R and α7nAChR labeling was seen in many of the same somata (co-localization over 97%) and dendrites (co-localization over 49%), where immunoreactivity for each of the receptors was localized to endomembranes as well as to non-synaptic or synaptic plasma membranes often near excitatory-type synapses. In comparison with somata and dendrites, many more small axons and axon terminals were separately labeled for each of the receptors. Thus, single-labeled axon terminals were predominant for both α7nAChR (57.9%) and D2R (89.0%). The majority of the immunolabeled axonal profiles contained D2R-immunoreactivity (81.6%) and formed either symmetric or asymmetric synapses consistent with involvement in the release of both inhibitory and excitatory transmitters. Of 160 D2R-labeled terminals, 81.2% were presynaptic to dendrites that expressed α7nAChR alone or together with the D2R. Numerous glial processes inclusive of those enveloping either excitatory- or inhibitory-type synapses also contained single labeling for D2R (n=152) and α7nAChR (n=561). These results suggest that classic antipsychotic drugs, all of which block the D2R, may facilitate α7nAChR-mediated burst-firing by elimination of D2R-dependent inhibition in neurons expressing both receptors as well as by indirect pre-synaptic and glial mechanisms.
authors: Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street, New York, NY 10065, USA; Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina UAM, Madrid 28029, Spain; Instituto de Investigación Hospital Universitario La Paz (IDIPAZ), Paseo de la Castellana 261, Madrid 28046, Spain.
authors: M
authors: M
authors: Garzón
authors: A M
authors: AM
authors: Duffy
authors: J
authors: J
authors: Chan
authors: M-K
authors: MK
authors: Lynch
authors: K
authors: K
authors: Mackie
authors: V M
authors: VM
authors: Pickel
mesh_terms: D000818:Animals; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000648:ultrastructure; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D017448:Receptors, Dopamine D2 / Q000648:ultrastructure*; D012201:Reward; D017557:Ventral Tegmental Area / Q000378:metabolism* / Q000648:ultrastructure; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000648:ultrastructure*
chemical_list: D017448:Receptors, Dopamine D2; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: ABC; ACh; Avidin–biotin complex; BSA; D(2)R; G-protein-coupled inwardly rectifying potassium; GIRK; MLA; N-methyl-d-aspartate receptor; NAc; NMDA; PB; PBS; TS; Tris-buffered saline; VTA; acetylcholine; addiction; alpha7 nicotinic acetylcholine receptors; bovine serum albumin; dopamine D(2) receptor; electron microscopic immunolabeling; mesocorticolimbic; methyllycaconitine; nAChR; nicotinic acetylcholine receptor; nucleus accumbens; phosphate buffer; phosphate-buffered saline; reward; schizophrenia; ventral tegmental area; α7nAChRs
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