title: Genetic blockade of the dopamine D3 receptor enhances hippocampal expression of PACAP and receptors and alters their cortical distribution.
abstract: Dopamine D3 receptors (D3Rs) are implicated in several aspects of cognition, but their role in aversive conditioning has only been marginally uncovered. Investigations have reported that blockade of D3Rs enhances the acquisition of fear memories, a phenomenon tightly linked to the neuropeptide pituitary adenylate cyclase-activating peptide (PACAP). However, the impact of D3R ablation on the PACAPergic system in regions critical for the formation of new memories remains unexplored. To address this issue, levels of PACAP and its receptors were compared in the hippocampus and cerebral cortex (CX) of mice devoid of functional D3Rs (D3R(-/-)) and wild-types (WTs) using a series of comparative immunohistochemical and biochemical analyses. Morphometric and stereological data revealed increased hippocampal area and volume in D3R(-/-) mice, and augmented neuronal density in CA1 and CA2/3 subfields. PACAP levels were increased in the hippocampus of D3R(-/-) mice. Expression of PACAP receptors was also heightened in mutant mice. In the CX, PACAP immunoreactivity (IR), was restricted to cortical layer V in WTs, but was distributed throughout layers IV-VI in D3R(-/-) mice, along with increased mRNAs, protein concentration and staining scores. Consistently, PAC1, VPAC1 and VPAC2 IRs were variably redistributed in CX, with a general upregulation in cortical layers II-IV in knockout animals. Our interpretation of these findings is that disturbed dopamine neurotransmission due to genetic D3R blockade may enhance the PACAP/PAC1-VPAC axis, a key endogenous system for the processing of fear memories. This could explain, at least in part, the facilitated acquisition and consolidation of aversive memories in D3R(-/-) mice.
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Human Anatomy and Histology, University of Catania, Catania 95123, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Marzagalli
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania 95123, Italy.
authors.forename: G M
authors.initials: GM
authors.lastname: Leggio
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania 95123, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bucolo
authors.affiliation: Department G.F. Ingrassia, Azienda Ospedaliero-Universitaria "Policlinico-Vittorio Emanuele", Section of Anatomic Pathology, University of Catania, Catania, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Pricoco
authors.affiliation: Discipline of Anatomy and Histology, School of Medical Sciences, The University of Sydney, Sydney 2006, NSW, Australia.
authors.forename: K A
authors.initials: KA
authors.lastname: Keay
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania 95123, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Cardile
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Human Anatomy and Histology, University of Catania, Catania 95123, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Castorina
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania 95123, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Salomone
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania 95123, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Drago
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Human Anatomy and Histology, University of Catania, Catania 95123, Italy; Discipline of Anatomy and Histology, School of Medical Sciences, The University of Sydney, Sydney 2006, NSW, Australia. Electronic address: alecasto@unict.it.
authors.forename: A
authors.initials: A
authors.lastname: Castorina
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics*; D006624:Hippocampus / Q000033:anatomy & histology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D059906:Neuroimaging; D009474:Neurons / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000172:deficiency* / Q000235:genetics; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism*; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000378:metabolism
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D050637:Receptors, Dopamine D3; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I
keywords: PAC1/VPAC receptors; PACAP; aversive conditioning; cerebral cortex; dopamine D(3) receptor; hippocampus