scholarly journals Prefrontal dopamine D1 receptor manipulation influences anxiety behavior and induces neuroinflammation within the hippocampus

2020 ◽  
Author(s):  
Dominik K E Beyer ◽  
Annika Mattukat ◽  
Nadja Freund
Keyword(s):  
Bipolar Disorder ◽  
Immune System ◽  
Lentiviral Vector ◽  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Male Adult ◽  
Over Expression ◽  
Tissue Manipulation ◽  
Inflammatory State ◽  
Anxiety Behavior

Abstract Background - Prefrontal dopamine D1 receptor (D1R) mediates behavior related to anxiety, reward and memory, and is involved in inflammatory processes, all of which are affected in bipolar disorder. Patients with bipolar disorder show alternations in the dopamingergic and immune system. Interleukin-6 (IL-6), a pro-inflammatory cytokine, is increased in plasma samples, imaging studies and post mortem tissue. Manipulation of the D1R in the medial prefrontal cortex (mPFC) e.g. results in BD-like behavior. The purpose of the study is the investigation of the influence of D1R over-expression and its termination on the immune system and anxiety behavior in rats.Methods – Expression of the gene for D1R in glutamatergic neurons within the mPFC of male, adult rats was manipulated through an inducible (Tet.On) lentiviral vector. Anxiety behavior was studied in the elevated plus maze and marble burying test in ‘ON’ (D1R over-expression) and ‘OFF’ (termination of D1R over-expression) states. IL-6-positive cells were counted to identify the inflammatory state within several subregions of the hippocampus.Results - D1R ‘OFF’ subjects buried more marbles compared to D1R ‘ON’ and their respective control animals indicating an increased anxiety behavior. D1R ‘OFF’ animals reflected an elevated pro-inflammatory state in the hippocampus, in the CA3 and dentate gyrus especially. Consistently, inflammatory state in the whole hippocampus and anxiety behavior correlated positively, indicating a connection between anxiety and inflammatory state of the hippocampus.Conclusions – Behavioral and molecular findings support the association of D1R’s impact on anxiety and inflammation. In addition, by confirming an involvement of IL-6, the new animal model for bipolar disorder has been further validated.

scholarly journals Prefrontal dopamine D1 receptor manipulation influences anxiety behavior and induces neuroinflammation within the hippocampus

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Dominik K. E. Beyer ◽  
Annika Mattukat ◽  
Nadja Freund
Keyword(s):  
Bipolar Disorder ◽  
Animal Model ◽  
Elevated Plus Maze ◽  
D1 Receptor ◽  
Adult Rats ◽  
Male Adult ◽  
Respective Control ◽  
Plus Maze ◽  
Inflammatory State ◽  
Anxiety Behavior

Abstract Background Prefrontal dopamine D1 receptor (D1R) mediates behavior related to anxiety, reward and memory, and is involved in inflammatory processes, all of which are affected in bipolar disorder. Interleukin-6 (IL-6), a pro-inflammatory cytokine, is increased in patients with bipolar disorder in plasma samples, imaging studies and postmortem tissue and is an indicator for an inflammatory state. We could previously show that lentiviral overexpression of D1R in the medial prefrontal cortex (mPFC) of male adult rats and its termination induces bipolar disorder-like behavior. The purpose of this study was to investigate anxiety and the role of the immune system, specifically IL-6 positive neurons in this animal model. Due to its high density of inflammatory mediator receptors and therewith sensibility to immune activation, the hippocampus was investigated. Methods Expression of the gene for D1R in glutamatergic neurons within the mPFC of male, adult rats was manipulated through an inducible lentiviral vector. Animals over-expressing the gene (mania-like state), after termination of the expression (depressive-like) and their respective control groups were investigated. Anxiety behavior was studied in the elevated plus maze and marble burying test. Furthermore, IL-6-positive cells were counted within several subregions of the hippocampus. Results D1R manipulation in the mPFC had only mild effects on anxiety behavior in the elevated plus maze. However, subjects after termination buried more marbles compared to D1R over-expressing animals and their respective control animals indicating elevated anxiety behavior. In addition, animals in the depressive-like state showed higher numbers of IL-6 positive cells reflecting an elevated pro-inflammatory state in the hippocampus, in the CA3 and dentate gyrus. Consistently, inflammatory state in the whole hippocampus and anxiety behavior correlated positively, indicating a connection between anxiety and inflammatory state of the hippocampus. Conclusions Behavioral and neurobiological findings support the association of manipulation of the D1R in the mPFC on anxiety and inflammation in the hippocampus. In addition, by confirming changes in the inflammatory state, the proposed animal model for bipolar disorder has been further validated.

Linkage disequilibrium between dopamine D1 receptor gene (DRD1) and bipolar disorder

2002 ◽  
Vol 52 (12) ◽  
pp. 1144-1150 ◽  
Author(s):  
Xingqun Ni ◽  
Joseph M Trakalo ◽  
Emanuela Mundo ◽  
Fabio M Macciardi ◽  
Sagar Parikh ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Linkage Disequilibrium ◽  
Receptor Gene ◽  
Dopamine D1 Receptor ◽  
D1 Receptor

Dopamine D1 Receptor Gene Polymorphism is Associated with Prophylactic Lithium Response in Bipolar Disorder

2009 ◽  
Vol 42 (01) ◽  
pp. 20-22 ◽  
Author(s):  
J. Rybakowski ◽  
M. Dmitrzak-Weglarz ◽  
A. Suwalska ◽  
A. Leszczynska-Rodziewicz ◽  
J. Hauser
Keyword(s):  
Bipolar Disorder ◽  
Gene Polymorphism ◽  
Receptor Gene ◽  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Receptor Gene Polymorphism ◽  
Lithium Response

scholarly journals Dopamine D1 receptor‐expressing neurons activity is essential for locomotor and sensitizing effects of a single injection of cocaine

2021 ◽  
Author(s):  
Yukari Nakamura ◽  
Sophie Longueville ◽  
Akinori Nishi ◽  
Denis Herve ◽  
Jean‐Antoine Girault ◽  
...  
Keyword(s):  
Single Injection ◽  
Dopamine D1 Receptor ◽  
D1 Receptor

Functional MHCI deficiency induces ADHD-like symptoms with increased dopamine D1 receptor expression

2021 ◽  
Author(s):  
Hong-Rui Meng ◽  
Toshiko Suenaga ◽  
Mitsuhiro Edamura ◽  
Atsuo Fukuda ◽  
Yasushi Ishida ◽  
...  
Keyword(s):  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Receptor Expression

scholarly journals Serine mutations in transmembrane V of the dopamine D1 receptor affect ligand interactions and receptor activation.

1992 ◽  
Vol 267 (25) ◽  
pp. 17780-17786
Author(s):  
N.J. Pollock ◽  
A.M. Manelli ◽  
C.W. Hutchins ◽  
M.E. Steffey ◽  
R.G. MacKenzie ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Ligand Interactions

scholarly journals Enantioenriched Positive Allosteric Modulators Display Distinct Pharmacology at the Dopamine D1 Receptor

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3799
Author(s):  
Tim J. Fyfe ◽  
Peter J. Scammells ◽  
J. Robert Lane ◽  
Ben Capuano
Keyword(s):  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Intrinsic Activity ◽  
Optical Isomers ◽  
Allosteric Modulators ◽  
Disease States ◽  
Starting Point ◽  
Significant Difference ◽  
Optically Pure ◽  
Allosteric Properties

(1) Background: Two first-in-class racemic dopamine D1 receptor (D1R) positive allosteric modulator (PAM) chemotypes (1 and 2) were identified from a high-throughput screen. In particular, due to its selectivity for the D1R and reported lack of intrinsic activity, compound 2 shows promise as a starting point toward the development of small molecule allosteric modulators to ameliorate the cognitive deficits associated with some neuropsychiatric disease states; (2) Methods: Herein, we describe the enantioenrichment of optical isomers of 2 using chiral auxiliaries derived from (R)- and (S)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (d- and l-pantolactone, respectively); (3) Results: We confirm both the racemate and enantiomers of 2 are active and selective for the D1R, but that the respective stereoisomers show a significant difference in their affinity and magnitude of positive allosteric cooperativity with dopamine; (4) Conclusions: These data warrant further investigation of asymmetric syntheses of optically pure analogues of 2 for the development of D1R PAMs with superior allosteric properties.

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