Combined α2- and D2-receptor blockade activates noradrenergic and dopaminergic neurons, but extracellular dopamine in the prefrontal cortex is determined by uptake and release from noradrenergic terminals

Frontiers in Pharmacology

Pharmacology

Sonia Aroni¹  Claudia Sagheddu¹  Marco Pistis²  Pierluigi Saba³  Paola Devoto³  Gian Luigi Gessa⁴ 

[1] Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy;Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy;Neuroscience Institute of CNR, Cagliari, Italy;Unit of Clinical Pharmacology, University Hospital of Cagliari, Cagliari, Italy;Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy;The Guy Everett Laboratory, University of Cagliari, Cagliari, Italy;Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy;The Guy Everett Laboratory, University of Cagliari, Cagliari, Italy;Neuroscience Institute of CNR, Cagliari, Italy;

关键词: antipsychotics;    locus coeruleus;    ventral tegmental area;    electrophysiology;    microdialysis;    rat;   

DOI  :  10.3389/fphar.2023.1238115

 received in 2023-06-10, accepted in 2023-08-10,  发布年份 2023

来源: Frontiers

【 摘 要 】

Experimental and clinical evidence indicates a deficit of release and function of dopamine in schizophrenia and suggests that α2-adrenoceptor antagonists rescue dopamine deficit and improve the antipsychotic efficacy of D2-receptor antagonists. In anesthetized male rats, we investigated how the blockade of α2- and D2-receptors by atipamezole and raclopride, respectively, modified the firing of noradrenergic neurons in the locus coeruleus (LC) and dopaminergic neurons in the ventral tegmental area (VTA). In freely moving rats, we studied how atipamezole and raclopride modified extracellular noradrenaline, dopamine, and DOPAC levels in the medial prefrontal cortex (mPFC) through microdialysis. When administered alone, atipamezole activated LC noradrenaline but not VTA dopamine cell firing. Combined with raclopride, atipamezole activated dopamine cell firing above the level produced by raclopride. Atipamezole increased extracellular dopamine to the same level, whether administered alone or combined with raclopride. In the presence of the noradrenaline transporter (NET) inhibitor, atipamezole combined with raclopride increased extracellular dopamine beyond the level produced by either compound administered alone. The results suggest that a) the D2-autoreceptor blockade is required for LC noradrenaline to activate VTA cell firing; b) the level of dopamine released from dopaminergic terminals is determined by NET; c) the elevation of extracellular dopamine levels in the mPFC is the resultant of dopamine uptake and release from noradrenergic terminals, independent of dopaminergic cell firing and release; and d) LC noradrenergic neurons are an important target for treatments to improve the prefrontal deficit of dopamine in neuropsychiatric pathologies.

【 授权许可】

Unknown   
Copyright © 2023 Sagheddu, Devoto, Aroni, Saba, Pistis and Gessa.