Chronic Administrations of Guanfacine on Mesocortical Catecholaminergic and Thalamocortical Glutamatergic Transmissions.
Adrenergic alpha-2 Receptor Agonists
/ administration & dosage
Animals
Attention Deficit Disorder with Hyperactivity
/ drug therapy
Dopamine
/ metabolism
Glutamic Acid
/ metabolism
Guanfacine
/ administration & dosage
Male
Norepinephrine
/ metabolism
Prefrontal Cortex
/ drug effects
Rats
Rats, Sprague-Dawley
Receptors, Adrenergic, alpha-2
/ genetics
Synaptic Transmission
/ drug effects
Thalamus
/ drug effects
gamma-Aminobutyric Acid
/ metabolism
GABA
L-glutamate
attention-deficit/hyperactivity disorder
dopamine
guanfacine
norepinephrine
α2A adrenoceptor
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
16 Apr 2021
16 Apr 2021
Historique:
received:
02
03
2021
revised:
06
04
2021
accepted:
14
04
2021
entrez:
30
4
2021
pubmed:
1
5
2021
medline:
13
5
2021
Statut:
epublish
Résumé
It has been established that the selective α2A adrenoceptor agonist guanfacine reduces hyperactivity and improves cognitive impairment in patients with attention-deficit/hyperactivity disorder (ADHD). The major mechanisms of guanfacine are considered to involve the activation of the postsynaptic α2A adrenoceptor of glutamatergic pyramidal neurons in the frontal cortex, but the effects of chronic guanfacine administration on catecholaminergic and glutamatergic transmissions associated with the orbitofrontal cortex (OFC) are yet to be clarified. The actions of guanfacine on catecholaminergic transmission, the effects of acutely local and systemically chronic (for 7 days) administrations of guanfacine on catecholamine release in pathways from the locus coeruleus (LC) to OFC, the ventral tegmental area (VTA) and reticular thalamic-nucleus (RTN), from VTA to OFC, from RTN to the mediodorsal thalamic-nucleus (MDTN), and from MDTN to OFC were determined using multi-probe microdialysis with ultra-high performance liquid chromatography. Additionally, the effects of chronic guanfacine administration on the expression of the α2A adrenoceptor in the plasma membrane fraction of OFC, VTA and LC were examined using a capillary immunoblotting system. The acute local administration of therapeutically relevant concentrations of guanfacine into the LC decreased norepinephrine release in the OFC, VTA and RTN without affecting dopamine release in the OFC. Systemically, chronic administration of therapeutically relevant doses of guanfacine for 14 days increased the basal release of norepinephrine in the OFC, VTA, RTN, and dopamine release in the OFC via the downregulation of the α2A adrenoceptor in the LC, OFC and VTA. Furthermore, systemically, chronic guanfacine administration did not affect intrathalamic GABAergic transmission, but it phasically enhanced thalamocortical glutamatergic transmission. The present study demonstrated the dual actions of guanfacine on catecholaminergic transmission-acute attenuation of noradrenergic transmission and chronic enhancement of noradrenergic transmission and thalamocortical glutamatergic transmission. These dual actions of guanfacine probably contribute to the clinical effects of guanfacine against ADHD.
Identifiants
pubmed: 33923533
pii: ijms22084122
doi: 10.3390/ijms22084122
pmc: PMC8073983
pii:
doi:
Substances chimiques
Adrenergic alpha-2 Receptor Agonists
0
Receptors, Adrenergic, alpha-2
0
Guanfacine
30OMY4G3MK
Glutamic Acid
3KX376GY7L
gamma-Aminobutyric Acid
56-12-2
Dopamine
VTD58H1Z2X
Norepinephrine
X4W3ENH1CV
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Japan Society for the Promotion of Science
ID : 19K08073
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