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Pharmacological characterization of the α 2 adrenergic receptor inhibiting mouse hippocampal CA3 epileptiform activity
Author(s) -
Nelson Brian,
Goldenstein Brianna,
Xu Ke,
Luger Elizabeth,
Pribula Jacquline,
Wald Jenna,
O'Shea Lorraine,
Jurgens Chris,
Doze Van
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.946.8
Subject(s) - prazosin , chemistry , hippocampal formation , rauwolscine , pharmacology , atipamezole , guanfacine , adrenergic receptor , inhibitory postsynaptic potential , dexmedetomidine , intrinsic activity , epilepsy , medicine , receptor , endocrinology , antagonist , neuroscience , agonist , biology , clonidine , biochemistry , medetomidine , sedation , heart rate , blood pressure
α 2 adrenergic receptor (AR) activation by epinephrine (EPI) inhibits epileptiform bursts in the mouse hippocampus. Which α 2 AR subtype(s) are involved is unclear. Pharmacological characteristics of α 2 ARs that inhibit epileptiform activity were investigated in mouse brain slices by examining AR agonists' efficacy and potency, and determining the equilibrium dissociation constants (pK b values) of selective α 2 AR antagonists. Dexmedetomidine, an imidazoline and guanfacine, a guanidine were the most potent. In contrast, the catecholamines EPI and norepinephrine were the most efficacious. Apparent pK b values calculated for selective α 2 AR antagonists correlated best with the mouse α 2A AR. EPI‐inhibited antiepileptic effects (pK b ) were competitively antagonized by atipamezole (8.79), rauwolscine (7.75), WB‐4101 (6.87), prazosin (5.71) and JP‐1302 (5.92). Transgenic α 2A AR and α 2C AR knockout mice further confirmed that the EPI‐mediated anti‐epileptic effect was through the α 2A AR subtype. The α 2A AR‐mediated inhibitory actions of EPI on hippocampal CA3 epileptiform burst frequencies were also not sex or age‐dependent. These findings suggest that the activation of α 2A AR could provide a new pharmacotherapeutic strategy for treating epilepsy and highlight the need for selective α 2A AR agonists. This project was supported by ND EPSCoR, NSF CAREER, NSF REU Site, UND REFUNDU, APS, ASPET and NIH INBRE.