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Norepinephrine has potent antiepileptic properties, the pharmacology of which is unclear. Under conditions in which GABAergic inhibition is blocked, norepinephrine reduces hippocampal cornu ammonis 3 (CA3) epileptiform activity through ␣ 2 adrenergic receptor (AR) activation on pyramidal cells. In this study, we investigated which ␣ 2 AR subtype(s) mediates this effect. First, ␣ 2 AR genomic expression patterns of 25 rat CA3 pyramidal cells were determined using real-time single-cell reverse transcription-polymerase chain reaction, demonstrating that 12 cells expressed ␣ 2A AR transcript; 3 of the 12 cells additionally expressed mRNA for ␣ 2C AR subtype and no cells possessing ␣ 2B AR mRNA. Hippocampal CA3 epileptiform activity was then examined using field potential recordings in brain slices. The selective ␣AR agonist 6-fluoronorepinephrine caused a reduction of CA3 epileptiform activity, as measured by decreased frequency of spontaneous epileptiform bursts. In the presence of ␤AR blockade, concentration-response curves for AR agonists suggest that an ␣ 2 AR mediates this response, as the rank order of potency was 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK-14304) Ն epinephrine Ͼ6-fluoronorepinephrine Ͼ norepinephrine phenylephrine. Finally, equilibrium dissociation constants (K b ) of selective ␣AR antagonists were functionally determined to confirm the specific ␣ 2 AR subtype inhibiting CA3 epileptiform activity. Apparent K b values calculated for atipamezole (1.7 nM), MK-912 (4.8 nM), BRL-44408 (15 nM), yohimbine (63 nM), ARC-239 (540 nM), prazosin (4900 nM), and terazosin (5000 nM) correlated best with affinities previously determined for the ␣ 2A AR subtype (r ϭ 0.99, slope ϭ 1.0). These results suggest that, under conditions of impaired GABAergic inhibition, activation of ␣ 2A ARs is primarily responsible for the antiepileptic actions of norepinephrine in the rat hippocampal CA3 region.The noradrenergic system is a key modulator of numerous physiological and pathological processes. Within the central nervous system (CNS), noradrenergic neurons innervate copious neural networks and regulate a number of essential neurological functions, including attention and arousal, sleep, and learning and memory (Pupo and Minneman, 2001).

Norepinephrine (NE), an endogenous neurotransmitter, is involved in cognition as well as anxiety and depression. NE mediates its actions through the activation of adrenergic receptors (ARs). This study explored the effects of increased α1AAR activation on anxiety and depression in mice. Different sets of mice with varying degrees of α1AAR expression and activation were used in behavioral tests for anxiety and depression. The mice sets included transgenic mice with increased α1AAR expression, transgenic mice with a knockout of the α1AAR, mice treated with the α1AAR agonist cirazoline, and groups of normal control mice. The tail suspension and forced swim tests were used as models of depression and the light/dark, marble burying and elevated plus‐maze tests were used as measurements of anxiety. In addition, the open field test was used to determine the mobility of these animals. It was found that mice with increased α1AAR activation, in comparison to normal mice, demonstrated anxiolytic and antidepressant‐like behavior in several of these models. The mobility of these animals was similar. These results suggest that activation of the α1AAR reduces anxiety and depression in mice without affecting their mobility. This study was supported by NSF CAREER 0347259, NSF REU Site 0639227, NIH P20 RR016741, UND REFUNDU Program, American Physiological Society, and the Bower, Bennet & Bennet Endowed Research Award from ONU.

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Norepinephrine (NE) has potent antiepileptic properties, the pharmacology of which is unclear. The hippocampal CA3 region is vulnerable to over‐excitation (epileptiform burst activity). When GABAergic inhibition is blocked, NE reduces epileptiform activity through alpha‐2 adrenergic receptor (α2 AR) activation on pyramidal cells. We investigated which α2 AR subtype(s) mediate this effect. α2 AR mRNA expression using RT‐PCR in the CA3 region suggested that α2A AR subtype predominates relative to α2C AR and no α2B AR. Using field potential recordings in hippocampal slices we tested CA3 epileptiform activity. With a beta AR blockade, concentration‐response curves for AR agonists suggest that α2A ARs mediate CA3 epileptiform activity inhibition. Equilibrium dissociation constants (Kb) of selective alpha AR antagonists were determined to confirm the specific α2 AR subtype involved. Kb values correlated best with the α2A, but not the α2B and α2C AR subtypes. The results show that under impaired GABAergic inhibition, activation of α2A ARs is primarily responsible for antiepileptic action of NE. These findings increase our understanding of the role NE plays in attenuating epileptogenesis, and may aid the development of a subtype‐selective α2 AR agonist‐based strategy for treating seizures. Supported by NSF ND EPSCoR, NSF CAREER, NSF REU Site, NSF RET, NIH INBRE, EF, APS Explorations Program for Native Americans.