Adrenergic receptor modulation of hippocampal CA3 network activity.
Norepinephrine (NE) has demonstrated proconvulsant and antiepileptic properties; however, the specific pharmacology of these actions has not been clearly established. To address this, we studied the effect of NE on hippocampal CA3 epileptiform activity. Frequency changes of burst discharges in response to NE were biphasic; low concentrations increased the number of bursts, while higher concentrations reduced their frequency, suggesting the involvement of multiple adrenergic receptor (AR) types. This hypothesis was confirmed when, in the presence of betaAR blockade, increasing concentrations of NE caused a monophasic decrease in epileptiform activity. Antagonists selective for alpha1 or alpha2ARs were then used to determine which alphaAR type was involved. While discriminating concentrations of the alpha1AR antagonists prazosin and terazosin had no effect, selective amounts of the alpha2AR antagonists RS79948 and RX821002 significantly reduced the potency of NE in decreasing epileptiform activity. Furthermore, this antiepileptic action of NE persisted when all GABA-mediated inhibition was blocked. This data suggests that, under conditions of impaired GABAergic inhibition, the excitatory and inhibitory effects of NE on hippocampal CA3 epileptiform activity are mediated primarily via beta and alpha2ARs, respectively. Moreover, our results imply that the antiepileptic effect of alpha2AR activation in CA3 is not dependent on the GABAergic system.
Jurgens
Chris W D
CW
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, 501 N. Columbia Road, Grand Forks, ND 58203, USA.
Boese
Sarah J
SJ
King
Jacob D
JD
Pyle
Sally J
SJ
Porter
James E
JE
Doze
Van A
VA
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D001640:Bicuculline; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004827:Epilepsy / Q000139:chemically induced / Q000503:physiopathology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D009415:Nerve Net / Q000187:drug effects / Q000503:physiopathology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D010646:Phentolamine / Q000494:pharmacology; D010721:Phosphinic Acids / Q000494:pharmacology; D010869:Pindolol / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000502:physiology*
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D018756:GABA Antagonists; D010721:Phosphinic Acids; D011412:Propanolamines; D011941:Receptors, Adrenergic; C085075:CGP 55845A; D010869:Pindolol; D009638:Norepinephrine; D001640:Bicuculline; D010646:Phentolamine