B1 adrenergic receptor-mediated enhancement of hippocampal CA3 network activity

Norepinephrine is an endogenous neurotransmitter distributed throughout the mammalian brain. In higher cortical structures such as the hippocampus, norepinephrine, via beta adrenergic receptor (AR) activation, has been shown to reinforce the cognitive processes of attention and memory. In this study, we investigated the effect of beta 1AR activation on hippocampal cornu ammonis 3 (CA3) network activity. AR expression was first determined using immunocytochemistry with antibodies against beta 1ARs, which were found to be exceptionally dense in hippocampal CA3 pyramidal neurons. CA3 network activity was then examined in vitro using field potential recordings in rat brain slices. The selective beta AR agonist isoproterenol caused an enhancement of hippocampal CA3 network activity, as measured by an increase in frequency of spontaneous burst discharges recorded in the CA3 region. In the presence of alpha AR blockade, concentration-response curves for isoproterenol, norepinephrine, and epinephrine suggested that a (1 beta)AR was involved in this response, and the rank order of potency was isoproterenol > norepinephrine = epinephrine. Finally, equilibrium dissociation constants (pK(b)) of subtype-selective beta AR antagonists were functionally determined to characterize the AR subtype modulating hippocampal CA3 activity. The selective beta 1AR antagonists atenolol and metoprolol blocked isoproterenol-induced enhancement, with apparent K b values of 85 +/- 36 and 3.9 +/- 1.7 nM, respectively. In contrast, the selective beta 2AR antagonists ICI-118,551 and butoxamine inhibited isoproterenol-mediated enhancement with apparent low affinities (K-b of 222 +/- 61 and 9268 +/- 512 nM, respectively). Together, this pharmacological profile of subtype-selective beta AR antagonists indicates that in this model, beta 1AR activation is responsible for the enhanced hippocampal CA3 network activity initiated by isoproterenol.