Received for publication March 18, 2005.
Revised May 14, 2005.
Accepted for publication May 17, 2005.

1 Adrenergic Receptor-Mediated Enhancement of Hippocampal CA3 Network Activity

Abstract

Norepinephrine is an endogenous neurotransmitter distributed throughout the mammalian brain. In higher cortical structures such as the hippocampus, norepinephrine, via adrenergic receptor (AR) activation, has been shown to reinforce the cognitive processes of attention and memory. In this study, we investigated the effect of 1AR activation on hippocampal CA3 network activity. AR expression was first determined using immunocytochemistry with antibodies against 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 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 AR blockade, concentration-response curves for isoproterenol, norepinephrine and epinephrine suggested that a 1AR was involved in this response, as the rank order of potency was isoproterenol > norepinephrine = epinephrine. Finally, equilibrium dissociation constants (pK_b) of subtype-selective AR antagonists were functionally determined to characterize the AR subtype modulating hippocampal CA3 activity. The selective 1AR antagonists, atenolol and metoprolol, blocked isoproterenol-induced enhancement with apparent K_b values of 85±36 and 3.9±1.7nM, respectively. In contrast, the selective 2AR antagonists, ICI-118,551 and butoxamine, inhibited isoproterenol-mediated enhancement with apparent low affinities (K_b = 222±61 and 9,268±512nM, respectively). Together, this pharmacological profile of subtype-selective AR antagonists indicates that in this model, 1AR activation is responsible for the enhanced hippocampal CA3 network activity initiated by isoproterenol.

Key words: adrenergic receptor, catecholamine, characterization, extracellular field recording, hippocampus, pyramidal neuron