Anxiolytic profile of pregabalin on elicited hippocampal theta oscillation

Previous published work with the novel anticonvulsant, analgesic and anti-anxiety medication, pregabalin (Lyrica (R)), has shown that it has anxiolytic-like actions in several animal behavioral models. However, pregabalin is structurally and pharmacologically different from other classes of known anxiolytic drugs, and the mechanisms that alter brain activity to produce anxiolytic-like actions are not well understood. In an effort to determine more about the cellular mechanisms of pregabalin, we studied its effects on hippocampal theta activity of urethane-anesthetized rats that was elicited by electrical stimulation of the nucleus pontis oralis (nPO) in the brainstem. We found that systemic administration of pregabalin significantly reduced the frequency of stimulation-induced hippocampal theta activity similarly to the effects of diazepam. In addition, pregabalin (but not diazepam) significantly altered the stimulus intensity/frequency relationship, and increased slow delta oscillation (< 3.0 Hz) in spontaneous hippocampal EEG in a dose-dependent manner. Our findings suggest that pregabalin may alter evoked theta frequency activity in the hippocampus by reducing neurotransmitter-mediated activation of either the septal nucleus or the hippocampus, and that its actions are unlikely to be mediated by direct activation of GABA neurotransmitter systems. These observations provide further insight to the action of pregabalin, and support the utilization of stimulation-induced theta model in discovery of novel anxiolytic drugs. (c) 2008 Elsevier Ltd. All rights reserved.