Anxiolytic profile of pregabalin on elicited hippocampal theta oscillation

doi:10.1016/j.neuropharm.2008.09.013

Neuropharmacology

Volume 56, Issue 2, February 2009, Pages 379-385

https://doi.org/10.1016/j.neuropharm.2008.09.013 Get rights and content

Abstract

Previous published work with the novel anticonvulsant, analgesic and anti-anxiety medication, pregabalin (Lyrica^®), 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.

Introduction

Pregabalin (Lyrica^®) is a novel drug first developed as an anticonvulsant, but has since found significant clinical utility in the treatment of various neuropathic pain syndromes, fibromyalgia and in reducing the symptoms of generalized anxiety disorders in humans. Pregabalin is structurally related to gabapentin (Neurotonin^®), and both compounds show similar pharmacological profiles. Because of the close chemical structural similarity to the neurotransmitter gamma-aminobutyric acid (GABA) much of the early work regarding gabapentin's and pregabalin's mechanism of action focused on GABA-related pharmacology. Subsequent work, however, has shown that the cellular and molecular actions of both gabapentin and pregabalin are not related to intrinsic activity at GABA receptors, GABA-related enzymes or other GABAergic related drug targets (Dooley et al., 2007).

Early studies of radioligand binding with tritiated gabapentin and pregabalin identified a saturable, high-affinity binding site in homogenates of brain membranes and in autoradiographs of rat brain (Hill et al., 1993, Suman-Chauhan et al., 1993). Soon afterwards, the protein responsible for high-affinity binding of these compounds was identified as the auxiliary α₂–δ subunit of voltage-gated calcium channels (Gee et al., 1996, Brown and Gee, 1998, Bian et al., 2006). Subsequent to drug binding to the α₂–δ subunit, it is thought that pregabalin alters the action of presynaptic calcium channels and/or additional closely related presynaptic proteins to subtly reduce the release of various neurotransmitters, including glutamate (reviewed in Dooley et al., 2007, Taylor et al., 2007). These changes in neurotransmission within the brain and spinal cord are thought to underlie the pharmacology responsible for analgesic, anticonvulsant and anxiolytic-like actions. Neuronal network activity of the hippocampus, including theta band oscillation is known to be regulated by a number of afferent inputs, originating both from brainstem structures as well as forebrain and cortical areas (Buzsaki, 2002, Vertes and Kocsis, 1997). A significant proportion of these afferent pathways are glutamatergic, and their activity impacts hippocampal theta oscillation via various glutamate receptors known to be present in the hippocampus abundantly (Vertes, 2005).

In the present experiments the effects of pregabalin on stimulation-induced hippocampal theta activity have been studies in anesthetized rats. High frequency (250 Hz) stimulation of the nucleus pontis oralis (nPO), a nucleus of the brainstem reticular formation, induces current-dependent theta oscillations in the hippocampus (McNaughton et al., 2007, Vertes, 1982). Since ascending nPO neurons involved in stimulation-induced hippocampal theta are glutamate-containing neurons (Vertes, 2005), it has been presumed that pregabalin, via attenuating stimulation-induced glutamate release will attenuate elicited hippocampal theta oscillation. In addition, this electrophysiological model has a particular relevance for pregabalin pharmacology, since previous work has shown that at least five different types of clinically useful anxiolytic agents each reduce the frequency of stimulus-induced theta rhythm in the hippocampus of anesthetized and non-anesthetized rats at anxiolytic dosages (for review see McNaughton et al., 2007). Therefore, the clinically proven anxiolytic diazepam was used as a positive control in the present study.

Section snippets

Animals and surgical procedures

Experiments were performed on male, Sprague–Dawley rats (weighing 275–325 g) anesthetized with 1.5–1.6 g/kg urethane intraperitoneally, under an approved animal use protocol and in compliance with the Animal Welfare Act Regulations (9 CFR parts 1, 2 and 3) and with the Guide for the Care and Use of Laboratory Animals, National Institutes of Health guidelines. A catheter was surgically implanted in the left femoral vein for administration of euthanizing chloral hydrate. After cannulation, the

Effect of nPO stimulation on hippocampal theta

Electrical stimulation of the brainstem nPO in urethane-anesthetized rats consistently elicited highly regular hippocampal theta oscillations, showing current-dependent theta frequency and power as previously reported (Siok et al., 2006, Vertes, 1982). Fig. 1 shows the data from a representative animal demonstrating a shift in theta to higher frequencies, and an increase in theta power in the 4–8 Hz frequency band in response to increasing stimulating current (0.06–0.16 mA). The response in theta

Discussion

The present findings demonstrate that systemic administration of pregabalin, a pharmacological ligand of the calcium channel α₂–δ binding site, significantly reduced the frequency of hippocampal theta activity induced by electrical stimulation of the brainstem nPO nucleus in urethane-anaesthetized rats. A similar reduction in hippocampal theta frequency was observed after administration of the GABA_A receptor positive allosteric modulator diazepam, but not after vehicle. In addition, pregabalin

Acknowledgements

We thank Dr. Christopher Wohlberg for helpful suggestions and critical reading of an earlier version of this article.

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Anxiolytic profile of pregabalin on elicited hippocampal theta oscillation

Abstract

Introduction

Section snippets

Animals and surgical procedures

Effect of nPO stimulation on hippocampal theta

Discussion

Acknowledgements

Brain Res.

J. Biol. Chem.

Neuron

Brain Res.

NeuroImage

Trends Pharmacol. Sci.

J. Biol. Chem.

Neuroscience

Eur. J. Pharmacol.

J. Affect. Disord.

Eur. J. Pharmacol.

Epilepsy Res.

Neuropharmacology

Neuropharmacology

Neuroscience

Prog. Neurobiol.

Structure–activity relationships of pregabalin and analogs that target the α2–δ protein

J. Med. Chem.

A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder

J. Clin. Psychopharmacol.

Hippocampal electrical activity and behavior in the rabbit

Arch. Ital. Biol.

State-dependent alterations in hippocampal oscillations in serotonin 1a receptor-deficient mice

J. Neurosci.

The intermediate stage and paradoxical sleep in the rat: influence of three generations of hypnotics

Eur. J. Neurosci.

Structure–activity relationships of pregabalin and analogs that target the α₂–δ protein