A critical test of the hippocampal theta model of anxiolytic drug action

Yeung, Michelle; Treit, Dallas; Dickson, Clayton T.

doi:10.1016/j.neuropharm.2011.06.011

Cited by 39 publications

(43 citation statements)

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“…The predictive value of our rat test has been confirmed by others [87][88][89][90]. We also proved that arti cial replacement of blocked RSA repairs behavioural dysfunction [91] (the first proof that any EEG rhythmicity is functional in and of itself ); and that changes in RSA mediate the action of anxiolytics on behavioural inhibition in an approach-avoidance conflict [92].…”

Section: Rhythmical Slow Activity (Rsa Theta) As a Potential Anxietysupporting

confidence: 79%

Development of a theoretically-derived human anxiety syndrome biomarker

McNaughton

2014

Translational Neuroscience

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"Anxiety disorders" are extremely common; and are a major source of health costs and lost work days. Their diagnosis is currently based on clinical symptom check lists and there are no biological markers to diagnose speci c syndromal causes. This paper describes: 1) a detailed theory of the brain systems controlling anxiolytic-insensitive threat-avoidance and anxiolytic-sensitive threat-approach -where, in specific brain structures, activity generates specific normal behaviours, hyperactivity generates abnormal behaviours, and hyper-reactivity (hypersensitivity to input) generates specific clinical syndromes; 2) a rodent model of systemic anxiolytic action (rhythmical slow activity), linked to the theory, that over a period of 40 years has shown predictive validity with no false positives or false negatives -and which is likely to assay the sensitivity of endogenous systems that control anxiety; and, 3) derivation from this rodent-based theory of a specific non-invasive biomarker (goal-conflict-specific rhythmicity) for the threat-approach system in humans. This new biomarker should allow division of untreated "anxiety" patients, with superficially similar clusters of symptoms, into distinct high scoring (syndromal) and low scoring groups with different treatment-responses. This would be the first theoretically-derived biomarker for any mental disorder and should: 1) predict treatment efficacy better than current symptom-based diagnoses; 2) provide a human single dose test of novel anxiolytics; 3) provide a starting point for developing biomarkers for other "anxiety" syndromes; and so, 4) greatly improve treatment outcomes and cost-effectiveness.

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Section: Rhythmical Slow Activity (Rsa Theta) As a Potential Anxietysupporting

confidence: 79%

Development of a theoretically-derived human anxiety syndrome biomarker

McNaughton

2014

Translational Neuroscience

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“…These behavioral data constitute the second demonstration that a pharmacological treatment that increases theta frequency can induce behavioral anxiolysis, an observation that is inconsistent with the influential theta suppression model of anxiolytic drug action (McNaughton et al 2007;Yeung et al 2012b).…”

Section: Discussionmentioning

confidence: 93%

“…Clinically effective anxiolytics (i.e., barbiturates, benzodiazepines, the 5-HT 1A agonist buspirone, and selective serotonin reuptake inhibitors), as well as experimental compounds that reduce defensive behaviors in animal models of anxiety, have all been shown to reduce hippocampal theta frequency (Engin et al 2008;McNaughton and Coop 1991;McNaughton and Sedgwick 1978;McNaughton et al 1986McNaughton et al , 2007Munn and McNaughton 2008;Yeung et al 2012aYeung et al , 2012b. Importantly, this effect is present in several experimental preparations, such as freely behaving and urethane-anesthetized rats (McNaughton et al 2007).…”

Section: Discussionmentioning

confidence: 99%

“…In both freely moving and anesthetized rats, theta frequency increases linearly with increasing stimulation intensities (McNaughton et al 2007). Interestingly, all classes of clinically effective anxiolytics (barbiturates, benzodiazepines, 5-HT 1A receptor agonists, and selective serotonin reuptake inhibitors), as well as experimental compounds that have been shown to reduce defensive behaviors in animal models of anxiety (e.g., somatostatin, phenytoin, and the bradycardic agent ZD7288), decrease the frequency of reticular-elicited theta (Engin et al 2008;McNaughton et al 2007;Yeung et al 2012aYeung et al , 2012b. Critically, antipsychotics or drugs with sedative but not anxiolytic effects (e.g., haloperidol and chlorpromazine) do not show this effect (McNaughton et al 2007).…”

mentioning

confidence: 99%

“…Critically, antipsychotics or drugs with sedative but not anxiolytic effects (e.g., haloperidol and chlorpromazine) do not show this effect (McNaughton et al 2007). Thus a decrease in the frequency of reticularly elicited theta seems to be a reliable, neurophysiological correlate of anxiolytic compounds; this hypothesis is referred to as the theta suppression model of anxiolysis (McNaughton et al 2007;Yeung et al 2012b).…”

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confidence: 99%

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The lateral septum as a regulator of hippocampal theta oscillations and defensive behavior in rats

Chee

Menard

Dringenberg

2015

Journal of Neurophysiology

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Chee S-SA, Menard JL, Dringenberg HC. The lateral septum as a regulator of hippocampal theta oscillations and defensive behavior in rats. J Neurophysiol 113: 1831-1841, 2015. First published January 14, 2015 doi:10.1152/jn.00806.2014.-Hippocampal theta oscillations are linked to various processes, including locomotion, learning and memory, and defense and affect. The lateral septum (LS) has been implicated in the generation of the hippocampal theta rhythm, but its precise role in this process is not well understood. Here, we investigated the effects of direct pharmacological inhibition or disinhibition of the dorsal LS (dLS) on the frequency of hippocampal theta activity elicited by stimulation of the reticular formation in urethane-anesthetized rats. We found that bilateral infusions of the GABA A receptor agonist muscimol into the dLS significantly increased theta frequency. Strikingly, intra-dLS infusions of the GABA A receptor antagonist GABAzine largely abolished reticularly elicited theta activity. We also locally injected these same compounds into the medial septum (MS) to test for neuroanatomical specificity. In contrast to the effects seen in the dLS, intra-MS infusions of muscimol had no effect on theta frequency, whereas intra-MS infusions of GABAzine increased theta frequency. Given the hypothesized role of hippocampal theta in behavioral defense, we also examined the effects of intra-dLS application of muscimol in two models of anxiety, the elevated plus maze and the novelty-induced suppression of feeding paradigm; both tests revealed clear, anxiolytic-like effects following muscimol infusions. The fact that dLS-muscimol increased theta frequency while also reducing anxiety-like behaviors challenges the influential theta suppression model of anxiolysis, which predicts a slowing of theta with anxiolytic compounds. More importantly, the experiments reveal a novel role of the LS, especially its dorsal aspects, as an important gating mechanism for the expression of theta oscillations in the rodent hippocampus.

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Intrahippocampal infusion of the I_h blocker ZD7288 slows evoked theta rhythm and produces anxiolytic‐like effects in the elevated plus maze

2012

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Hippocampal theta rhythm has been associated with a number of behavioral processes, including learning and memory, spatial behavior, sensorimotor integration and affective responses. Suppression of hippocampal theta frequency has been shown to be a reliable neurophysiological signature of anxiolytic drug action in tests using known anxiolytic drugs (i.e., correlational evidence), but only one study to date (Yeung et al. (2012) Neuropharmacology 62:155-160) has shown that a drug with no known effect on either hippocampal theta or anxiety can in fact separately suppress hippocampal theta and anxiety in behavioral tests (i.e., prima facie evidence). Here, we attempt a further critical test of the hippocampal theta model by performing intrahippocampal administrations of the Ih blocker ZD7288, which is known to disrupt theta frequency subthreshold oscillations and resonance at the membrane level but is not known to have anxiolytic action. Intrahippocampal microinfusions of ZD7288 at high (15 µg), but not low (1 µg) doses slowed brainstem-evoked hippocampal theta responses in the urethane anesthetized rat, and more importantly, promoted anxiolytic action in freely behaving rats in the elevated plus maze. Taken together with our previous demonstration, these data provide converging, prima facie evidence of the validity of the theta suppression model.

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A critical test of the hippocampal theta model of anxiolytic drug action

Cited by 39 publications

References 44 publications

Development of a theoretically-derived human anxiety syndrome biomarker

Development of a theoretically-derived human anxiety syndrome biomarker

The lateral septum as a regulator of hippocampal theta oscillations and defensive behavior in rats

Intrahippocampal infusion of the I_h blocker ZD7288 slows evoked theta rhythm and produces anxiolytic‐like effects in the elevated plus maze

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A critical test of the hippocampal theta model of anxiolytic drug action

Cited by 39 publications

References 44 publications

Development of a theoretically-derived human anxiety syndrome biomarker

Development of a theoretically-derived human anxiety syndrome biomarker

The lateral septum as a regulator of hippocampal theta oscillations and defensive behavior in rats

Intrahippocampal infusion of the Ih blocker ZD7288 slows evoked theta rhythm and produces anxiolytic‐like effects in the elevated plus maze

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Intrahippocampal infusion of the I_h blocker ZD7288 slows evoked theta rhythm and produces anxiolytic‐like effects in the elevated plus maze