The effects of mGlu7 receptor modulation in behavioural models sensitive to antidepressant action in two mouse strains

O’Connor, Richard M.; Cryan, John F.

doi:10.1097/fbp.0b013e32835efc78

Cited by 25 publications

(17 citation statements)

References 42 publications

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“…Furthermore, it is important to choose an appropriate rodent strain in which to conduct these assays. For example, CD-1 mice are insensitive to modulation of the glutamatergic system and the subsequent antidepressant-like effects of AMNO82 and the mGluR 7 negative modulator MMPIP (O'Connor and Cryan, 2013). …”

Section: Ketamine—molecular Mechanisms Of Actionmentioning

confidence: 99%

Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants

2013

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Newer antidepressants are needed for the many individuals with major depressive disorder (MDD) that do not respond adequately to treatment and because of a delay of weeks before the emergence of therapeutic effects. Recent evidence from clinical trials shows that the NMDA antagonist ketamine is a revolutionary novel antidepressant because it acts rapidly and is effective for treatment-resistant patients. A single infusion of ketamine alleviates depressive symptoms in treatment-resistant depressed patients within hours and these effects may be sustained for up to 2 weeks. Although the discovery of ketamine's effects has reshaped drug discovery for antidepressants, the psychotomimetic properties of this compound limit the use of this therapy to the most severely ill patients. In order to develop additional antidepressants like ketamine, adequate preclinical behavioral screening paradigms for fast-acting antidepressants need to be established and used to identify the underlying neural mechanisms. This review examines the preclinical literature attempting to model the antidepressant-like effects of ketamine. Acute administration of ketamine has produced effects in behavioral screens for antidepressants like the forced swim test, novelty suppression of feeding and in rodent models for depression. Protracted behavioral effects of ketamine have been reported to appear after a single treatment that last for days. This temporal pattern is similar to its clinical effects and may serve as a new animal paradigm for rapid antidepressant effects in humans. In addition, protracted changes in molecules mediating synaptic plasticity have been implicated in mediating the antidepressant-like behavioral effects of ketamine. Current preclinical studies are examining compounds with more specific pharmacological effects at glutamate receptors and synapses in order to develop additional rapidly acting antidepressants without the hallucinogenic side effects or abuse potential of ketamine.

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Section: Ketamine—molecular Mechanisms Of Actionmentioning

confidence: 99%

Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants

2013

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“…The TST, one of the most widely used assays for assessing antidepressant activity in rodents (Cryan et al, 2005), was carried out using male C57BL/ 6JOlaHsd mice (Harlan Laboratories; 6-8 weeks old; total n ¼ 67), as described previously (O'Connor and Cryan, 2013). This allowed an assessment of the pharmacodynamic impact of pre-treatment with the P-gp inhibitor verapamil on escitalopram activity.…”

Section: In Vivo Pharmacodynamic Studiesmentioning

confidence: 99%

“…To investigate potential locomotor effects, which would confound analysis of behavioral data from the TST, the impact of drug treatment on locomotor activity was assessed as described previously (O'Connor and Cryan, 2013). A separate cohort of mice were pre-treated with either the P-gp inhibitor verapamil (20 mg/kg intraperitoneally) or saline 1 h before administration of either escitalopram (0.1 mg/kg intraperitoneally) or saline, thereby resulting in four groups.…”

Section: In Vivo Pharmacodynamic Studiesmentioning

confidence: 99%

P-glycoprotein Inhibition Increases the Brain Distribution and Antidepressant-Like Activity of Escitalopram in Rodents

O’Brien

O’Connor

Clarke

et al. 2013

Neuropsychopharmacol

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Despite the clinical prevalence of the antidepressant escitalopram, over 30% of escitalopram-treated patients fail to respond to treatment. Recent gene association studies have highlighted a potential link between the drug efflux transporter P-glycoprotein (P-gp) and response to escitalopram. The present studies investigated pharmacokinetic and pharmacodynamic interactions between P-gp and escitalopram. In vitro bidirectional transport studies revealed that escitalopram is a transported substrate of human P-gp. Microdialysisbased pharmacokinetic studies demonstrated that administration of the P-gp inhibitor cyclosporin A resulted in increased brain levels of escitalopram without altering plasma escitalopram levels in the rat, thereby showing that P-gp restricts escitalopram transport across the blood-brain barrier (BBB) in vivo. The tail suspension test (TST) was carried out to elucidate the pharmacodynamic impact of P-gp inhibition on escitalopram effect in a mouse model of antidepressant activity. Pre-treatment with the P-gp inhibitor verapamil enhanced the response to escitalopram in the TST. Taken together, these data indicate that P-gp may restrict the BBB transport of escitalopram in humans, potentially resulting in subtherapeutic brain concentrations in certain patients. Moreover, by verifying that increasing escitalopram delivery to the brain by P-gp inhibition results in enhanced antidepressant-like activity, we suggest that adjunctive treatment with a P-gp inhibitor may represent a beneficial approach to augment escitalopram therapy in depression.

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“…However, although initially thought to be a useful tool to assess mGlu7 function ( Mitsukawa et al., 2005 , Fendt et al., 2008 , O'Connor and Cryan, 2013 ) the finding that AMN082 has metabolites with strong monoamine activity ( Sukoff Rizzo et al., 2011 ) detracts from it's overall utility. The current finding that negative modulation of mGlu7 receptors using ADX71743 ameliorates visceral pain is somewhat paradoxical as mGlu7 receptors act as auto-receptors to inhibit neurotransmitter release.…”

Section: Discussionmentioning

confidence: 99%

Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain

Moloney

Golubeva

O’Connor

et al. 2015

Neurobiology of Stress

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Glutamate, the main excitatory neurotransmitter in the central nervous system, exerts its effect through ionotropic and metabotropic receptors. Of these, group III mGlu receptors (mGlu 4, 6, 7, 8) are among the least studied due to a lack of pharmacological tools. mGlu7 receptors, the most highly conserved isoform, are abundantly distributed in the brain, especially in regions, such as the amygdala, known to be crucial for the emotional processing of painful stimuli. Visceral hypersensitivity is a poorly understood phenomenon manifesting as an increased sensitivity to visceral stimuli. Glutamate has long been associated with somatic pain processing leading us to postulate that crossover may exist between these two modalities. Moreover, stress has been shown to exacerbate visceral pain. ADX71743 is a novel, centrally penetrant, negative allosteric modulator of mGlu7 receptors. Thus, we used this tool to explore the possible involvement of this receptor in the mediation of visceral pain in a stress-sensitive model of visceral hypersensitivity, namely the Wistar Kyoto (WKY) rat. ADX71743 reduced visceral hypersensitivity in the WKY rat as exhibited by increased visceral sensitivity threshold with concomitant reductions in total number of pain behaviours. Moreover, AD71743 increased total distance and distance travelled in the inner zone of the open field. These findings show, for what is to our knowledge, the first time, that mGlu7 receptor signalling plays a role in visceral pain processing. Thus, negative modulation of the mGlu7 receptor may be a plausible target for the amelioration of stress-induced visceral pain where there is a large unmet medical need.

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The effects of mGlu7 receptor modulation in behavioural models sensitive to antidepressant action in two mouse strains

Cited by 25 publications

References 42 publications

Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants

Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants

P-glycoprotein Inhibition Increases the Brain Distribution and Antidepressant-Like Activity of Escitalopram in Rodents

Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain

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