Neurokinin-1 receptor deletion modulates behavioural and neurochemical alterations in an animal model of depression

Roche, Michelle; Kerr, Daniel M.; Hunt, Stephen P.; Kelly, John

doi:10.1016/j.bbr.2011.11.035

Cited by 20 publications

(7 citation statements)

References 87 publications

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“…NK1 levels in the orbitofrontal cortex of depressed patients are decreased (Stockmeier et al, 2002), which might be a compensatory response to increased levels of SP. Similarly, frontal cortical SP levels are increased in different animal models of depression (Husum et al, 2001; Roche et al, 2012). Abnormally high cortical SP levels might be linked to a depressive phenotype by excitation of inhibitory cortical nNOS neurons.…”

Section: Discussionmentioning

confidence: 97%

Cortical nNOS neurons co-express the NK1 receptor and are depolarized by Substance P in multiple mammalian species

Dittrich¹,

Heiss²,

Warrier³

et al. 2012

Front. Neural Circuits

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We have previously demonstrated that Type I neuronal nitric oxide synthase (nNOS)-expressing neurons are sleep-active in the cortex of mice, rats, and hamsters. These neurons are known to be GABAergic, to express Neuropeptide Y (NPY) and, in rats, to co-express the Substance P (SP) receptor NK1, suggesting a possible role for SP in sleep/wake regulation. To evaluate the degree of co-expression of nNOS and NK1 in the cortex among mammals, we used double immunofluorescence for nNOS and NK1 and determined the anatomical distribution in mouse, rat, and squirrel monkey cortex. Type I nNOS neurons co-expressed NK1 in all three species although the anatomical distribution within the cortex was species-specific. We then performed in vitro patch clamp recordings in cortical neurons in mouse and rat slices using the SP conjugate tetramethylrhodamine-SP (TMR-SP) to identify NK1-expressing cells and evaluated the effects of SP on these neurons. Bath application of SP (0.03–1 μM) resulted in a sustained increase in firing rate of these neurons; depolarization persisted in the presence of tetrodotoxin. These results suggest a conserved role for SP in the regulation of cortical sleep-active neurons in mammals.

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Section: Discussionmentioning

confidence: 97%

Cortical nNOS neurons co-express the NK1 receptor and are depolarized by Substance P in multiple mammalian species

Dittrich¹,

Heiss²,

Warrier³

et al. 2012

Front. Neural Circuits

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“…Western immunoblotting was carried out essentially as previously described (Butler et al, 2008;Roche et al, 2012). In brief, approximately 30mg of cortical tissue was homogenised in 400μl of RIPA lysis buffer followed by centrifugation at 13,000g at 4°C for 20 min.…”

Section: Western Immunoblottingmentioning

confidence: 99%

Pharmacological inhibition of FAAH modulates TLR-induced neuroinflammation, but not sickness behaviour: An effect partially mediated by central TRPV1

Henry

Kerr

Flannery

et al. 2017

Brain, Behavior, and Immunity

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Aberrant activation of toll-like receptors (TLRs), key components of the innate immune system, has been proposed to underlie and exacerbate a range of central nervous system disorders. Increasing evidence supports a role for the endocannabinoid system in modulating inflammatory responses including those mediated by TLRs, and thus this system may provide an important treatment target for neuroinflammatory disorders. However, the effect of modulating endocannabinoid tone on TLR-induced neuroinflammation in vivo and associated behavioural changes is largely unknown. The present study examined the effect of inhibiting fatty acid amide hydrolyase (FAAH), the primary enzyme responsible for the metabolism of anandamide (AEA), in vivo on TLR4-induced neuroimmune and behavioural responses, and evaluated sites and mechanisms of action. Systemic administration of the FAAH inhibitor PF3845 increased levels of AEA, and related FAAH substrates N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA), in the frontal cortex and hippocampus of rats, an effect associated with an attenuation in the expression of pro- and anti-inflammatory cytokines and mediators measured 2hrs following systemic administration of the TLR4 agonist, lipopolysaccharide (LPS). These effects were mimicked by central i.c.v. administration of PF3845, but not systemic administration of the peripherally-restricted FAAH inhibitor URB937. Central antagonism of TRPV1 significantly attenuated the PF3845-induced decrease in IL-6 expression, effects not observed following antagonism of CB CB, PPARα, PPARγ or GPR55. LPS-induced a robust sickness-like behavioural response and increased the expression of markers of glial activity and pro-inflammatory cytokines over 24hrs. Systemic administration of PF3845 modulated the TLR4-induced expression of neuroimmune mediators and anhedonia without altering acute sickness behaviour. Overall, these findings support an important role for FAAH substrates directly within the brain in the regulation of TLR4-associated neuroinflammation and highlight a role for TRPV1 in partially mediating these effects.

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“…To our knowledge, this is the first study showing efficacy of buprenorphine and the buprenorphine-samidorphan combination in the OB model. Following bulbectomy, rats exhibit hyperactivity upon exposure to a stressful novel environment (Burke, Finn, & Roche, 2015;Burke, Kerr, Moriarty, Finn, & Roche, 2014;Leonard & Tuite, 1981;Roche, Kerr, Hunt, & Kelly, 2012;Stock et al, 2000;Willner & Mitchell, 2002). This stress-induced hyperactivity is the most widely reported behavioural output following bulbectomy, is reproducible and reliable, and is hypothesised to reflect a lack of normal defensive behaviours and disinhibition of the amygdala (Harkin, Kelly, & Leonard, 2003;Leonard & Tuite, 1981).…”

Section: Discussionmentioning

confidence: 99%

Chronic administration of buprenorphine in combination with samidorphan produces sustained effects in olfactory bulbectomised rats and Wistar-Kyoto rats

Burke

Deaver

et al. 2019

J Psychopharmacol

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Background: The combination of buprenorphine, a partial mu-opioid receptor agonist and a functional kappa-opioid receptor antagonist, with samidorphan, a functional mu-opioid receptor antagonist, is being developed as an adjunct therapy for major depressive disorder, in order to harness the mood-enhancing effects of opioids without unwanted side-effects such as a risk of addiction. Acute and subacute administration of the combination of buprenorphine and samidorphan is effective in reducing forced swim immobility in the Wistar-Kyoto rat, but the chronic effects have not been examined. Aims and methods: The purpose of this study was to assess if chronic (14-day) administration of buprenorphine (0.1 mg/kg, subcutaneous) alone or in combination with samidorphan (0.3 mg/kg, subcutaneous) maintains antidepressant-like activity in the olfactory bulbectomised rat model and the Wistar-Kyoto rat, two models that exhibit ongoing behavioural deficits in tests commonly used to study effects of antidepressants. Results: Olfactory bulbectomised-induced hyperactivity was attenuated by chronic administration of buprenorphine alone and in combination with samidorphan, to that of sham control activity levels. Neither buprenorphine nor samidorphan altered stress-associated defecation in sham or olfactory bulbectomised rats in the open field. In Wistar-Kyoto rats, buprenorphine alone significantly reduced forced swim immobility and increased locomotor activity three hours post-final dosing. Buprenorphine plus samidorphan significantly reduced forced swim immobility without changing locomotor activity at this time point. Buprenorphine alone also significantly reduced forced swim immobility 24 h post-final dosing. Conclusion: Chronic treatment of buprenorphine alone or buprenorphine plus samidorphan is effective in reversing behavioural deficits in distinct non-clinical paradigms. These non-clinical results complement the antidepressant effect of this combination observed in clinical studies.

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Neurokinin-1 receptor deletion modulates behavioural and neurochemical alterations in an animal model of depression

Cited by 20 publications

References 87 publications

Cortical nNOS neurons co-express the NK1 receptor and are depolarized by Substance P in multiple mammalian species

Cortical nNOS neurons co-express the NK1 receptor and are depolarized by Substance P in multiple mammalian species

Pharmacological inhibition of FAAH modulates TLR-induced neuroinflammation, but not sickness behaviour: An effect partially mediated by central TRPV1

Chronic administration of buprenorphine in combination with samidorphan produces sustained effects in olfactory bulbectomised rats and Wistar-Kyoto rats

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