Nitric oxide involvement in the antidepressant-like effect of ketamine in the Flinders sensitive line rat model of depression

ObjectiveWe investigated whether the nitric oxide (NO) precursor, l-arginine, can prevent the antidepressant-like action of the fast-acting antidepressant, ketamine, in a genetic rat model of depression, and/or induce changes in the glutamate (Glu)/N-methyl-d-aspartate receptor (NMDAR)/NO/cyclic guanosine monophosphate (cGMP) signalling pathway. Hereby it was evaluated whether the NO signalling system is involved in the antidepressant mechanism of ketamine.MethodsFlinders sensitive line (FSL) rats received single i.p. injections of ketamine (15 mg/kg) with/without pre-treatment (30 min prior) with l-arginine (500 mg/kg). Depression-like behaviour was assessed in the forced swim test (FST) in terms of immobility, and the activation state of the Glu/NMDAR/NO/cGMP pathway was evaluated ex vivo in the frontal cortex and hippocampus regions in terms of total constitutive NOS (cNOS) activity and cGMP concentration.Resultsl-Arginine pre-treatment prevented the antidepressant-like effect of ketamine in the FST, as well as a ketamine-induced increase in cGMP levels in the frontal cortex and hippocampus of FSL rats. Ketamine reduced cNOS activity only in the hippocampus, and this effect was not reversed by l-arginine.ConclusionBoth the behavioural and molecular results from this study indicate an involvement for the NO signalling pathway in the antidepressant action of ketamine. Although not easily interpretable, these findings broaden our knowledge of effects of ketamine on the NO system.

Download Full-text

Corticolimbic changes in acetylcholine and cyclic guanosine monophosphate in the Flinders Sensitive Line rat: a genetic model of depression

Acta Neuropsychiatrica ◽

10.1111/j.1601-5215.2011.00622.x ◽

2012 ◽

Vol 24 (4) ◽

pp. 215-225 ◽

Cited By ~ 1

Author(s):

Linda Brand ◽

Jurgens van Zyl ◽

Estella L. Minnaar ◽

Francois Viljoen ◽

Jan L. du Preez ◽

...

Keyword(s):

Nitric Oxide ◽

Liquid Chromatography ◽

Frontal Cortex ◽

High Performance ◽

Genetic Model ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Liquid Chromatography Tandem Mass ◽

Sensitive Line ◽

Flinders Sensitive Line

Objective: Depression is suggested to involve disturbances in cholinergic as well as glutamatergic pathways, particularly the N-methyl-d-aspartate receptor-mediated release of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). The aim of this study was to determine whether the Flinders Sensitive Line (FSL) rat, a genetic model of depression, presents with corticolimbic changes in basal acetylcholine (ACh) levels and NO/cGMP signalling.Methods: Basal levels of nitrogen oxides (NOx) and both basal and l-arginine-stimulated nitric oxide synthase (NOS) formation of l-citrulline were analysed in hippocampus and frontal cortex in FSL and control Flinders resistant line (FRL) rats by fluorometric and electrochemical high-performance liquid chromatography, respectively. In addition, ACh and cGMP levels were analysed by liquid chromatography tandem mass spectrometry and radioimmunoassay, respectively.Results: Significantly elevated frontal cortical but reduced hippocampal ACh levels were observed in FSL versus FRL rats. Basal cGMP levels were significantly reduced in the frontal cortex, but not hippocampus, of FSL rats without changes in NOx and l-citrulline, suggesting that the reduction of cGMP follows through an NOS-independent mechanism.Conclusions: These data confirm a bidirectional change in ACh in the frontal cortex and hippocampus of the FSL rat, as well as provide evidence for a frontal cortical ACh-cGMP interaction in the depressive-like behaviour of the FSL rat.

Download Full-text

Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat

Acta Neuropsychiatrica ◽

10.1017/neu.2019.15 ◽

2019 ◽

Vol 31 (04) ◽

pp. 213-219 ◽

Cited By ~ 7

Author(s):

Oskar Jefsen ◽

Kristoffer Højgaard ◽

Sofie Laage Christiansen ◽

Betina Elfving ◽

David John Nutt ◽

...

Keyword(s):

Locomotor Activity ◽

Rat Model ◽

Serotonin Receptor ◽

Therapeutic Potential ◽

Forced Swim Test ◽

Psychiatric Illnesses ◽

Immobility Time ◽

Sensitive Line ◽

Behavioural Tests ◽

Flinders Sensitive Line

AbstractObjective:Psilocybin is a serotonin receptor agonist with a therapeutic potential for treatment-resistant depression and other psychiatric illnesses. We investigated whether the administration of psilocybin had an antidepressant-like effect in a rat model of depression.Methods:Using the Flinders Sensitive Line (FSL) rat model of depression, we assessed the antidepressant-like effect of psilocin and psilocybin, measured as a reduction in immobility time in the forced swim test (FST). We measured locomotor activity in an open field test (OFT) to control for stimulant properties of the drugs. We performed a set of experiments to test different doses, treatment paradigms, and timing of the tests in relation to the drug administration.Results:Psilocin and psilocybin showed no effect on immobility, struggling, or swimming behaviour in the FST and no effect on locomotor activity in the OFT. FSL rats did show significantly more immobility than their control strain, the Flinders Resistant Line, as expected.Conclusion:Psilocin and psilocybin showed no antidepressant-like effect in the FSL rats, despite a positive effect in humans. This suggests that other animal models of depression and other behavioural tests may be more appropriate for translational studies in the effects of psilocybin.

Download Full-text

Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression

Progress in Neuro-Psychopharmacology and Biological Psychiatry ◽

10.1016/j.pnpbp.2010.05.029 ◽

2010 ◽

Vol 34 (6) ◽

pp. 1075-1084 ◽

Cited By ~ 8

Author(s):

Olga Kotsovolou ◽

Magnus Ingelman-Sundberg ◽

Matti A. Lang ◽

Marios Marselos ◽

David H. Overstreet ◽

...

Keyword(s):

Rat Model ◽

Hepatic Drug ◽

Sensitive Line ◽

Flinders Sensitive Line

Download Full-text

Gene expression related to serotonergic and glutamatergic neurotransmission is altered in the flinders sensitive line rat model of depression: Effect of ketamine

Synapse ◽

10.1002/syn.21940 ◽

2016 ◽

Vol 71 (1) ◽

pp. 37-45 ◽

Cited By ~ 4

Author(s):

Kristian Gaarn Du Jardin ◽

Heidi Kaastrup Müller ◽

Connie Sanchez ◽

Gregers Wegener ◽

Betina Elfving

Keyword(s):

Gene Expression ◽

Rat Model ◽

Glutamatergic Neurotransmission ◽

Depression Effect ◽

Sensitive Line ◽

Flinders Sensitive Line

Download Full-text

Brain Arachidonic Acid Incorporation and Turnover are not Altered in the Flinders Sensitive Line Rat Model of Human Depression

Neurochemical Research ◽

10.1007/s11064-015-1719-6 ◽

2015 ◽

Vol 40 (11) ◽

pp. 2293-2303

Author(s):

Helene Blanchard ◽

Lisa Chang ◽

Amir H. Rezvani ◽

Stanley I. Rapoport ◽

Ameer Y. Taha

Keyword(s):

Arachidonic Acid ◽

Rat Model ◽

Acid Incorporation ◽

Sensitive Line ◽

Flinders Sensitive Line

Download Full-text

NMDA receptors and L-arginine/nitric oxide/cyclic guanosine monophosphate pathway contribute to the antidepressant-like effect of Yueju pill in mice

Bioscience Reports ◽

10.1042/bsr20190524 ◽

2019 ◽

Vol 39 (9) ◽

Author(s):

Wei Wang ◽

Tong Zhou ◽

Rong Jia ◽

Hailou Zhang ◽

Yi Zhang ◽

...

Keyword(s):

Nitric Oxide ◽

Forced Swim Test ◽

Specific Inhibitor ◽

Tail Suspension Test ◽

Cyclic Guanosine Monophosphate ◽

Nmda Receptor Antagonist ◽

No Synthase ◽

Guanosine Monophosphate ◽

Immobility Time ◽

Cgmp Signaling

Abstract The present study aims to evaluate the involvement of N-methyl-d-aspartate receptor and nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) system in antidepressant-like effects of Yueju pill (YJ), a Chinese herbal medicine. The immobility time in tail suspension test (TST) and forced swim test (FST) was used to assess the antidepressant effects. Prior administration of L-arginine (750 mg/kg, intraperitoneal [i.p.]), a NO synthase substrate that enhances NO signaling or sildenafil (5 mg/kg, i.p.), a phosphodiesterase 5 inhibitor that enhances cGMP, blunted the antidepressant-like activity of YJ (2.7 g/kg, i.g.). Co-treatment of ineffective dose of YJ (1.35 g/kg, i.g.) with one of the reagents that suppress the NO/cGMP signaling, including methylene blue (10 mg/kg, i.p.), an inhibitor of NO synthase; 7-NI (7-nitroinidazole, 30 mg/kg, i.p.), an nNOS specific inhibitor; L-NAME (10 mg/kg, i.p.), a non-specific inhibitor of NO synthase; and MK-801 (0.05 mg/kg, i.p.), an NMDA receptor antagonist, reduced the immobility time in TST and FST, compared with those in vehicle or single drug treatment groups. Neither above drugs alone or co-administrated with YJ affected locomotor activity or anxiety behavior in open field test. Thus, our results suggest that the antidepressant-like action of YJ may depend on the inhibition of NMDA/NO/cGMP pathway.

Download Full-text

Sirtuins and Neuropeptide y downregulation in Flinders Sensitive Line Rat Model of Depression

Acta Neuropsychiatrica ◽

10.1017/neu.2021.36 ◽

2021 ◽

pp. 1-19

Author(s):

Miranda Stiernborg ◽

Paschalis Efstathopoulos ◽

Andreas Lennartsson ◽

Catharina Lavebratt ◽

Aleksander A. Mathé

Keyword(s):

Rat Model ◽

Histone Deacetylases ◽

Sirtuin 1 ◽

Model Organisms ◽

Age Related ◽

Age Dependent ◽

Sensitive Line ◽

And Control ◽

Temporal Trajectory ◽

Flinders Sensitive Line

Abstract Objective: Since the NAD+-dependent histone deacetylases sirtuin-1 (SIRT1) and sirtuin-2 (SIRT2) are critically involved in epigenetics, endocrinology and immunology and affect the longevity in model organisms, we investigated their expression in brains of 3 month old and 14-15 month old rat model of depression Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats. In view of the dysregulated NPY system in depression we also studied NPY in young and old FSL to explore the temporal trajectory of depressive-like-ageing interaction. Methods: Sirt1, Sirt2 and Npy mRNA were determined using qRT-PCR in prefrontal cortex (PFC) from young and old FSL and FRL, and in hippocampi from young FSL and FRL. Results: PFC. Sirt1 expression was decreased in FSL (p=0.001). An interaction between age and genotype was found (p=0.032); young FSL had lower Sirt1 with respect to both age (p=0.026) and genotype (p=0.001). Sirt2 was lower in FSL (p=0.003). Npy mRNA was downregulated in FSL (p=0.001) but did not differ between the young and old rat groups. Hippocampus.Sirt1 was reduced in young FSL compared to young FRL (p=0.005). There was no difference in Sirt2 between FSL and FRL. Npy levels were decreased in hippocampus of young FSL compared to young FRL (p=0.003). Effects of ageing could not be investigated due to loss of samples. Conclusions: i. This is the first demonstration that SIRT1 and SIRT2 are changed in brain of FSL, a rat model of depression ; ii. The changes are age dependent; iii. Sirtuins are potential targets for treatment of age-related neurodegenerative diseases.

Download Full-text