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

Abstract

Liebenberg N, Joca S, Wegener G. Nitric oxide involvement in the antidepressant-like effect of ketamine in the Flinders sensitive line rat model of depression.Objective: We 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. Methods: Flinders 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. Results: L-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. Conclusion: Both 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. Signficant outcomes• The behavioural results indicate the involvement of the nitric oxide (NO) signalling system in the antidepressant-like action of ketamine;• The molecular data reveals ketamine-induced changes in NO signalling in the frontal cortex and hippocampus, and indicates that increased cyclic guanosine monophosphate (cGMP) levels may be important for the antidepressant action of ketamine. Limitations• The behavioural test used in this study is not appropriate for the evaluation of onset of action of antidepressants, and the results can therefore not reveal whether NO signalling is specifically involved in the time of onset of ketamine's antidepressant effect.• The observation that L-arginine on its own did not increase, but instead decreased constitutive NOS (cNOS) activity in both brain regions tested, complicates the interpretation of the results. 90https://www.cambridge.org/core/terms. https://doi

S-Ketamine Rapidly Reverses Synaptic and Vascular Deficits of Hippocampus in Genetic Animal Model of Depression

“…These structural changes mimic the alteration of neurovascular plasticity of hippocampus following chronic treatment with traditional antidepressant drugs (Chen et al, 2008, 2010). These findings go hand-in-hand with the behavioral observations, where ketamine acts as a fast and potent antidepressant without negative effect on locomotion (Liebenberg et al, 2015). Regarding the type of ketamine, it has been known that the affinity of S-ketamine is greater than R-ketamine.…”

“…They found that ketamine treatment did not change locomotor activity in FSL rats [F(3,28)=0.864, P =.47] (Liebenberg et al, 2015). …”

Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic

“…A third hypothesis, which might be viewed as a variant of the prior hypothesis, suggests that a ketamine metabolite, 2R,6R–hydroxynorketamine, enhances AMPA signaling through a mechanism that remains to be determined [118•]. Other hypotheses include the possibility that antidepressant effects of ketamine are mediated by its anti-inflammatory effects [119, 120], its effects on nitric oxide signaling [121, 122], its modulation of GABA-B receptor signaling [123], and other effects.…”

Role of the nitric oxide donor sodium nitroprusside in the antidepressant effect of ketamine in mice

“…Another NO precursor, L-arginine was shown to reduce antidepressant-like effects induced by venlafaxine or by selenide (Kumar et al, 2010;Jesse et al, 2010) and to exhibit alone dual (pro-and antidepressant) effects (Ergun and Ergun, 2007). L-arginine was shown to prevent the antidepressant-like action of ketamine in rats (Liebenberg et al, 2015). However, in contrast to SNP, it did not influence the psychosis-like effects and c-fos induction triggered by the NMDAR antagonist PCP (Bujas-Bobanovic et al, 2000).…”