P.2.a.015 MAPK pathway inhibition as target to potentiate the antidepressant-like effect of desipramine via the serotonergic system

Resumen

Background: It is widely known that one problem with current antidepressants is the high percentage of non-response or nonsatisfactory response in depressed patients, being necessary to implement the treatment with other central nervous system drugs. In addition, this problem is compounded by the delayed onset of action of these drugs. Thus, the efficacy and the onset of action of antidepressants are mechanistically conditionated by long-term adaptative intracellular signalling changes at several brain levels, such as the locus coeruleus (LC). Indeed, long termsynaptic plasticity in response to stress situations has been closely related with mitogen-activated protein kinases (MAPK) pathway modulation.Furthermore, previous reports have implicated components of this signalling cascade in the antidepressant behavioural effects. Thus, MAPK pathway could be an interesting candidate to become an antidepressant-enhancer. Purpose of the study: Therefore, the aim of this study was evaluate the effect of MAPK pathway inhibition by the administration of SL327 on the effectiveness of antidepressant treatment with desipramine.Methods: The effect of SL327 (selective MAPK inhibitor) and/or the antidepressant desipramine (noradrenaline reuptake inhibitor) were studied in male Sprague-Dawley rats. The MAPK inhibitor was intracerebroventricularly administered through a cannula located into the right lateral ventricle. The modified forced swimming test (mFST) was used as a model predictive of antidepressant-like activity. Additionally, in order to evaluate the effect of MAPK inhibition on LC neurons, single-unit extracellular recordings was performed in this nucleus. The administration of PCPA (para-chloro-phenylalanine), serotonin synthesis inhibitor, was used to evaluate the serotoninergic system implication in the antidepressant-like effect. Western blot assays in prefrontal cortex and hippocampus were performed to check the MAPK pathway inhibition by SL327, measuring the levels of phosphorylated ERK (active form of this MAPK protein). Additionally, spontaneous locomotor activity was monitored during 15 minutes in each experimental group after the corresponding pharmacological treatment. Results were analyzed by one or two-ways ANOVA followed by Bonferroni test. p <0.05 were considered to be significant.Results: The results showed that SL327 inhibited the phosphorylation of ERK in prefrontal cortex and hippocampus areas. On the contrary, SL327 did not modify neither behavioural nor electrophysiological patterns of LC neurons. However, SL327 in combination with desipramine enhanced the antidepressantlike effect of desipramine in the mFST. Thus, the combined treatment with desipramine and SL327 produced a decrease ofimmobility behaviour and an increase of swimming behaviour in this test. These behavioural changes are not due to an increase of spontaneous locomotor activity. The increase of the desipramine’s effect induced by SL327 was counteracted by PCPA treatment.Conclusions: These findings showed that SL327 potentiates the antidepressant-like behavioural effect of desipramine through an increase of serotoninergic neurotransmission. This data suggests that MAPK pathway inhibition may potentiate antidepressant effect, opening novel therapeutic approaches to depression.