Neurokinin 1 Receptor Antagonism Promotes Active Stress Coping Via Enhanced Septal 5-HT Transmission

Abstract

Antagonists of the substance P (SP) preferring neurokinin 1 receptor (NK1R) represent a promising novel class of drugs for the treatment of stress-related disorders such as depression and anxiety disorders; however, the involved neuronal pathways releasing SP in response to stressors are ill defined. By using in vivo microdialysis in combination with a highly sensitive and selective radioimmunoassay we found that exposure to forced swim stress increased SP release in the rat lateral septum (LS), a key area in processing emotions and stress responses. Acute administration of the selective NK1R antagonist L-822429 injected either systemically or locally into the LS reduced passive and facilitated active stress-coping strategies in the forced swim test. This effect seems to be mediated by enhanced intraseptal serotonergic transmission via serotonin (5-HT)1A receptors since NK1R blockade reversed the swim stress-induced decrease to an increase in extracellular 5-HT efflux, and furthermore the behavioral effects of L-822429 were blocked by intraseptal 5-HT1A receptor antagonism. A direct heterosynaptic regulation by NK1R on 5-HT release from serotonergic fibers was ruled out by immunocytochemistry at the light and electron microscopic level indicating involvement of GABAergic interneuron(s) in this interaction. Taken together, our data identify the LS as a critical brain area for the involvement of SP transmission in the modulation of stress responses and demonstrate that NK1R blockade can elicit a functionally significant facilitatory effect on 5-HT transmission, which does not necessarily involve the previously proposed interaction with neuronal firing at the cell body level of raphe neurons.

Prefrontal/Amygdalar System Determines Stress Coping Behavior Through 5-HT/GABA Connection

“…Here evidence is reported of a brain system which, through modulation of GABA in the amygdala prefrontal cortical 5-HT, controls behavioral responses to stressful experiences sustaining immobility in the forced swimming paradigm that models depressive-like outcomes in rodents (Ebner et al, 2005(Ebner et al, , 2008Singewald et al, 2011). It was first demonstrated that, in mice, a stressful experience such as restraint induces a time-dependent increase of 5-HT output in the mpFC and of GABA in the BLA, in agreement with previous reports (Reznikov et al, 2009;Pascucci et al, 2009), and that selective depletion of cortical 5-HT canceled out these stress-induced responses, thus pointing to a controlling role of GABAergic transmission in amygdala by prefrontal 5-HT during stress.…”

“…This suggests that 5-HT transmission in the mpFC is likely to engage GABA in the amygdala in stressful situations in order to determine coping outcomes. Here, using mice, it was attempted to assess whether amygdalar GABA regulation by prefrontal cortical 5-HT is a common neural substrate involved in processing stressful experiences and in determining active or passive coping behavior during forced swimming (Ebner et al, 2005(Ebner et al, , 2008Singewald et al, 2011). In particular, it was investigated whether 5-HT in prefrontal cortex is involved in brain response to uncontrollable stress through its modulating action on GABA in amygdala and whether these brain areas are part of a neural system necessary for the implementation of adaptive coping strategies.…”

Neurokinin1 Antagonists Potentiate Antidepressant Properties of Serotonin Reuptake Inhibitors, Yet Blunt Their Anxiogenic Actions: A Neurochemical, Electrophysiological, and Behavioral Characterization

“…That is, in line with the present observations, NK 1 receptors are 'upstream' of 5-HT 1A autoreceptors. Interestingly, by analogy to lateral septum (Ebner et al, 2008), frontocortical perfusion of substance P suppressed local release of 5-HT in mice, an effect blocked by GR205171 and absent in mice lacking NK 1 receptors (Guiard et al, 2007). Thus, NK 1 antagonists conceivably also enhance SSRI-induced increase in 5-HT levels by actions in the FCX and other structures innervated by the DRN.…”

“…Possible Involvement of Gabaergic, Glutatamergic, and Adrenergic Mechanisms NK 1 receptors have been identified on GABAergic neurones surrounding 5-HT cell bodies in the DRN, and studies in the septum and cortex suggest that NK 1 receptor antagonists may indirectly excite serotonergic neurones via a reduction of inhibitory GABAergic tone (Sloviter et al, 2001;Ma and Bleasdale, 2002;Stacey et al, 2002;Szeidemann et al, 1995;Ebner et al, 2008). This would enhance their responsiveness to SSRIs, by analogy to GABA B antagonists (Millan, 2006;Cremers et al, 2007).…”

“…These observations support the finding of a recent study of GR205171 and paroxetine by Chenu et al (2006)Fthough stereospecificity was not demonstrated. Apart from the hippocampus, the septum is implicated in antidepressant actions of SSRIs (Sheehan et al, 2004;Millan, 2006), and NK 1 antagonists may enhance 5-HT release in this region via inhibition of GABAergic interneurons (Szeidemann et al, 1995;Millan, 2006;Ebner et al, 2008). As GR205171 blunted the increase in locomotor activity elicited by citalopram herein (Table 3), potentiation of the actions of citalopram in the FS procedure is unlikely to reflect stimulation of motor behavior (Redrobe and Bourin, 1998;Brocco et al, 2006).…”