Substance P in the medial amygdala: Emotional stress-sensitive release and modulation of anxiety-related behavior in rats

Abstract

Increasing evidence implicates the substance P (SP)͞neurokinin-1 receptor system in anxiety and depression. However, it is not known whether emotional stimulation alters endogenous extracellular SP levels in brain areas important for processing of anxiety and mood, a prerequisite for a contribution of this neuropeptide system in modulating these behaviors. Therefore, we examined in rats whether the release of SP is sensitive to emotional stressors in distinct subregions of the amygdala, a key area in processing of emotions. By using in vivo micropush-pull superfusion and microdialysis techniques, we found a pronounced and long-lasting increase (150%) in SP release in the medial nucleus of the amygdala (MeA), but not in the central nucleus of the amygdala, in response to immobilization stress. SP release in the MeA was transiently enhanced (40%) in response to elevated platform exposure, which is regarded as a mild emotional stressor. T he neuropeptide substance P (SP) and its preferred neurokinin-1 (NK 1 ) receptor have been proposed as possible targets for new antidepressant and anxiolytic therapies. Several preclinical studies have demonstrated a range of anxiety-related behaviors and defensive cardiovascular changes in response to central administration of SP agonists (1-6). Conversely, NK 1 receptor antagonists have been shown to produce anxiolytic-like effects after intracerebroventricular (4) or systemic administration (5,7,8). In addition, mice with selective deletion of the gene encoding the NK 1 receptor or the peptide itself also showed decreased anxiety-related behaviors (9-11). Thus, these findings suggest that SP acting as neurotransmitter͞neuromodulator (for review, see ref. 12) may be of relevance in the regulation of emotional states including anxiety-related behavior. Confirmation of this proposal was obtained by using a highly selective NK 1 receptor antagonist MK-0869, which relieved the symptoms of depression and anxiety in patients with major depressive disorder and a significant degree of anxiety (5). Although it has been shown that emotional and physical stressors modulate SP tissue levels or SP immunoreactivity in brain areas that are implicated in fear and anxiety (13-17), a change in extracellular SP levels, which is a direct and dynamic marker of SP neurotransmission, cannot be reliably predicted from these studies. Hence, at present it is not clear whether emotional stimuli actually do alter the in vivo release of SP, which is a prerequisite for a contribution of this neuropeptide system in modulating emotional states. Since stressful life experiences are thought to play a role in precipitating episodes of neuropsychiatric disorders including anxiety and depression (18,19), and laboratory stressors can produce behavioral and physiological changes resembling these mental disorders (20), it is of particular interest to examine the effect of emotional stressors on SP neurotransmission.The amygdala is critical for the processing of emotions including fear and anxiety (21, 22), and SP-cont...

Effects of Substance P in the Amygdala, Ventromedial Hypothalamus, and Periaqueductal Gray on Fear-Potentiated Startle

“…Ebner et al (2004) showed that immobilization stress caused a significant increase in SP release within the MeA but not the CeA. They also found that intra-MeA SP infusions produced anxiety-like behaviors as assessed with elevated plus maze, an effect similar to that induced by immobilization.…”

“…These expression patterns suggest a differential involvement of amygdaloid nuclei in SP-mediated affective behaviors. In fact, increases in SP mRNA and SP release induced by emotional stressors have been found in the MeA, but not in the CeA (Ebner et al, 2004;Sergeyev et al, 2005), and an increase in SP receptor internalization, a marker of SP release, was found in the BLA (Kramer et al, 1998;Smith et al, 1999). Direct infusion of SP into the MeA was shown to be anxiogenic in the elevated plus maze test (Ebner et al, 2004), and infusion of an SP receptor antagonist into the BLA blocked maternal separation-induced vocalization (Boyce et al, 2001).…”

“…SP appears to influence affective behaviors, at least in part, by actions within the amygdala (Boyce et al, 2001;Ebner et al, 2004;Kramer et al, 1998;Smith et al, 1999). Importantly, however, SP-containing neurons and SP receptors are heterogeneously distributed within this area.…”

Exposure to Stressors during Juvenility Disrupts Development-Related Alterations in the PSA-NCAM to NCAM Expression Ratio: Potential Relevance for Mood and Anxiety Disorders

“…Elevated platform, 12 Â 12 cm at a height of 70 cm above floor level, located in the middle of a small closet-like room (adapted from Maroun and Richter-Levin, 2003). Similar elevated platform protocols affected the stressresponse mechanisms of adult rats (Degroot et al, 2004;Ebner et al, 2004). Day 3 (aged 29 days) Foot-shock or restraint stressors: rats were randomly subjected to a short foot-shock session or to 2 hours of restraint.…”

The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement

“…Because NK1 receptors display considerable divergence between species, NK1R antagonists developed for activity at the human NK1R may possess limited efficacy in rat studies (Leffler et al, 2009). We therefore used L822429, a brain-penetrant NK1R antagonist with high affinity for the rat NK1R that produces anxiolytic-like effects after systemic administration (Ebner et al, 2004;Ebner et al, 2008;Singewald et al, 2008). We examined the effects of L822429 on heroin self-administration in short (ShA; 1 h per day) and long access (LgA; 12 h per day) rats.…”