Stress-induced release of substance P in the locus coeruleus modulates cortical noradrenaline release

Several lines of evidence implicate the neuropeptide substance P (SP) in the modulation of emotional behavior. Interaction between SP and noradrenergic systems has been proposed to be important in the regulation of stress, depression, and anxiety mechanisms; however, most evidence so far is based on studies in unchallenged and/or anesthetized animals. Thus, by using a dual-probe microdialysis approach in freely moving animals, the aim of the present study was to investigate whether a relevant stressor can trigger the release of SP in the locus coeruleus (LC) and whether and how this response modulates noradrenaline (NA) transmission both in the LC and in the medial prefrontal cortex (mPFC), an important LC terminal region involved in emotional processing. While confirming previous reports that neurokinin 1 receptor (NK1R) antagonists activate cortical noradrenergic transmission under resting conditions, we present evidence that this interaction is opposite during stress challenge. Our results show that exposure to forced swimming considerably enhanced the release of SP and NA in the LC. Administration of a selective NK1R antagonist into the LC potentiated this NA response within the LC but abolished the stress-induced increase in NA release within the mPFC. These findings demonstrate stress-induced increase in endogenous extracellular SP levels within the LC exerting a facilitatory effect on the noradrenergic pathway to the mPFC. The attenuation of stress-induced hyperactivation of this pathway by NK1R antagonists, presumably via enhancing NA and autoinhibition in the LC, may contribute to the therapeutic efficacy of these drugs known to ameliorate symptoms of stress-related disorders.