Behavioral and Physiologic Effects of Genetic or Pharmacologic Inactivation of the Substance P Receptor (NK1)

Depression and anxiety are among the most common diseases in the United States, thus constitutinga substantial financial burden for the health care system. Experimental studies of these affectivedisorders to date have largely focused on the neurotransmitter pathways with well-established pathophysiologicroles, such as serotonergic, noradrenergic, and γ-aminobutyric acid (GABA)-ergic systems;agents modulating the activity of these pathways are known to be clinically effective. More recently,the neuropeptide substance P (SP) and its receptor (the neurokinin-1 receptor [NK1R]) havebeen implicated in the pathophysiology of affective disorders, including depression. Earlier preclinicaland clinical studies, though, did not provide a clear consensus on the role of SP in the regulationof affective behavior and related pathologic conditions. Recent studies in mice clearly demonstratethat both the genetic disruption and acute pharmacologic blockade of the NK1R result in markedreduction in anxiety-like behavior and stress-related responses. In parallel with these behavioraleffects, physiologic changes, such as an increased firing rate of 5-hydroxytryptamine (5-HT) neuronsin the dorsal raphe nuclei and a desensitization of presynaptic 5-HT_1A inhibitory autoreceptors, wereobserved. These findings provide further evidence for the regulatory role of the SP-NK1R system inmodulation of affective behavior and indicate that its effects are mediated, at least in part, via the serotonergicsystem. Future studies will attempt to delineate the interaction between the SP-NK1R systemand various neurotransmitter pathways in greater detail and to address the specific role(s) of this systemin different brain regions.