The Neurokinin-1 Receptor in Addictive Processes

Abstract

Stress can trigger drug-seeking behavior, increase selfadministration rates, and enhance drug reward. A number of stress-related neuropeptides have been shown to mediate these behavioral processes. The most studied peptide in this category is corticotropin-releasing hormone (CRH), which has been shown to mediate stress-induced reinstatement of drug seeking, escalated self-administration, and drug withdrawal, but it does not seem to be involved in baseline drug self-administration or cue-induced reinstatement. This pattern of effects holds for many classes of drugs, including alcohol, opiates, and psychostimulants. The neurokinin-1 receptor (NK1R) is the preferred receptor for the endogenous stress-related neuropeptide substance P (SP).The SP/NK1R system is a major mediator of stress and anxiety, and over the last several years, it has been demonstrated that the SP/NK1R system can have effects similar to those of CRH on drug taking and drug seeking. Specifically, NK1R inhibition attenuates escalated self-administration of alcohol as well as stress-induced reinstatement of alcohol and cocaine seeking; however, in contrast to other stress systems, the NK1R also appears to have a role in primary reward and reinforcement for opiates. This review outlines the role of NK1R in drug-seeking behaviors and highlights recent results from clinical studies that suggest that the NK1R may be a promising drug target going forward.

Substance P Antagonist Aprepitant Shows no Additive Effect Compared with Standardized Topical Treatment Alone in Patients with Atopic Dermatitis

“…The dose chosen for our study was 80 mg/day, based on an earlier study of pruritus by Ständer et al (7). Regarding the dose of aprepitant, it has been suggested that, for treatment of depression, near complete receptor occupancy for the NK-1R antagonist is needed, and that an occupancy of below 90% may be ineffective (15). In a study of co-morbid alcohol dependence and post-traumatic stress disorder a dosage of 125 mg/day for 4 weeks was used, based on positron emission tomography studies reporting > 90% central receptor occupancy at this dose (16).…”

“…However, no effect was found. In addition, the influence of polymorphism of the tachykinin receptor (TacR) -1 gene may be of importance (15).…”

Cellular and behavioral effects of lipopolysaccharide treatment are dependent upon neurokinin-1 receptor activation

“…Therefore, the efficacy of this drug could be tested in clinical trials for psychiatric conditions mediated by inflammation. While past clinical trials using NK1R antagonists have produced mixed results, negative findings have possibly been influenced by complex factors including drug dosing and pharmacogenetic interactions (see [45,46] for discussion of this topic).…”

Gut-brain peptides in corticostriatal-limbic circuitry and alcohol use disorders

“…Intra-amygdala infusion of the NK1R antagonist L822429 reduced alcohol self-administration in P rats while injections in the PFC did not (Schank et al, 2013). The amygdala is a component of the extended stress system, thus may play an important role in motivating drug seeking (reviewed by Schank, 2014). In fact, some preclinical studies indicate that NK1R antagonists may suppress stress-mediated alcohol relapse.…”