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THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright ª 2014 by The American Society for Pharmacology and Experimental Therapeutics
http://dx.doi.org/10.1124/jpet.113.210799
J Pharmacol Exp Ther 351:2–8, October 2014
Minireview
The Neurokinin-1 Receptor in Addictive Processes
Jesse R. Schank
Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, Georgia
Received March 23, 2014; accepted July 17, 2014
Introduction
Substance P (SP) is an 11-amino-acid neuropeptide of the
tachykinin family, which also includes neurokinin A and neurokinin B. There are three receptor subtypes for the tachykinins,
and SP preferentially binds to the neurokinin-1 receptor (NK1R)
(Pennefather et al., 2004). Whereas SP has historically gained
attention for its physiologic actions in the periphery, there is
extensive literature indicating a role for the SP/NK1R system in
complex behaviors, such as stress and anxiety (reviewed in
Ebner and Singewald, 2006). Recent work has also indicated
a role of the NK1R in responses to drugs of abuse (including
alcohol), and those findings are outlined in detail in this review.
Importantly, NK1Rs are located in a wide range of brain regions
involved in the regulation of affective behaviors and addiction,
including the striatum, extended amygdala, hippocampus, and
brainstem monoaminergic nuclei (Quirion et al., 1983; Mantyh
et al., 1984; Shults et al., 1984; Yip and Chahl, 2000).
Another well known neuropeptide, corticotropin-releasing
hormone (CRH), has been considered by many to be the
prototypical stress-responsive signaling molecule, and much
research supports its role in stress and drug-seeking behaviors,
especially through activation of CRH type-1 receptor (CRH-R1)
dx.doi.org/10.1124/jpet.113.210799.
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.
(for review, see Heilig and Koob, 2007; Koob, 2010; Koob and
Zorrilla, 2010). Generally, inhibition of CRH-R1 function can
suppress escalated self-administration in dependent animals
and can suppress stress-induced reinstatement of drug seeking
without affecting baseline self-administration or cue-induced
reinstatement of drug seeking. This pattern of effects holds for
most drugs of abuse. As described in detail in this review, the
SP/NK1R system appears to have a similar stress-specific impact in drug-seeking behaviors, with some exceptions that are
discussed here. This review outlines the role for the SP/NK1R
system in these phenomena and describes its role in primary
reward and reinforcement for some classes of drugs. It also
describes the promising clinical findings that suggest that the
NK1R may be a useful target in the development of medications
for the treatment of addiction, comparing this along the way
with findings pertaining to CRH and CRH-R1.
SP and CRH: Siblings in Behavioral,
Neurochemical, and Endocrine Stress
Responses
Substance P is released in stress-sensitive brain regions in
response to acute stressors (Ebner et al., 2004, 2008b; Singewald
et al., 2008), and exogenous SP infusion induces anxiety-like
ABBREVIATIONS: AMG, amygdala; CeA, central nucleus of the amygdala; CPP, conditioned place preference; CRH, corticotropin-releasing
hormone; CRH-R1, corticotropin-releasing hormone receptor type 1; HPA axis, hypothalamic-pituitary-adrenal axis; L822429, (2S,3S)-N-{[2cyclopropoxy-5-(5-trifluoromethyl)tetrazol-1-yl]benzyl}-2-phenylpiperidin-3-amine dihydrochloride; LC, locus coeruleus; MOR, m-opioid receptor;
NE, norepinephrine; NK1R, neurokinin-1 receptor; P rat, alcohol-preferring rat; SP, substance P.
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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).
Neurokinin-1 Receptor in Addiction
paraventricular nucleus of the hypothalamus, a region that
drives HPA axis activity and endocrine responses to stress, is
innervated by SP-positive fibers (Kawano and Masuko, 1992;
Womack and Barrett-Jolley, 2007; Womack et al., 2007), and
NK1R antagonists attenuate stress-induced neuronal activation (as measured by c-fos expression) in this region (Ebner
et al., 2008a). CRH is a major player in the HPA axis, as it is
the biochemical intermediary that is produced in the hypothalamus and activates adrenocorticotropic hormone release
from the pituitary via activation of the CRH-R1. The HPA axis
is one point of convergence in which NK1R could influence
stress responses in a manner similar to the actions of CRH.
However, a large body of evidence has demonstrated that
many CRH effects that regulate affective function occur in
extrahypothalamic regions of the brain, such as the extended
amygdala. In addition, evidence for direct interactions between SP and CRH are rather sparse (but see Hamke et al.,
2006). Taken together, these findings suggest that the CRH
and SP systems play similar roles and function in parallel to
affect drug seeking behavior, as opposed to directly interacting.
Preclinical Findings in Rodent Models of Drug
Addiction
There is a large body of literature, and many excellent
reviews, outlining the role of CRH in drug-seeking and drugtaking behaviors, and those are not outlined in detail here
(see, for example, Sarnyai et al., 2001; Heilig and Koob, 2007;
Koob, 2010; Koob and Zorrilla, 2010; Shalev et al., 2010).
Given its role in stress responses, monoaminergic signaling,
and neuroanatomic pathways that mediate drug reward and
reinforcement, much research has focused on the impact of
NK1R manipulations on stress-induced drug seeking. The
preclinical findings for the NK1R system with three major
classes of drugs of abuse are outlined below, followed by
a conclusion relating this to the effects of CRH.
Opiates. Likely owing to a purported role of SP in pain
processing, there has been much interest in the role of the
NK1R in opiate reward and reinforcement, and some of the
earliest studies using mice with a genetic deletion of the NK1R
explored these behaviors. For example, morphine reward is
absent in NK1R2/2 mice, as evidenced by a complete lack of
conditioned place preference (CPP) for the drug (Murtra et al.,
2000). Morphine-induced locomotor activation, psychomotor
sensitization, and Fos B immunoreactivity are also attenuated
in these animals (Murtra et al., 2000; Ripley et al., 2002);
however, the analgesic properties of opiate drugs are unaffected. Further studies focused on outlining the neuroanatomy
of NK1R mediation of morphine reward used a targeted lesion
approach, where a saporin neurotoxin linked to SP was used to
selectively ablate NK1R containing cells. Lesions using this
method identified the amygdala (AMG) as a major anatomic
locus for NK1R effects on morphine reward but found no effect
of targeted lesions in the nucleus accumbens (Gadd et al.,
2003). In support of a role of the SP/NK1R system in motivational properties of opioids, it was recently reported that
NK1R antagonism attenuates the ability of morphine to lower
intracranial self-stimulation thresholds (Robinson et al., 2012),
a method largely believed to assess the rewarding properties
of pharmacologic agents, with a lowering of stimulation thresholds believed to indicate increased reward processing.
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behavior in rodents that is NK1R-dependent (Teixeira et al.,
1996; Duarte et al., 2004; Ebner et al., 2004). In addition, mice
with genetic deletion of the NK1R show decreased anxiety in
the elevated plus maze, novelty-suppressed feeding paradigm,
and ultrasonic vocalization during maternal separation, three
commonly used measures of anxiety-like behavior in rodents
(Santarelli et al., 2001). Interestingly, NK1R antagonists also
have anxiolytic properties under basal conditions (Teixeira
et al., 1996; Santarelli et al., 2001; Ebner et al., 2008a), in
contrast to the effects that are typically observed with CRH-R1
antagonism. CRH-R1 inhibitors generally show anxiolysis only
under conditions in which anxiety has been elevated, such as
after stress, drug withdrawal, or genetic selection for increased
anxiety (Heilig and Koob, 2007; Rotzinger et al., 2010).
Thinking in terms of receptor-specific pharmacotherapies, this
finding may argue for a more general effect of NK1R antagonists on anxiety disorders; however, clinical results have not
been particularly promising in this regard (Tauscher et al.,
2010; Michelson et al., 2013).
To mediate stress- and anxiety-related effects, the NK1R
may act via modulation of monoaminergic neurotransmission
and neuroendocrine responses. For example, NK1R antagonism promotes active coping behavior and prevents suppression of septal serotonin release after forced swim stress
(Ebner et al., 2008b). NK1R activation generally suppresses
the output of the dorsal raphe nucleus (Valentino et al., 2003;
Guiard et al., 2007), and inhibition of the NK1R can increase
serotonergic activity (Santarelli et al., 2001; Conley et al.,
2002; Gobbi et al., 2007). Also, NK1Rs are found on the
noradrenergic cell bodies of the locus coeruleus (LC) (Chen
et al., 2000; Ma and Bleasdale, 2002) and influence the output
of these neurons, although the direction of this influence is
unclear. Most studies suggest that SP can increase LC firing
and that NK1R antagonists attenuate stress-induced norepinephrine (NE) release (Guyenet and Aghajanian, 1977;
Cheeseman et al., 1983; Renoldi and Invernizzi, 2006); however, there has been some suggestion that NK1R antagonists
themselves can increase NE in some terminal fields (Millan
et al., 2001; Maubach et al., 2002). When considering the
regulation of behaviors that lie at the intersection of stress
and addiction, the ability of NK1R to modulate NE transmission is especially intriguing because the NE system has
been shown to mediate stress-induced reinstatement and
escalated self-administration of multiple drugs of abuse (Erb
et al., 2000; Shaham et al., 2000; Leri et al., 2002; Gilpin and
Koob, 2010; Mantsch et al., 2010; Vranjkovic et al., 2012).
Although it is known primarily as a reward-related neurotransmitter, dopamine activity is increased during exposure
to some stressors. NK1R antagonists can prevent immobilization stress–induced dopamine release in the prefrontal
cortex (Hutson et al., 2004; Renoldi and Invernizzi, 2006),
which is of particular interest for the NK1R’s targeted role in
stress-elicited drug seeking (see later discussion). The effect of
the NK1R on monoamine signaling is a major mechanistic
area of overlap with the functions of CRH receptors, which can
influence the activity of the monoaminergic systems (Dunn et al.,
2004; Valentino and Commons, 2005; Valentino et al., 2010).
The NK1R can also mediate hypothalamic-pituitary-adrenal
(HPA) axis responses to environmental stressors. For example, anxiety-like behavior and elevations in cortisol during
exposure to the elevated-plus maze are attenuated in mice
with genetic deletion of the NK1R (Santarelli et al., 2001). The
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Schank
group. We found that yohimbine-induced reinstatement of
cocaine-seeking is attenuated by treatment with a specific
NK1R antagonist. Yohimbine is an antagonist of a2-adrenergic
autoreceptors that increases NE output and is considered
a pharmacologic stressor. Yohimbine injection, like intermittent footshock stress, can trigger a reactivation of drug
seeking after extinction of operant self-administration.
Thus, NK1R antagonism is ineffective at suppressing
baseline self-administration of cocaine in short-access sessions, demonstrating a lack of effect of NK1R on baseline
cocaine reinforcement. An intriguing question for future
studies is whether NK1R antagonism might influence cocaine
self-administration during long-access sessions, which promote escalated cocaine self-administration rates, potentially
through recruitment of stress-related systems, as mentioned
already.
Alcohol. In the last several years, a series of studies has
indicated that the SP/NK1R system is involved in alcoholrelated behaviors. Similar to morphine, NK1R2/2 mice on
a C57/BL6 background exhibit a complete lack of CPP for
alcohol (Thorsell et al., 2010). Also, these animals consume
less alcohol in voluntary two-bottle choice drinking over
a range of pharmacologically active concentrations (George
et al., 2008). Decreased alcohol consumption in NK1R2/2 mice
was replicated by NK1R antagonist administration in wildtype C57/BL6 mice (Thorsell et al., 2010). In this study, there
appeared to be an interaction between genotype and NK1R
antagonist efficacy, with wild-type mice responding to lower
doses of the antagonist than heterozygotes. These effects did
not result from off-target action of the antagonist since
NK1R2/2 mice were insensitive to its effects. Consistent with
decreased alcohol consumption observed as a result of genetic
or pharmacologic inhibition of the NK1R, microRNA silencing
of NK1R expression using intracerebroventricular infusions
also suppressed alcohol consumption in mice (Baek et al.,
2010). Thus, both pharmacologic blockade of NK1Rs and
transient knock-down of their expression mimic the effects of
constitutive NK1R gene inactivation. Thorsell et al. (2010)
further demonstrated that NK1R2/2 mice do not escalate
their voluntary alcohol consumption after repeated cycles of
deprivation, suggesting that the SP/NK1R system may be
involved in neuroadaptations that influence the development
of escalated alcohol seeking.
In pharmacologic studies using rats, the specific NK1R
antagonist L822429 [(2S,3S)-N-{[2-cyclopropoxy-5-(5-trifluoromethyl)tetrazol-1-yl]benzyl}-2-phenylpiperidin-3-amine dihydrochloride] (Singewald et al., 2008) was found to suppress
stress-induced reinstatement of alcohol-seeking (Schank et al.,
2011, 2014). This effect was observed for reinstatement induced
by both pharmacologic (yohimbine) and physical/environmental
(intermittent footshock) stressors. In these studies, L822429 was
used at doses that had no effect on operant self-administration of
sucrose, cue-induced reinstatement of alcohol seeking, or novel
environment-induced locomotion. L822429 also had no effect on
baseline alcohol self-administration rates. In agreement with
these findings, Steensland et al. (2010) also did not observe
a suppression of alcohol self-administration or two-bottle choice
consumption in rats after NK1R antagonism with ezlopitant
until doses were reached that also suppressed sucrose consumption, indicating nonspecific suppression on consummatory
behavior at these doses. Thus, similar to the effects of CRH on
alcohol consumption and the effects of NK1R antagonists on
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These assessments of opiate reward are consistent with
decreased morphine reinforcement that has been observed in
NK1R2/2 mice (Ripley et al., 2002). Specifically, NK1R2/2
mice show decreased self-administration rates for morphine,
with no effect on cocaine self-administration. Accordingly,
NK1R antagonism suppresses heroin self-administration in
rats in both short- and long-access sessions (Barbier et al.,
2013). It is largely believed that long-access sessions (longer
than 6 hours) lead to escalated drug self-administration that,
in part, is driven by the recruitment of stress systems (for
review, see Specio et al., 2008; Wee et al., 2008, 2009). The
effects of CRH-R1 on drug reinforcement are observed only
during such long-access sessions. However, the evidence
suggests a more general role for the NK1R in primary reward
and reinforcement for opiates that may not involve stress
interactions.
On an intracellular level, an intriguing interaction between
the NK1R and m-opioid receptor (MOR) has been described.
Specifically, coadministration of SP prevents morphineinduced internalization and acute desensitization of the
MOR (Yu et al., 2009), a result of sequestering of b-arrestin by
NK1Rs, which are internalized following activation by SP,
thereby depleting the available cytoplasmic pool of b-arrestin
neccessary for MOR internalization. This in vitro effect was
also observed in dissociated AMG and LC neurons, some of
which endogenously coexpress NK1R and MOR. This intracellular interaction may explain in part why the NK1R mediates reward and reinforcement for opiates but not for other
drugs. In addition, it has been reported that chronic morphine
administration leads to upregulation of the NK1R in vitro
(Wan et al., 2006), further suggesting an important functional
interaction between NK1R and MORs.
Cocaine. Some of the earliest studies exploring the role of
the NK1R in drug-related behaviors investigated the influence of this receptor on cocaine-induced locomotion and DA
release in the dorsal striatum. It was found that inhibition of
the NK1R attenuated both of these responses (Kraft et al.,
2001a,b; Noailles and Angulo, 2002; Loonam et al., 2003).
However, NK1R deletion did not affect locomotor sensitization to cocaine in mice (Ripley et al., 2002). Furthermore, in
contrast to its role in opioid-related behaviors, genetic
deletion of NK1R does not affect cocaine CPP (Murtra et al.,
2000). In agreement with this finding, lesions targeted
specifically to NK1R-containing neurons of the AMG had no
effect on cocaine CPP (Gadd et al., 2003). However, the effect
of NK1R-targeted lesions of the nucleus accumbens on cocaine
reward was not assessed.
When considering the results from operant self-administration
experiments, the picture becomes more complex. First, cocaine
self-administration rates were not affected by NK1R deletion
in mice (Ripley et al., 2002) or NK1R antagonism in rats
(Placenza et al., 2006; Schank et al., 2014). However, Placenza
et al. (2004, 2005) showed that extinguished cocaine seeking
can be reinstated by infusion of specific NK1R agonists into
the lateral ventricles or ventral tegmental area but found that
an NK1R-specific antagonist was unable to prevent reinstatement of cocaine seeking induced by noncontingent cocaine
injection. This finding suggests that the NK1R is involved in
reinstatement of cocaine seeking triggered by some stimuli
but not that induced by drug priming.
Because of the role of SP/NK1R in stress responses, reinstatement induced by stress was therefore examined by our
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Neurokinin-1 Receptor in Addiction
entirely. NK1R and CRH-R1 antagonists suppress stressinduced reinstatement of drug seeking and escalated drug selfadministration without affecting baseline self-administration
or cue-induced reinstatement. One aspect of this relationship
that still requires exploration is whether NK1R antagonists
can suppress escalated cocaine self-administration during
long-access self-administration sessions. For opioid drugs,
there appears to be a divergence between the effects of CRH-R1
and NK1R inhibition in that the NK1R mediates baseline
reward and reinforcement for opioids in addition to escalated
self-administration rates, whereas CRH-R1 effects are selective for the latter. Although this has not yet been examined, it
is hypothesized that NK1R antagonism would attenuate
stress-induced reinstatement of opiate seeking due to the
influence of the NK1R system on stress-induced reinstatement for other drugs and to its more general effects on
responding for opiates. One issue that has not been discussed
is drug withdrawal. CRH systems have also been demonstrated to have an important role in drug withdrawal
symptoms, but this has not yet been explored with NK1R
antagonists.
The SP/NK1R System as a Promising
Therapeutic Target
The NK1R was the first neuropeptide receptor for which
a potent, highly selective nonpeptide antagonist was developed (Snider et al., 1991), and early studies focused on developing treatments for analgesia and inflammation. Another
physiologic role of the NK1R is the mediation of emesis, and
the Food and Drug Administration (FDA)–approved compound aprepitant is an NK1R antagonist that is indicated for
treatment of chemotherapy-induced nausea (for review, see
Quartara et al., 2009). In addition to its use for this purpose,
this compound has provided a somewhat useful clinical tool
for off-label testing of NK1R therapeutics for other conditions.
Given the largely promising results from preclinical animal
studies, NK1R antagonists have been subsequently explored
for the treatment of affective disorders such as depression and
anxiety. NK1R inhibition has antidepressant properties in
multiple animal models, but promising results in early
clinical trials (Kramer et al., 1998) have not been replicated
(see, for example, Keller et al., 2006). However, more recent
studies have suggested the possibility that NK1R antagonists
may in fact have antidepressant properties but require nearcomplete receptor occupancy to produce these effects reliably
TABLE 1
Summary of the effects of NK1R inhibition on drug-related behaviors
The bottom two rows indicate drug-seeking behaviors that are typically associated
with increased involvement of stress neurocircuitry. It is of note that all drug-seeking
behaviors examined that fall within this realm are attenuated by NK1R antagonist
administration.
Effect of NK1R Inhibition
Summary
As outlined here, the NK1R system has many similarities
but also some important differences compared with the effects
of CRH on drug seeking (for summary of NK1R effects, see
Table 1). For cocaine and alcohol, the effects of NK1R antagonism on drug seeking and drug taking seem to overlap
Baseline self-administration
Conditioned place preference (mouse)
Drug-primed reinstatement
Locomotor sensitization
Cue-induced reinstatement
Stress-induced reinstatement
Escalated self-administration
a
Cocaine
No
No
No
No
effect
effect
effect
effect
?
↓
?
Ethanol
Opiates
No effect
↓a
?
?
No effect
↓
↓
↓
↓
?
↓
?
?
↓
Experiment was performed in high alcohol-consuming C57/BL6 mouse strain.
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cocaine seeking, it appears that the effects of the NK1R on
operant responding for alcohol in rats are specifically targeted to
stress-elicited drug seeking.
As stated already, the behavioral profile of L822429 to
suppress stress-induced reinstatement of alcohol seeking
without affecting baseline self-administration or cue-induced
reinstatement is similar to compounds that target the CRF-1R
(Koob and Zorrilla, 2010; Shalev et al., 2010). Importantly,
these compounds also attenuate escalated alcohol consumption that results from the induction of alcohol dependence or
where increased alcohol preference is achieved by genetic
selection (Heilig and Koob, 2007). In other words, compounds
that act on the CRH system are selectively effective under
conditions where stress systems have been hypersensitized. A
hypothesis that remained to be addressed, therefore, was
whether NK1R antagonists, while leaving basal alcohol
intake unaffected, could suppress escalated alcohol consumption. In support of this idea, NK1R antagonists suppress
alcohol consumption in a high alcohol preferring line of mice
(C57/BL6J, see preceding) and attenuate escalated alcohol
self-administration in alcohol-preferring (P) rats but do not
affect alcohol self-administration in nondependent, nonpreferring rats (Thorsell et al., 2010; Schank et al., 2011, 2013). It
was also demonstrated that P rats show an upregulated
NK1R system, as evidenced by increased transcript levels of
the Tacr1 gene, as well as increased receptor binding in specific
brain regions. Of the regions explored, NK1R upregulation was
specific to the central nucleus of the AMG (CeA), and direct
infusion of NK1R antagonists into this region mimicked the
effect of systemic treatment in P rats. A similar upregulation of
CRH-R1 has been observed in the CeA of a different alcohol
preferring rat line, the Marchegian Sardinian Alcohol Preferring rat (Hansson et al., 2006). Altered CeA function is
especially intriguing, as this structure is an important part of
the extended amygdala stress circuitry. This network is
thought to be recruited to influence drug reinforcement under
conditions of stress or dependence, when negative reinforcement to alleviate drug-withdrawal–related dysphoria plays
a major role in motivating drug seeking (Koob, 2003, 2009a,b;
Koob and Le Moal, 2008).
The heightened NK1R function in P rats described above
was associated with increased transcription factor–binding
potential at a region of the Tacr1 promoter that shows single
nucleotide variation between P rats and the founder Wistar
strain. Specifically, approximately 20% of Wistar rats were
CC homozygous at position 21372 from the transcriptional
start site of the Tacr1 gene, whereas P rats were 100% CC
homozygous at this location. CC homozygosity was associated
with increases in transcription factor binding potential (as
measured by gel shift assays) and promoter activity (as
measured by luciferase expression assays). We have observed
that P rats are generally more sensitive to the effects of NK1R
antagonists, suggesting a potential pharmacogenetic interaction that is mediated by this locus.
6
Schank
when given in combination with a drug that acts on other facets
of the addictive process, such as naltrexone. Naltrexone has
a more targeted effect on cue-elicited drug seeking with no
effect on stress-elicited drug seeking. The fact that NK1R
antagonists influence a restricted set of drug seeking behaviors
may underlie negative results from clinical trials and may have
a more important impact than receptor occupancy (as mentioned already herein). On the other hand, the stress-selective
effect of NK1R antagonists may suggest efficacy in only
a portion of the population with specific psychiatric comorbidities. Future studies would benefit from taking these issues
into consideration.
When comparing the effects of NK1R antagonism to the body
of literature examining CRH effects on drug seeking, NK1R
antagonists may hold greater promise as addiction pharmacotherapies for a number of reasons. First, the existence of safe,
well tolerated NK1R-targeted pharmacotherapies is perhaps
the most important advantage of the NK1R over the CRH
system as a target of drug development. Even though CRH-R1
antagonists have shown promise in small clinical trials, the
compounds that have been tested have side effects that prohibit
their development for use in medical treatment. In addition to
aprepitant, which is approved by the FDA, several NK1R
antagonists have been developed by the pharmaceutical
industry and tested for efficacy in anxiety, mood disorders,
and alcohol cravings in humans (see preceding description).
Second, NK1R antagonists suppress opiate reward and reinforcement in preclinical studies, which would suggest that
these agents would have utility for treating opiate dependence.
Third, NK1R antagonists have anxiolytic properties in animal
models under baseline conditions, suggesting that these drugs
would be effective at preventing alcohol abuse in patients with
high levels of anxiety, which can increase the risk of problematic alcohol consumption as a means to alleviate elevated
anxiety states. Finally, clinical trials for alcoholism have shown
efficacy of NK1R antagonists in alleviating cravings and neural
processing abnormalities in detoxified, anxious alcoholics.
The preclinical and clinical findings reviewed here suggest
that NK1R antagonists hold promise as potential addiction
pharmacotherapies. However, no clinical trials pertaining to
drugs of abuse other than alcohol have been performed, and
future efforts should address this gap in the literature. One
exception is a recent clinical trial in prescription opiate
abusers. Unexpectedly, however, NK1R antagonism seemed
to heighten the effects of these drugs (Walsh et al., 2013). How
this relates to voluntary use of prescription opioid medications or illicit opiate drugs is unknown and will need to be
addressed in future studies. Recent findings also suggest that
NK1R antagonists could have utility for the treatment of
cocaine abuse, especially in cases with increased risk of stressinduced relapse in abstinent cocaine addicts, but this also has
not been examined clinically.
Conclusions
Taken together, the findings outlined here would predict
that NK1R antagonists could be potentially useful treatments
for some subpopulations of substance abusers such as those
with certain genetic variants of the Tacr1 gene, patients that
are especially sensitive to stress-triggered craving, anxious
alcoholics, and those that abuse opiates alone or in combination with other drugs. The recent development of new, more
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(Ratti et al., 2011; Zamuner et al., 2012). Indeed, a retrospective assessment of clinical trials for depression suggests that
greater than 95% receptor occupancy is required for efficacy,
whereas occupancy even up to 90% is ineffective (Ratti et al.,
2013; Trist et al., 2013). These observations may also be
relevant for clinical research aimed at developing NK1Rs for
addiction pharmacotherapy as well as for treatment of chronic
pain. The findings outlined above suggest that a reassessment
of recent pessimism concerning clinical efficacy of NK1R
antagonists should be reconsidered (Borsook et al., 2012).
The preclinical findings indicating a role for NK1R in
alcohol-related behaviors have translational value when considered in light of clinical studies where alcohol-dependent
inpatients were treated with an NK1R antagonist (George
et al., 2008). This compound decreased spontaneous alcohol
craving as well as craving triggered in response to a combined
social stressor and alcohol-associated cue challenge. NK1R
antagonist treatment also suppressed cortisol release during
cue/stress exposure, supporting a role of the NK1R in regulation of HPA axis function (see preceding). In this study,
prescreening selected for alcoholics with high anxiety. This
selection based on anxiety phenotype may have inadvertently
selected for a genetically defined subpopulation of alcoholics.
Genetic analyses of alcoholic patients has suggested an association of specific TacR1 gene (which encodes the NK1R)
polymorphisms with increased risk for alcohol dependence
(Seneviratne et al., 2009) and increased sensitivity to alcoholrelated cues (Blaine et al., 2013). This is especially intriguing
in light of the pharmacogenetic interactions that we have
observed in our preclinical studies using P rats (see preceding)
and suggests that genetically defined subgroups of patients
may therefore be particularly responsive to NK1R antagonist
treatment. This genetic variation may need to be taken into
account in the course of clinical development. A lack of consideration for this potential interaction may underlie the
mixed results of clinical trials for psychiatric conditions,
including alcoholism. Whether TacR1 polymorphisms (or
another genetic factor) may influence the efficacy of NK1Rbased treatments, the human and animal data support the
prediction that NK1R antagonists would be effective only in
a subpopulation of alcoholics, namely, those that have increased anxiety or stress reactivity. Attempts to target patient
populations heterogeneous for important determinants of
treatment response combined with a failure to achieve adequate
central receptor occupancy may have led to termination of
NK1R antagonist programs. Recent identification of the
factors mentioned here suggests that carefully designed clinical
studies will be more successful. Given that prior failures of
NK1R programs limit the willingness of the pharmaceutical
industry to further invest in this mechanism, public-private
partnerships may be needed going forward.
It is important to highlight again the fact that NK1R
antagonists specifically mediate stress-elicited drug seeking
for most drugs of abuse studied in preclinical settings.
Although this seems to suggest a promise of clinical efficacy
for addiction, it is unclear whether this targeted effect would
translate into beneficial pharmacotherapy when given alone.
A recent clinical trial (ClinicalTrials.gov Identifier: NCT00835718)
explored the effect of the NK1R antagonist serlopitant on
alcohol consumption but was terminated prematurely; thus,
conclusions cannot be drawn from this study. Ultimately, it
may be that NK1R antagonists will serve as useful medications
Neurokinin-1 Receptor in Addiction
potent NK1R antagonists will likely stimulate a reimagining
of the pharmaceutical utility of this class of drugs and it is
hoped will lead to clinical trials for addiction, anxiety, and
depression. Some considerations to acknowledge going forward are the apparent need to tailor dosing to achieve nearly
complete receptor occupancy and the potential for pharmacogenetic interactions that are influenced by polymorphisms of
the Tacr1 gene.
Acknowledgments
The author thanks Dr. Markus Heilig (National Institute on
Alcohol Abuse and Alcoholism, Bethesda, MD) for valuable comments
in the revision of this manuscript.
Authorship Contributions
Wrote or contributed to the writing of the manuscript: Schank.
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