the neurokinin-1 receptor in addictive processes...

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The Neurokinin-1 Receptor in Addictive Processes

Jesse R. Schank

Department of Physiology and Pharmacology, College of Veterinary Medicine, University

of Georgia, Athens GA

This article has not been copyedited and formatted. The final version may differ from this version.JPET Fast Forward. Published on July 18, 2014 as DOI: 10.1124/jpet.113.210799

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Running Title: Neurokinin-1 Receptor in Addiction

Corresponding Author:

Jesse R. Schank, Ph.D.

Department of Physiology and Pharmacology

College of Veterinary Medicine

University of Georgia

501 DW Brooks Drive

Athens, GA 30602

Phone: 706-542-0661

Email: [email protected]

Pages: 34

Tables: 1

Figures: 0

References: 87

Section: Neuropharmacology

Abbreviations:

CeA: Central Nucleus of the Amygdala

CPP: Conditioned Place Preference

CRH: Corticotropin Releasing Hormone

CRH-R1: Corticotropin Releasing Hormone Receptor Type 1

DR: Dorsal Raphe Nucleus


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EPM: Elevated Plus Maze

HPA axis: Hypothalamic-Pituitary-Adrenal axis

ICSS: Intracranial Self-Stimulation

msP rat: Marchegian Sardinian Alcohol Preferring rat

NK1R: Neurokinin-1 Receptor

P rat: Alcohol Preferring rat

PVN: Paraventricular Nucleus of the Hypothalamus

VTA: Ventral Tegmental Area


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Abstract

Stress can trigger drug-seeking, increase self-administration 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 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 CRH on drug taking and

drug seeking. Specifically, NK1R inhibition has been shown to attenuate escalated self-

administration of alcohol and 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. Here, we outline the role of NK1R in drug seeking

behaviors, and highlight recent results from clinical studies that suggest that the NK1R may be a

promising drug target going forward.


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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).

While SP has historically gained attention for its physiological actions in the periphery, there is

an 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 will be

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; 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 below, the

SP/NK1R system appears to have a similar stress-specific impact in drug seeking behaviors, with

some exceptions that will be discussed here. In this review, I will outline the role for the

SP/NK1R system in these phenomena and describe its role in primary reward and reinforcement


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for some classes of drugs. I will also describe promising clinical findings that suggest that the

NK1R may be a useful target in medications development 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

SP is released in stress-sensitive brain regions in response to acute stressors (Ebner et al.,

2004, Ebner et al., 2008b, Singewald et al., 2008), and exogenous SP infusion induces anxiety-

like 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 (EPM), 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 following

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 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 (5HT)


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release following forced swim stress (Ebner et al., 2008b). It has been shown that NK1R

activation generally suppresses the output of the dorsal raphe nucleus (DR; Valentino et al.,

2003, Guiard et al., 2007), and that 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 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 norepinephrine (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). While being known

primarily as a reward-related neurotransmitter, dopamine (DA) activity is increased during

exposure to some stressors. NK1R antagonists can prevent immobilization stress-induced DA

release in the prefrontal cortex (PFC; Hutson et al., 2004, Renoldi and Invernizzi, 2006), which

is of particular interest due to the NK1R’s targeted role in stress-elicited drug seeking (see

below). 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).


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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 EPM are attenuated in mice with genetic deletion of the NK1R (Santarelli et al.,

2001). The paraventricular nucleus of the hypothalamus (PVN), 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 similar manner 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, this suggests 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 drug taking behaviors, and those will not be 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 this role in stress responses, monoaminergic signaling, and


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neuroanatomical pathways that mediate drug reward and reinforcement, much research has

focused on the impact of NK1R manipulations on stress-induced drug seeking. Below I will

describe preclinical findings for the NK1R system with three major classes of drugs of abuse,

and conclude by relating this to the effects of CRH.

Opiates

Likely due to a purported role of SP in pain processing, there has been much interest 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 NK1R-/- 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 anatomical locus for NK1R effects on morphine reward but found no effect of targeted

lesions in the nucleus accumbens (NAC; 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 (ICSS) thresholds

(Robinson et al., 2012). ICSS is a method largely believed to assess the rewarding properties of

pharmacological agents, with a lowering of stimulation thresholds believed to indicate increased

reward processing.


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These assessments of opiate reward are consistent with decreased morphine

reinforcement that has been observed in NK1R -/- mice (Ripley et al., 2002). Specifically, NK1R

-/- 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 is in part driven by

the recruitment of stress systems (for review see Specio et al., 2008, Wee et al., 2008, Wee et al.,

2009). CRH-R1 effects on drug reinforcement are only observed during such long access

sessions. However, the evidence outlined above 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 µ opioid

receptor (MOR) has been described. Specifically, co-administration of SP prevents morphine-

induced internalization and acute desensitization of the MOR (Yu et al., 2009). This was found

to result from sequestering of β-arrestin by NK1Rs, which are internalized following activation

by SP, thereby depleting the available cytoplasmic pool of β-arrestin neccessary for MOR

internalization. This in vitro effect was also observed in dissociated AMG and LC neurons,

some of which endogenously co-express NK1R and MOR. This intracellular interaction may

explain in part why the NK1R mediates reward and reinforcement for opiates, but not other

drugs. In addition, it has been reported that chronic morphine administration leads to an

upregulation of the NK1R in vitro (Wan et al., 2006), further suggesting an important functional

interaction between NK1R and MORs.

Cocaine


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Some of the earliest studies exploring the role of the NK1R in drug related behaviors

explored 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, Kraft et al., 2001b, Noailles and Angulo, 2002, Loonam et al., 2003).

However, NK1R deletion was not found to 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; see above). However, the effect of NK1R-targeted lesions of

the NAC on cocaine reward was not assessed.

When considering 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., 2013a). However, Placenza and colleagues showed that extinguished cocaine seeking can

be reinstated by infusion of specific NK1R agonists into the lateral ventricles or ventral

tegmental area (VTA; Placenza et al., 2004, Placenza et al., 2005), but found that an NK1R

specific antagonist was unable to prevent reinstatement of cocaine seeking induced by non-

contingent cocaine injection . This 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 group. We found that yohimbine-induced reinstatement of cocaine seeking is attenuated by

treatment with a specific NK1R antagonist. Yohimbine is an antagonist of alpha-2 adrenergic

autoreceptors that increases NE output and is considered to be a pharmacological stressor.


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Yohimbine injection, like intermittent footshock stress, can trigger a reactivation of drug seeking

following the 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 above.

Alcohol

In the last several years, a series of studies has indicated that the SP/NK1R system is

involved in alcohol-related behaviors. Similar to morphine, NK1R -/- 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 NK1R -/- mice was replicated by NK1R antagonist administration in wild-type C57/BL6 mice

(Thorsell et al., 2010). In this study, there appeared to be an interaction between genotype and

NK1R antagonist efficacy, with wildtype mice responding to lower doses of the antagonist than

heterozygotes. These effects did not result from off-target action of the antagonist, since NK1R -

/- mice were insensitive to its effects. Consistent with decreased alcohol consumption observed

as a result of genetic or pharmacological inhibition of the NK1R, microRNA silencing of NK1R

expression using ICV infusions also suppressed alcohol consumption in mice (Baek et al., 2010).

Thus, both pharmacological blockade of NK1Rs and transient knock-down of their expression


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mimic the effects of constitutive NK1R gene inactivation. Thorsell and colleagues (Thorsell et

al., 2010) further demonstrated that NK1R -/- mice do not escalate their voluntary alcohol

consumption following repeated cycles of deprivation, suggesting that the SP/NK1R system may

be involved in neuroadaptations that influence the development of escalated alcohol seeking.

In pharmacological studies using rats, the specific NK1R antagonist L822429 (Singewald

et al., 2008) was found to suppress stress-induced reinstatement of alcohol seeking (Schank et

al., 2011, Schank et al., 2013a). This effect was observed for reinstatement induced by both

pharmacological (yohimbine) and physical/environmental (intermittent footshock) stressors. In

these studies, L822429 was used at doses that had no effect on baseline 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 and colleagues also failed to observe a suppression of

alcohol self-administration and two bottle choice consumption in rats following NK1R

antagonism with ezlopitant, until doses were reached that also suppressed sucrose consumption,

indicating non-specific suppression on consummatory behavior at these doses (Steensland et al.,

2010). Thus, similar to the effects of CRH on alcohol consumption and the effects of NK1R

antagonists on cocaine seeking, it appears that the effects of the NK1R on operant responding for

alcohol in rats is specifically targeted to stress-elicited drug seeking.

As stated above, 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 in rodent models where increased alcohol


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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 was therefore 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 above) and attenuate escalated alcohol self-

administration in alcohol preferring (P) rats, but do not affect alcohol self-administration in non-

dependent, non-preferring rats (Thorsell et al., 2010, Schank et al., 2011, Schank et al., 2013b).

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 (msP) 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, Koob and Le Moal, 2008, Koob, 2009a, b).

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 -1372 from the transcriptional start site of


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the Tacr1 gene, while 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.

Summary

As outlined above, the NK1R system has many similarities, but also some important

differences, when compared to 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 entirely. NK1R and CRH-R1 antagonists suppress stress-

induced reinstatement of drug seeking and escalated drug self-administration 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, while CRH-R1 effects are selective for the latter. While it has not yet been

examined, it is hypothesized that NK1R antagonism would attenuate stress-induced

reinstatement of opiate seeking in operant models due to its effect on stress-induced

reinstatement for other drugs, and to its more general effects on responding for opiates. One

item which has not been discussed is drug withdrawal. CRH systems have also been


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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 non-

peptide antagonist was developed (Snider et al., 1991) and early studies focused on developing

treatments for analgesia and inflammation. Another physiological role of the NK1R is the

mediation of emesis, and the 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 largely promising results from preclinical animal studies, NK1R antagonists have

subsequently been 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) were not replicated (see for example Keller et

al., 2006). However, recent studies have suggested the possibility that NK1R antagonists may in

fact have antidepressant properties, but require near-complete receptor occupancy to reliably

produce these effects (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, while occupancy even up to 90% is ineffective (see 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


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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 above). 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 alcohol-related

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 above), 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 in 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 or not TacR1 polymorphisms (or another genetic factor) may influence the efficacy of

NK1R-based treatments, the human and animal data support the prediction that NK1R

antagonists would only be effective in a subpopulation of alcoholics: namely, those that have

increased anxiety or stress-reactivity. Attempts to target patient populations heterogeneous for


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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 again highlight the fact that NK1R antagonists specifically mediate

stress-elicited drug seeking for most drugs of abuse studied in preclinical settings. While 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

explored the effect of the NK1R antagonist serlopitant on alcohol consumption, but was

terminated prematurely and thus conclusions cannot be drawn from this study. Ultimately, it

may be that NK1R antagonists will serve as useful medications when given in combination with

a drug that acts on other facets of the addictive process, such as naltrexone. Naltrexone has been

shown to have 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 (mentioned above). 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


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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, there are several NK1R antagonists that have been developed by the pharmaceutical

industry and tested for efficacy in mood and anxiety disorders and alcohol cravings in humans

(see above). 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.

This suggests 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 to this 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


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with increased risk of stress-induced relapse in abstinent cocaine addicts, but this also has not

been examined clinically.

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 potent NK1R antagonists will likely stimulate a

reimagining of the pharmaceutical utility of this class of drugs, and will hopefully 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.

Acknowledgements

The author would like to acknowledge valuable comments provided by Dr. Markus Heilig

(NIAAA, Bethesda, Maryland) in the revision of this manuscript.

Authorship

JRS is fully responsible for the writing of this manuscript.


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Table 1

Summary of effects of NK1R inhibition on drug-related behaviors. The two bottom rows that

are shaded in gray 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.

*Experiment performed in high alcohol consuming C57/BL6 mouse strain.

Effect of NK1R inhibition Cocaine Ethanol Opiates

Baseline Self-administration No Effect No Effect ↓

Conditioned Place Preference (mouse) No Effect ↓* ↓

Drug-primed Reinstatement No Effect ? ?

Locomotor Sensitization No Effect ? ↓

Cue-induced Reinstatement ? No Effect ?

Stress-induced Reinstatement ↓ ↓ ?

Escalated Self-administration ? ↓ ↓


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