Neurokinin-1 receptors (NK1R:s), alcohol consumption, and alcohol reward in mice

Thorsell, Annika; Schank, Jesse R.; Singley, Erick; Hunt, Stephen P.; Heilig, Markus

doi:10.1007/s00213-010-1775-1

Cited by 55 publications

(63 citation statements)

References 55 publications

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“…For example, NK1R À / À mice consume less alcohol in a two-bottle free-choice paradigm, and do not exhibit alcohol CPP (George et al, 2008;Thorsell et al, 2010). The decreased alcohol consumption and reward found in NK1R-null mutants is unlikely to be the result of compensatory developmental processes caused by constitutive gene deletion because these behavioral effects were replicated by NK1R antagonist administration in wildtype animals (Thorsell et al, 2010). Taken together, these observations have provided support for the hypothesis that NK1R antagonism may have utility as a pharmacotherapy for alcoholism.…”

Section: Introductionmentioning

confidence: 99%

The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement

Barbier

Vendruscolo

Schlosburg

et al. 2012

Neuropsychopharmacol

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Genetic deletion of the neurokinin 1 receptor (NK1R) has been shown to decrease the reinforcing properties of opioids, but it is unknown whether pharmacological NK1R blockade has the same effect. Here, we examined the effect of L822429, a rat-specific NK1R antagonist, on the reinforcing properties of heroin in rats on short (1 h: ShA) or long (12 h: LgA) access to intravenous heroin selfadministration. ShA produces heroin self-administration rates that are stable over time, whereas LgA leads to an escalation of heroin intake thought to model important dependence-related aspects of addiction. L822429 reduced heroin self-administration and the motivation to consume heroin, measured using a progressive-ratio schedule, in both ShA and LgA rats. L822429 also decreased anxietylike behavior in both groups, measured on the elevated plus maze, but did not affect mechanical hypersensitivity observed in LgA rats. Expression of TacR1 (the gene encoding NK1R) was decreased in reward-and stress-related brain areas both in ShA and LgA rats compared with heroin-naïve rats, but did not differ between the two heroin-experienced groups. In contrast, passive exposure to heroin produced increases in TacR1 expression in the prefrontal cortex and nucleus accumbens. Taken together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with ShA and LgA to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from LgA self-administration. Instead, the NK1R antagonist appears to attenuate acute, positively reinforcing properties of heroin and may be useful as an adjunct to relapse prevention in detoxified opioid-dependent subjects.

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Section: Introductionmentioning

confidence: 99%

The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement

Barbier

Vendruscolo

Schlosburg

et al. 2012

Neuropsychopharmacol

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“…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 2/2 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.…”

Section: Preclinical Findings In Rodent Models Of Drug Addictionmentioning

confidence: 53%

“…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 NK1R 2/2 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.…”

Section: Preclinical Findings In Rodent Models Of Drug Addictionmentioning

confidence: 94%

“…In the last several years, a series of studies has indicated that the SP/NK1R system is involved in alcoholrelated behaviors. Similar to morphine, NK1R 2/2 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).…”

Section: Preclinical Findings In Rodent Models Of Drug Addictionmentioning

confidence: 99%

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The Neurokinin-1 Receptor in Addictive Processes

Schank

2014

J Pharmacol Exp Ther

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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.

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“…Furthermore, in healthy young men infusion of SP caused an anxiogenic and memorydisturbing effect (Herpfer et al 2007). On the other hand, mice genetically deficient in NK1R displayed suppressed alcohol consumption (George et al 2008;Thorsell et al 2010) and disrupted behaviors associated with morphine reward (Gadd et al 2003). Furthermore, systemic application of an NK1R antagonist into mice with high anxiety-related behavior as well as microinjection of an NK1R antagonist into the amygdala of gerbils caused anxiolytic-like effects (Heldt et al 2009;Sartori et al 2011).…”

Section: Possible Synaptic Network Correlates and Functional Significmentioning

confidence: 99%

Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation

Sosulina

Strippel

Romo-Parra

et al. 2015

Journal of Neurophysiology

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HC. Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation. J Neurophysiol 114: 2500 -2508, 2015. First published September 2, 2015; doi:10.1152/jn.00883.2014.-Substance P (SP) is implicated in stress regulation and affective and anxiety-related behavior. Particularly high expression has been found in the main output region of the amygdala complex, the central amygdala (CE). Here we investigated the cellular mechanisms of SP in CE in vitro, taking advantage of glutamic acid decarboxylase-green fluorescent protein (GAD67-GFP) knockin mice that yield a reliable labeling of GABAergic neurons, which comprise 95% of the neuronal population in the lateral section of CE (CEl). In GFP-positive neurons within CEl, SP caused a membrane depolarization and increase in input resistance, associated with an increase in action potential firing frequency. Under voltage-clamp conditions, the SP-specific membrane current reversed at Ϫ101.5 Ϯ 2.8 mV and displayed inwardly rectifying properties indicative of a membrane K ϩ conductance. Moreover, SP responses were blocked by the neurokinin type 1 receptor (NK1R) antagonist L-822429 and mimicked by the NK1R agonist [Sar 9 ,Met(O 2 ) 11 ]-SP. Immunofluorescence staining confirmed localization of NK1R in GFP-positive neurons in CEl, predominantly in PKC␦-negative neurons (80%) and in few PKC␦-positive neurons (17%). Differences in SP responses were not observed between the major types of CEl neurons (late firing, regular spiking, low-threshold bursting). In addition, SP increased the frequency and amplitude of GABAergic synaptic events in CEl neurons depending on upstream spike activity. These data indicate a NK1R-mediated increase in excitability and GABAergic activity in CEl neurons, which seems to mostly involve the PKC␦-negative subpopulation. This influence can be assumed to increase reciprocal interactions between CElon and CEloff pathways, thereby boosting the medial CE (CEm) output pathway and contributing to the anxiogenic-like action of SP in the amygdala. substance P; central amygdala; neurokinin type 1 receptor; PKC␦

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Neurokinin-1 receptors (NK1R:s), alcohol consumption, and alcohol reward in mice

Cited by 55 publications

References 55 publications

The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement

The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement

The Neurokinin-1 Receptor in Addictive Processes

Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation

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