Article

Lack of self-administration and behavioural sensitisation to morphine, but not cocaine, in mice lacking NK1 receptors

Laboratory of Experimental Psychology, University of Sussex, Falmer, BN1 9QG, Brighton, UK.
Neuropharmacology (Impact Factor: 4.82). 01/2003; 43(8):1258-68. DOI: 10.1016/S0028-3908(02)00295-2
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ABSTRACT Mice lacking the NK1 receptor, the preferred receptor for substance P, demonstrate normal analgesic responses to morphine on the hot plate assay, but have been predicted, on the basis of conditioned place preference studies, to be insensitive to the rewarding properties of opiates. In this study, self-administration and the development and maintenance of locomotor sensitisation of both morphine and cocaine were investigated in mice that lacked the NK1 gene (NK1 knockout mice, NK1(-/-)). Both wildtype and NK1(-/-) mice learned an operant lever-press response to obtain food. When intravenous infusions of morphine (0.2 mg/kg/infusion) were substituted for the food reward, the wildtype mice initially reduced rates of lever pressing, but then increased them on the rewarded lever to obtain approx. 10 infusions per 90 min session; in contrast, NK1(-/-) mice continued to operate both the rewarded, and non-rewarded levers at low rates. Additionally, NK1(-/-) mice failed, following repeated administration, to sensitise to the locomotor stimulant effects of morphine (15 mg/kg, i.p.). These deficits were specific to opiates, since NK1(-/-) mice responding for food or cocaine self-administration (0.65 mg/kg/infusion) did not differ from wildtypes, and they showed normal behavioural sensitisation to repeated cocaine administration (10 mg/kg, i.p.). These results demonstrate that NK1 receptors are critical for the reinforcing properties of morphine, and for adaptive responses elicited by repeated opiate administration. It is postulated that substance P and the NK1 receptor may be necessary for the development of opiate, but not cocaine addiction.

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    • "Initial findings indicated a selective role of NK1Rs in opioid reward and self-administration, in that neither CPP for cocaine (Murtra et al, 2000) nor self-administration of this drug (Ripley et al, 2002) were affected by a genetic deletion of the NK1R. More recently, however, data have also emerged in support of a role for NK1Rs in the rewarding properties of alcohol. "
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    ABSTRACT: 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 self-administration. 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 anxiety-like 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 to 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. Together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with short and long access to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from long access 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.Neuropsychopharmacology accepted article preview online, 18 December 2012; doi:10.1038/npp.2012.261.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2012; 38(6). DOI:10.1038/npp.2012.261 · 7.83 Impact Factor
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    • "Furthermore, this effect of SP was reported to occlude the actions of cocaine (Kombian et al., 2009). Although chronic SP administration has been reported to produce certain behavioral modifications (Hasenohrl et al., 1992; Krappmann et al., 1994), and mice lacking the NK1 receptor gene failed to show cocaine-induced reward and locomotor behavior (Murtra et al., 2000; Ripley et al., 2002), the question is whether SP can by itself induce behavioral sensitization similar to cocaine or interact with cocaine-induced behavioral sensitization and the accompanying plasticity in excitatory synaptic transmission. Given the reported interaction between cocaine and SP (Kraft et al., 2001a,b), we tested the hypothesis that SP can cause hyperlocomotion in rats and induce behavioral sensitization and the accompanying changes in excitatory synaptic transmission as those seen using cocaine. "
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    ABSTRACT: Substance P (SP) and cocaine employ similar mechanisms to modify excitatory synaptic transmission in the nucleus accumbens (NAc), a region implicated in substance abuse. Here we explored, using NAc slices, whether SP effects on these synaptic responses were altered in rats that have been sensitized to cocaine and whether SP could mimic cocaine in triggering increased locomotion in sensitized rats. Intraperitoneal (IP) injection of naïve rats with cocaine (15 mg/kg) caused increased locomotion by 408.5 ± 85.9% (n = 5) which further increased by 733.1 ± 157.8% (n = 5) following a week of cocaine sensitization. A similar challenge with 10 mg/kg of SP after cocaine sensitization did not produce significant changes in locomotion (170.6 ± 61.0%; n = 4). In contrast to cocaine, IP injection of rats with SP or SP(5-11) (10-100 mg/kg) with or without phosphoramidon did not elicit changes in locomotion. In electrophysiological studies, both cocaine and SP depressed evoked NMDA and non-NMDA receptor-mediated excitatory synaptic currents (EPSCs) in slices obtained from naïve rats. In slices derived from cocaine-sensitized rats, cocaine but not SP produced a more profound decrease in non-NMDA compared to NMDA responses. Similar to that in naïve rats, cocaine's effect on the EPSCs in these sensitized rats occluded those of SP. Thus, although SP and cocaine may employ similar mechanisms to depress EPSCs in the NAc, IP injection of SP does not mimic cocaine-induced hyperlocomotion indicating that not all of cocaine's effects are mimicked by SP. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
    Neuropharmacology 09/2011; 62(2):825-32. DOI:10.1016/j.neuropharm.2011.09.008 · 4.82 Impact Factor
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    • "However, animals lacking NK1R display no difference in CPP or the self-administration of cocaine (Gadd et al. 2003; Murtra et al. 2000) or food reinforcers (Murtra et al. 2000), suggesting that the observed reward deficits are specific to opioids. In addition, these mice are less sensitive to the locomotor-stimulating effects of morphine and fail to display behavioral sensitization to morphine, but not cocaine (Ripley et al. 2002). Blockade of NK1 receptors could be one approach to limiting the rewarding and reinforcing effects of morphine. "
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    ABSTRACT: The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists. This study was conducted to measure the effects of opioid and NK1R blockade on the potentiation of brain stimulation reward (BSR) by morphine using the intracranial self-stimulation method. Adult male C57BL/6J mice (n = 15) were implanted with unipolar stimulating electrodes in the lateral hypothalamus and trained to respond for varying frequencies of rewarding electrical stimulation. The BSR threshold (θ(0)) and maximum response rate (MAX) were determined before and after intraperitoneal administration of saline, morphine (1.0-17.0 mg/kg), or the NK1R antagonists L-733,060 (1.0-17.0 mg/kg) and L-703,606 (1.0-17.0 mg/kg). In morphine antagonism experiments, naltrexone (0.1-1.0 mg/kg) or 10.0 mg/kg L-733,060 or L-703,606 was administered 15 min before morphine (1.0-10.0 mg/kg) or saline. Morphine dose-dependently decreased θ(0) (maximum effect = 62% of baseline) and altered MAX when compared to saline. L-703,606 and L-733,060 altered θ(0); 10.0 mg/kg L-733,060 and L-703,606, which did not affect θ(0) or MAX, attenuated the effects of 3.0 and 10.0 mg/kg morphine, and 1.0 and 0.3 mg/kg naltrexone blocked the effects of 10.0 mg/kg morphine. Naltrexone given before saline did not affect θ(0) or MAX. The decrease in θ(0) by morphine reflects its rewarding effects, which were attenuated by NK1R and opioid receptor blockade. These results demonstrate the importance of substance P signaling during limbic reward system activation by opioids.
    Psychopharmacology 09/2011; 220(1):215-24. DOI:10.1007/s00213-011-2469-z · 3.99 Impact Factor
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