Manipulations of the SP/NK1R system have been shown to influence several addiction-related GDC0199 behaviors. For example, NK1R knockout mice do not display morphine-CPP and self-administer morphine at lower rates. Morphine-induced locomotor activation

and psychomotor sensitization are also blunted in these mice (Murtra et al., 2000; Ripley et al., 2002). Lesions of NK1R-containing neurons in the AMG, but not NAC, suppressed morphine-induced CPP, a finding suggesting that NK1Rs in the AMG contribute to rewarding properties of morphine (Gadd et al., 2003). Reduced opioid reward after NK1R blockade was recently also supported by observations that this treatment attenuates the ability of morphine to lower intracranial self-stimulation thresholds (Robinson et al., 2012). Coadministration of SP and morphine prevents the internalization and acute desensitization of the mu opioid receptor typically induced by morphine, which may account for the involvement of the NK1R in opioid reward (Yu et al., 2009). These data collectively support a role of NK1R activation in rewarding properties of opioids and suggest the possibility that NK1R antagonists may be useful for the treatment of opioid addiction through blockade of opioid reward. Surprisingly,

however, an initial human laboratory study found that a single administration of the NK1R antagonist aprepitant potentiated, rather than inhibited, subjective as well as physiologic responses to an opioid challenge in prescription opioid abusers (Walsh et al., 2012). A direct assessment of opioid self-administration after NK1R blockade is therefore critical but has to date not been obtained in laboratory animals or humans. Furthermore, the Selleck LDN 193189 role of the NK1R in opioid-related behaviors influenced by stress, for example, stress-induced reinstatement of opioid seeking after extinction, has not been explored. In contrast to its role in opioid-related behaviors, disruption of NK1R signaling does not affect cocaine CPP, self-administration, or locomotor sensitization (Gadd et al., 2003; Murtra et al., 2000; Ripley et al., 2002). However, there is some evidence that NK1R antagonists tuclazepam can suppress

cocaine-induced locomotion (Kraft et al., 2001) and that relapse to cocaine seeking after extinction can be triggered by ICV infusion of a specific NK1R agonist (Placenza et al., 2005) or intra-VTA infusion of an SP analog (Placenza et al., 2004). However, an NK1R specific antagonist was unable to prevent reinstatement of cocaine seeking induced by cocaine priming (Placenza et al., 2005). One possibility is therefore that exogenous SP is able to activate pathways involved in reinstatement of cocaine seeking, but that this does not reflect actions of endogenous SP. Alternatively, cocaine-induced reinstatement may be mediated by an NK receptor other than NK1R, such as NK3R. Finally, it is possible that the NK1R is involved in reinstatement of cocaine seeking triggered by some stimuli, but not that induced by drug priming.