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The Role of NK1 Receptors in Addiction

Biological activities of neurokinins, including substance P, are mediated via neurokinin (NK) receptors.  These receptors are divided into at least three types, NK1, NK2 and NK3, all of which are G-protein linked, with species homologues for each receptor type (Maggi 1995).  Substance P is the preferred binding ligand for NK1 receptors, NKA for NK2 receptors and NKB for NK3 receptors, although they do not act as exclusive agonists for the respective receptors.

Substance P was the first neuropeptide to be discovered and was recognized as a sensory neurotransmitter.  Substance P is commonly found in C-fiber sensory nerves and is well known for a wide range of peripheral and central activities that include inflammation, pain, emesis, anxiety, depression and addiction.  Activation of the NK1 receptor is thought to contribute to the motivational aspects of the rewarding properties of morphine but not cocaine (Murtra et al. 2000; Gadd et al. 2003).  Mice lacking the NK1 receptor (NK1-/-) do not show behaviors associated with morphine reward (Ripley et al. 2002; Gadd et al. 2003).  Substance P and the NK1 receptor are expressed in many areas of the brain involved in affective behaviors, including the hypothalamus, amygdala, and nucleus accumbens.  Recent work has provided evidence that NK1-/- mice are insensitive to opiates in models of drug abuse (Murtra et al. 2000;Ripley et al. 2002). For example, NK1-/- mice fail to develop a preference using the conditioned place preference paradigm and also self-administer morphine at lower levels than wild-type controls (Ripley et al. 2002).  These effects are specific to opioids as behaviors associated with cocaine are unaffected.  An intriguing finding is that the analgesic properties of morphine are not impaired in the NK1-/- mice despite the loss of the rewarding and addictive properties of morphine indicating that the NK1 receptor is not critically involved in opioid analgesia (De Felipe et al. 1998).  These results therefore suggest that the NK1 receptor plays a critical and specific role in the motivational, but not analgesic, properties of opiates.

NK1 Receptors in Alcohol Consumption and Relapse
Ethanol exposure in adult rats has been shown to significantly increase levels of substance P immunoreactivity in the caudate (Thorsell et al. 2005) and NK1-/- mice have reduced ethanol preference using a two bottle choice drinking paradigm (Pastor et al. 2005).  It has also been shown that NK3 receptor specific agonists markedly suppress alcohol intake in rats offered both water and 8% ethanol (2 h/day), while the NK1 selective agonist substance P and the NK2 selective agonist GR 64349 did not (Ciccocioppo et al. 1994).  We have generated preliminary data suggesting the NK1 antagonist LY303870 causes a long lasting decrease in ethanol consumption.  This specific antagonist has a relatively low affinity for the NK1 receptor (Iyengar et al. 1997) and poor blood brain barrier penetration, suggesting that its effects may be predominantly associated with inhibition of NK1 receptors in the peripheral nervous system (Olive and Whistler 2003). However, the fact that the NK1-/- mice have reduced ethanol preference using a 2 bottle choice drinking paradigm (Pastor et al. 2005) suggests that this may be a good target for the modulation of ethanol-mediated behaviors.  There are currently few studies addressing the role of substance P and the NK1 receptor in mediating the addictive properties of ethanol.  We are investigating whether ethanol-mediated behaviors are modulated by substance P interacting with NK1 receptors. Our methodology for achieving this involves further validating and extending our preliminary findings to examine the role of substance P and NK1 receptors in the central nervous system to determine their respective roles in ethanol-mediated reward pathways using an array of preclinical models of drinking.

NK1 Receptors in Phase II human Clinical Trials
Compounds targeting the NK1 receptor have been developed for a number of indications including anxiety, depression and emesis.  At least two NK1 receptor antagonists (aprepitant and L-759274) have been shown to have significant beneficial effects in placebo-controlled clinical trials of patients with moderate and severe depression (Kramer et al. 2004). The incidence of side effects is low indicating an important therapeutic potential of these compounds. However, the first registered clinical use for NK1 receptor antagonists has been found in the treatment of emesis, associated with cancer therapies, following results in animal models, involving NK1 receptors in emesis (Chawla et al. 2003).  If the experiments we are conducting validate the role of the NK1 receptor in alcohol consumption and/or self administration and reinstatement, then we will identify partners in industry willing to collaborate to test their Phase II NK1 receptor antagonist compounds in “proof of concept” small scale human clinical trials.