Ernest Gallo Clinic and Research Center       At the University of California, San Francisco
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Preclinical Development Projects

Orexin-1 Receptors in Relapse Prevention

Orexin-A is a hypothalamic peptide that acts via orexin type 1 receptors (OX-A). The most widely studied biological functions of orexins are the central control of feeding and sleep; however, in the past few years, there have been findings that the orexin system modulates the hypothalamic-pituitary-adrenal (HPA) axis, acting on both its central and peripheral branches (for review see Spinazzi et al. 2006). Orexin (OX) plays an important role in mediating behaviors such as motivational drive produced by drugs of abuse such as cocaine, morphine, and nicotine (DiLeone et al. 2003; Paneda et al. 2005; Harris et al. 2005; Borgland et al. 2006; Pasumarthi et al. 2006). In the central nervous system, OX-A is expressed in the lateral hypothalamus (LH) and orexin-containing neurons project throughout the brain, with a prominent input to basal forebrain structures involved in motivation, reward, and stress. In addition, neurons expressing these neuropeptides have extensive projections to regions of the brain important for behavioral responses to drugs of abuse, such as dopamine neurons of the ventral tegmental area (VTA), raising the possibility that these pathways may also be important in addiction. Further, the extrahypothalamic distribution of OX-A parallels its involvement in affective behavioral responses to stress. For example, OX-induced reinstatement of cocaine seeking was prevented by blockade of noradrenergic and corticotropin-releasing factor systems, suggesting that orexin-A reinstated drug seeking through induction of a stress-like state (Boutrel et al. 2005).  Extensive coexpression of tyrosine hydroxylase, a marker for dopamine neurons, with orexin receptors has been observed in the mouse VTA (Narita et al. 2006). An intra-VTA injection of a selective orexin receptor antagonist, SB334867, significantly suppressed morphine-induced place preference in rats (Narita et al. 2006). These findings provide new evidence that orexin A-containing neurons overlap with VTA dopamine neurons and are implicated in behaviors associated with substance abuse.

Delta Opioid Receptors in Ethanol Consumption

The non-selective opioid antagonist naltrexone has been previously shown to reduce ethanol consumption in humans (O'Malley et al. 2002; Volpicelli et al. 1992) and animals (Critcher et al. 1983; Ulm et al. 1995; Gardell et al. 1996; Rodefer et al. 1999; Stromberg et al. 2002; Becker et al. 2002; Roberts et al. 2000), and has since been approved and marketed for the treatment of alcohol dependence in humans. However, recent reports have indicated that naltrexone appears to have limited therapeutic success (Swift 1999; Bouza et al. 2004), which may result from compliance issues arising from possible side-effects such as nausea, vomiting, or headache, and possible hepatotoxicity with higher doses (Volpicelli et al. 1992; Croop et al. 1997; Hartmann 1997). Previous studies indicate that mu opioid (MOP), delta opioid (DOP), and kappa opioid (KOP) receptors are involved in different aspects of ethanol-mediated behaviors (Matsuzawa et al. 1999; Hyytia and Kiianmaa 2001; Margolis et al. 2003; Mitchell et al. 2005). Results from many laboratories suggest that the MOP receptor mediates the rewarding properties of ethanol during ethanol consumption and relapse in both rats and mice behaviors (Matsuzawa et al. 1999; Hyytia and Kiianmaa 2001; Margolis et al. 2003; Mitchell et al. 2005). In contrast, data surrounding the DOP and KOP receptors is not as conclusive.

CRF-BP in Alcohol Dependence

Military women and men are subject to a wide range of additional stressors as part of their military duties.  Exposure to traumatic stressors has been strongly implicated in the elevated rates of substance abuse and dependence among veterans, and substance abuse has been found to be highly co-morbid with post-traumatic stress disorder (McFall et al. 1992). There is also accumulating scientific evidence showing stressors enhance addictive behaviors and are a common cause of relapse drinking (for reviews see Sarnyai et al. 2001; Shalev et al. 2002). One of the most difficult aspects of treating alcohol dependence is the relapse to uncontrolled drinking that frequently occurs after a period of abstinence. Factors such as stress and exposure to situations previously associated with alcohol drinking (referred to as "cues") are found to contribute to relapse drinking. Corticotrophin releasing factor (CRF) is a 41-amino acid peptide that has been shown to induce various behavioral changes related to adaptation to stress. CRF has also been shown to play a key role in stress-induced reinstatement of alcohol and cocaine seeking. The CRF system, including the CRF-binding protein (CRF-BP), and the CRF receptors CRF-R1 and CRF-R2, is thought to contribute in different ways to the physiological adaptations that result from stress. The main goal of this project is to determine the role of CRF-BP, a protein that binds CRF, in the development of alcohol dependence and relapse using rodent models of drinking.

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). Therefore, these results suggest that the NK1 receptor plays a critical and specific role in the motivational, but not analgesic, properties of opiates.

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