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Orexin Receptors in Addiction
Collaboration with Bonci Lab
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.

Role for Orexin Receptors in Alcohol Drinking and Relapse
Activation of lateral hypothalamic orexin neurons is strongly linked to preferences for cues associated with drug and food reward and is able to reinstate an extinguished drug-seeking behavior (Harris et al. 2005).  Recently, research in the Bonci and Fields laboratories at the Gallo Center has shown that orexin A induces potentiation of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission via a PLC/PKC-dependent insertion of NMDARs in VTA dopamine neuron synapses (Borgland et al. 2006).  Furthermore, in vivo administration of an orexin A receptor antagonist blocks locomotor sensitization to cocaine and occludes cocaine-induced potentiation of excitatory currents in VTA dopamine neurons (Borgland et al. 2006).  These results provide in vitro and in vivo evidence for a critical role of orexin signaling in the VTA in neural plasticity relevant to addiction.  This suggests that orexin may play a significant role in stress-induced relapse to drug seeking in drug-experienced animals.  There have been a number of studies showing the role of orexin receptors in cocaine and morphine mediated behaviors, but there is little evidence investigating the role of the orexin receptors in ethanol-mediated behaviors.  Stressors enhance addictive behaviors and are a common cause of relapse drinking (for reviews see Sarnyai et al. 2001; Shalev et al. 2002).  Orexin has been shown to induce various behavioral changes related to adaptation to stress and has also been shown to play a key role in stress-induced reinstatement of cocaine seeking (Harris et al. 2005).  We hypothesize that orexin bound to the orexin-A receptor contributes to stress-induced relapse to alcohol seeking in alcohol-experienced animals.  Therefore, the aim of this project is to determine the role of orexin-A and orexin-A receptors in the development of alcohol dependence and relapse using rodent models of drinking.