The data discussed in this chapter is suggestive of a direct involvement of the ORX/HCRT system in response to morphine. However, a number of critical questions remain with regard to the role of ORX/HCRT neuropeptides in drug addiction. First, it should be emphasized that the above studies focus on morphine dependence and do not evaluate the role of ORX/HCRT in the reinforcing properties of drugs of abuse. Studies using conditioned place preference, or drug self-administration are needed to garner a more complete picture of the role of ORX/HCRT in addiction.
Nonetheless, the development of physical dependence is an important component of drug addiction. Koob and colleagues have proposed that negative physical and emotional states are the critical components that drive addiction.45 Thus, it is essential to define the molecular adaptations that lead to dependence and the development of negative states since they represent potential targets for treatment of drug addiction. The development and application of ORX/HCRT receptor antagonists46,47 will make it possible to test the effects of pharmacological blockage on morphine dependence and withdrawal.
11.1. Is ORX/HCRT Essential for the Development of Dependence and/or the Expression of Withdrawal?
Since the ORX/HCRT mutant mice lack gene function during both the chronic morphine exposure as well as the withdrawal phase, it is difficult to discern whether the neuropeptide is necessary for the development of drug dependence. It is possible that ORX/HCRT plays a role in both the development of dependence as well as the expression of physical withdrawal signs. In fact, our molecular experiments suggest that the ORX/HCRT neurons are modulated during both chronic morphine exposure (CRE-LacZ induction) as well as during withdrawal (c-Fos induction). However, it is not possible to conclude on the basis of this data that ORX/HCRT has a function in both the development of dependence and expression of withdrawal. Studies aimed at addressing this question require analysis of ORX/HCRT function during drug exposure or withdrawal only.
12. ORX/HCRT RECEPTORS AND NEURAL CIRCUITS RELEVANT TO ADDICTION
While other hypothalamic peptides have been studied for their role in addiction behavior and physiology (e.g. see refs 48,49-51), the ORX/HCRT neuropeptides exhibit several distinct characteristics. First, ORX/HCRT is expressed solely in the lateral hypothalamic region, an area implicated in reward and drug-related behaviors, but whose molecular effectors have remained unidentified. Second, neurons expressing ORX/HCRT have extensive projections to, and corresponding receptor expression within, the mesolimbic dopamine and noradrenergic (LC) pathways. This suggests multiple possible connections between the LH and regions well-studied regions for their role in drug addiction.
12.1. What Brain Regions are the Critical ORX/HCRT Targets?
The two ORX/HCRT receptors, OxR1 and OxR2, are expressed in distinct patterns in the adult brain,52,53 and both are GPCRs; OxR1 appears to signal through Gq while OxR2 can couple to Gi/Go as well as Gq subunits.16,54 ORX/HCRTs stimulate neuronal activity at target sites by raising cytoplasmic Ca2+ levels postsynaptically.54 Interestingly, ORX/HCRT receptors are expressed at high levels in the ventral tegmental area (VTA) and the locus coeruleus (LC)52,53 and ORX/HCRT can activate neurons in both regions.55-59 The LC regulates alertness and vigilance, and is known to undergo dramatic molecular responses to chronic opiates and withdrawal.60,61 In the LC, the neuronal responses are mediated largely via OxR1,62 while the primary receptor remains untested at most other target sites. In addition, ORX/HCRTs have been shown to inhibit nucleus accumbens neurons,63 indicating that the relationship between ORX/HCRT and neuronal response may be complex and site-specific.
There are, therefore, multiple potential connections between LH ORX/HCRT systems and drug-regulated neural circuitry. ORX/HCRT-OxR pathways modulate the activity of VTA and NAc neurons, potentially altering both ends of the mesolimbic reward pathway, while also playing a role in LC neuron excitability that may influence components of opiate withdrawal. These molecular connections provide a potential link between the classical substrates of brain stimulation reward and the well-studied neural and molecular circuitry of drug reward. Future studies are needed to better define the relevant neural circuits by which ORX/HCRT modulates morphine dependence and withdrawal.
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