Hypocretin Antagonists as a Novel Approach to Medication Development

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DESCRIPTION (provided by applicant): The neuropeptides hypocretin-1 and -2 (de Lecea et al., 1998) also known as orexin-A and -B (Sakurai et al., 1998) derive from the lateral hypothalamus and project throughout the brain. Hypocretin plays a role in modulating arousal, foraging for food in rodents, the response to stress, and learning and memory. Hypocretins also play a role in drug-reinforced behavior by modulating 1) the salience of stimuli paired with drug, as assessed using condition-place preference models, 2) the magnitude of response to drug following repeated dosing, i.e., sensitization, and 3) the ability of environmental cues and stress to elicit reinstatement in relapse models. These data suggest that hypocretin-mediated arousal has motivating effects and increases the salience of cues associated with reinforcement. Given the societal problems of eating disorders and cocaine- dependence, a carefully controlled assessment of the influence of hypocretin agonists and antagonists on cocaine- and food-seeking and self-administration in non-human primates is highly significant. Aim 1a: Determine the effects of a hypocretin-1 antagonist, and agonist and agonist/antagonist combinations on the appetitive and consummatory aspects of responding for banana-flavored food pellets by 6 rhesus monkeys. Acute i.v. insulin administration causes a rapid drop in glucose levels an increase in cFos activation in hypothalamic hypocretin neurons and cortisol. We will use insulin infusions to naturally increase hypocretin activity. Aim 1b: Determine the effects of insulin-induced hypocretin activation on hypocretin levels, the appetitive and consummatory aspects of responding for banana-flavored food pellets, and if the effects can be attenuated by a hypocretin-1 antagonist. Aim 2: Determine the effects of a hypocretin-1 antagonist and agonist and agonist/antagonist combinations on the appetitive and consummatory aspects of cocaine self-administration and responding for candy by rhesus monkeys, and determine if the effects of a stressor can be attenuated by a hypocretin-1 antagonist. Our second goal is to examine the effects of hypocretin manipulations on reinstatement of responding reinforced by cocaine and candy. We will use a choice procedure in which monkeys choose to take candy or self-administer cocaine. Aim 3: Determine if a hypocretin-1 antagonist can block reinstatement of responding previously reinforced with cocaine or candy in rhesus monkeys induced by 1) a hypocretin-1 agonist; 2) insulin-induced hypocretin activation; 3) cues paired with the commodity; and 4) the commodity itself. A choice procedure will allow us to demonstrate the selectivity of reinstatement blockade by the antagonist. Impact: Because the hypocretin system plays a complex modulatory role in a wide range of behaviors, we believe that this 2-step approach of first analyzing non-specific, incentive effects of hypocretin manipulations and then the specific effects of a hypocretin antagonist on drug reinstatement will provide the basis for using hypocretins as a novel therapeutic approach for drug abuse, as well as eating disorders.