| Abstract No.: | B-G2203 |
| Country: | Canada |
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| Title: | OREXIN A/HYPOCRETIN 1 PROMOTES INCENTIVE MOTIVATION SELECTIVELY FOR HIGHLY SALIENT APPETITIVE STIMULI. |
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| Authors/Affiliations: | 2 Stephanie Borgland*; 1 Shao-Ju Chang; 1 Scott Bowers; 1 Billy Chen; 1 Jonathan Chou; 1 Antonello Bonci;
1 Ernest Gallo Clinic & Research Center at UCSF, Emeryville, USA; 2 University of British Columbia, Vancouver, BC, Canada
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| Content: | Objective: The ventral tegmental area (VTA) is an important brain structure for relaying salient information. However, currently there is debate about whether dopamine release occurs selectively from positive reward or from salient stimuli that could be of either positive or negative valence. Although recent studies have highlighted the role of orexin A (hypocretin-1; oxA/hcrt-1) as a powerful modulator of dopamine neuronal activity and dopamine-dependent behaviors, its role in driving motivated behaviors is poorly understood. Therefore, we tested if orexin A signalling was involved in motivation for cocaine, regular food and highly palatable high fat chocolate self-administration.
Materials and methods: After rats were trained to self-administer reinforcers on a fixed ratio schedule. Once stably pressing, rats were switched to four consecutive days of progressive ratio testing, whereby the response requirements to earn a drug injection or food pellet escalate after the delivery of each reinforcer. The final successfully completed ratio to obtain the reinforcer is defined as the breakpoint. In a separate group of rats, we examined the effects of orexin A on excitatory synaptic transmission in VTA dopamine neurons using patch clamp electrophysiology in animals that had self-administered cocaine, food, or high fat food under a fixed ratio schedule or received 7 days of food shocks.
Results: We show that orexin receptor 1 (OXR1) signalling is important for incentive motivation specifically for highly salient reinforcers, as blockade of OXR1 selectively reduced the breakpoint in cocaine or high fat food self-administering rats, but not regular food. Furthermore, oxA/hcrt-1 signaling increased presynaptic glutamatergic inputs to the VTA selectively in cocaine or high fat self- administering animals. Finally, oxA/hcrt-1-mediated glutamatergic synaptic transmission was potentiated only by highly salient appetitive reinforcers, as footshock stress, an arousing aversive stimulus, did not potentiate oxA/hcrt-1-mediated excitatory synaptic transmission in VTA dopamine neurons.
Conclusion: These experiments provide evidence for a critical, selective role of oxA/hcrt-1 signalling in incentive motivation for highly salient rewards such as cocaine and high fat chocolate food. This selectively heightened oxA/hcrt1 signaling by cocaine or high fat food may represent a unique opportunity to design novel drugs to reduce OXR1 activity, and thus selectively reduce excessive drive to consume highly salient rewards.
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