Orexin A/hypocretin-1 (oxA/hcrt-1) is known to be a modulator of dopamine-dependent neuronal activity and behaviors. However, the role of this system in driving motivated behaviors remains poorly understood. Here, we show that orexin/hypocretin receptor-1 (ox/hcrt-1R) signaling is important for motivation for highly salient, positive reinforcement. Blockade of ox/hcrt-1R selectively reduced work to self-administer cocaine or high fat food pellets. Moreover, oxA/hcrt-1 strengthened presynaptic glutamatergic inputs to the ventral tegmental area (VTA) only in cocaine or high fat self-administering rats. Finally, oxA/hcrt-1-mediated excitatory synaptic transmission onto VTA neurons was not potentiated following an arousing, aversive stimulus, suggesting that oxA/hcrt-1-mediated glutamatergic synaptic transmission was potentiated selectively with highly salient positive reinforcers. These experiments provide evidence for a selective role of oxA/hcrt-1 signaling in motivation for highly salient reinforcers and may represent a unique opportunity to design novel therapies that selectively reduce excessive drive to consume positive reinforcers of high salience.

Measurement of the surface area of airborne nanoparticles as administered to an experimental subject is critical for characterizing exposures during inhalation experiments. A filter-based surface area measurement methodology is described herein that allows for such determinations. Krypton gas adsorption was used to determine total particle surface area. Track-etched polycarbonate 0.4 μm pore filters were chosen as the collection substrate for metal oxide particles due to their highly reproducible surface areas and low background weights. The subject nanomaterials included two different batches of ultrafine TiO₂, TiO₂ nanorods, and SiO₂. The instrument detection limit for surface area was 200 cm² (0.02 m²). Ninety percent confidence interval estimates of method accuracy were 17.7-23.5% with a point estimate of 20.8%. The filter-based surface area measurement strategy is demonstrated to be a viable sampling and analysis methodology that provides much needed physical characterization information of particles as administered in an animal inhalation chamber.