Choosing between cocaine and sucrose under the influence: testing the effect of cocaine tolerance

Cocaine use not only depends on the reinforcing properties of the drug, but also on its intoxicating effects on alternative nondrug activities. In animal models investigating choice between cocaine and alternative sweet rewards, the latter influence can have a dramatic impact on choice outcomes. When cocaine intoxication at the moment of choice is prevented by imposing sufficiently long intervals between choice trials, animals typically prefer the sweet reward. However, when choosing under the drug influence is permitted, animals shift their preference in favor of cocaine. We previously hypothesized that this preference shift is mainly due to a direct suppression of responding for sweet reward by cocaine intoxication. Here we tested this hypothesis by making rats tolerant to this drug-induced behavioral suppression. Contrary to our expectation, tolerance did not prevent rats from shifting their preference to cocaine when choosing under the influence. Thus, other mechanisms must be invoked to explain the influence of cocaine intoxication on choice outcomes.

Novel small molecule agonists of an Aedes aegypti neuropeptide Y receptor block mosquito biting behavior

Female Aedes aegypti mosquitoes bite humans to obtain a blood-meal to develop their eggs. Remarkably, strong attraction to humans is suppressed for several days after the blood-meal by an unknown mechanism. We investigated a role for neuropeptide Y (NPY)-related signaling in this long-term behavioral suppression, and discovered that drugs targeting human NPY receptors modulate mosquito host-seeking behavior. In a screen of all 49 predicted Ae. aegypti peptide receptors, we identified NPY-like receptor 7 (NPYLR7) as the sole target of these human drugs. To obtain small molecule agonists selective for NPYLR7, we carried out a high-throughput cell-based assay of 265,211 compounds, and isolated 6 highly selective NPYLR7 agonists that inhibit mosquito attraction to humans. NPYLR7 CRISPR-Cas9 null mutants are defective in behavioral suppression, and resistant to these drugs. Finally, we show that these drugs are capable of inhibiting biting and blood-feeding on a live host, suggesting a novel approach to control infectious disease transmission by controlling mosquito behavior.