Summary. While the established electrochemical and microdialysis-based techniques for measuring drugs and neurotransmitters in the brain have unimpeachably contributed to our understanding of brain function, they are not without limitations. For example, when the same dose of cocaine is infused over 5 s versus 90 s the behavioral, metabolic, and even genetic outcomes vary dramatically, suggesting that the 2 min resolution of the most highly resolved of prior in-brain cocaine measurements are poorly matched to timescale of the drug's psychobiology. More generally, no drugs and only a small number of neurotransmitters have been measured to date in the brain with the most behaviorally relevant seconds time resolution. In response, our vision is to adapt electrochemical aptamer-based (E-AB) sensors, an in-vivo measurement platform that does not rely on the chemical or enzymatic reactivity of its targets (thus ensuring generality), to the problem of simultaneously monitoring drugs of abuse and the neurotransmitters they modulate in situ in the brains of freely moving, normally behaving rodents. To this end, we have already demonstrated feasibility by performing the high frequency, multi-hour measurement of more than a half dozen molecules in the blood and brains of live rats. Leveraging these preliminary results we propose here the adaptation of E-AB sensors to the problem of studying of brain chemistry. If successful, the proposed work will greatly expand the number of neurochemically relevant molecules that can be measured in real time and with second resolution in the living brain, thus creating a new window into brain chemistry that provides unique capabilities for closed-loop study and intervention.

Health relevance. We are developing a technology that will expand our ability to measure both psychoactive drugs and the neurotransmitters they interact with in situ in the brains of freely moving, normally behaving animals. By creating a uniquely versatile, highly time-resolved, real-time window into neurochemistry and pharmacodynamics, such an advance will provide new insights into the physiological and pharmacological control of brain function.