Real‐time pharmacokinetic and pharmacodynamic measurements of drugs within the brains of freely behaving rats.

Abstract

The drug cocaine evokes complex neurochemical responses that mediate their influence of neural circuits underlying behavioral control, such as the dopamine pathways that we now know drive reward anticipation and locomotor behavior. In contrast, the anesthetic drug procaine functions as both a local anesthetic in the periphery, and a general anesthetic when it reaches the brain, affecting breathing, heart rate, and locomotion. However, the time resolution with which existing methods can measure these drugs is orders of magnitude poorer than the resolution with which physiological responses to these drugs occur. In response to this problem, our group has recently developed a new technology, electrochemical aptamer‐based sensors (E‐AB sensors), which are the size of a human hair and can detect physiologically relevant concentrations of specific drugs in‐situ, in awake, freely behaving animals. Here, we tested this new technology on rats that have been administered either cocaine or procaine intravenously and measured the concentrations of these drugs within the lateral ventricle concurrent with monitoring locomotor activity. We successfully measured the concentration of cocaine and procaine every 10 s for 2 hours and generated a full pharmacokinetic and pharmacodynamic profile for these drugs within the lateral ventricle. As cocaine concentrations increased (from 0 to 5 μM), they directly corresponded with increased locomotor activity and stereotypy, whereas increased levels of procaine in the lateral ventricle coincided with decreased heart rate, oxygen saturation (SPO2), and locomotion. In conclusion, we have developed a novel, potentially revolutionary, technology that can measure the pharmacokinetics and pharmacodynamics of psychoactive drugs within the brains of awake, freely behaving animals.Support or Funding InformationFunding was provided by the National Institutes of Health R01EB022015 and the W.M. Keck foundation.