Pharmacological Manipulation of Neuronal Ensemble Activity by Reverse Microdialysis in Freely Moving Rats: A Comparative Study of the Effects of Tetrodotoxin, Lidocaine, and Muscimol

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Abstract
To be able to address the question how neurotransmitters or pharmacological agents influence activity of neuronal populations in freely moving animals, the combidrive was developed. The combidrive combines an array of 12 tetrodes to perform ensemble recordings with a moveable and replaceable microdialysis probe to locally administer pharmacological agents. In this study, the effects of cumulative concentrations of tetrodotoxin, lidocaine, and muscimol on neuronal firing activity in the prefrontal cortex were examined and compared. These drugs are widely used in behavioral studies to transiently inactivate brain areas, but little is known about their effects on ensemble activity and the possible differences between them. The results show that the combidrive allows ensemble recordings simultaneously with reverse microdialysis in freely moving rats for periods at least up to 2 wk. All drugs reduced neuronal firing in a concentration dependent manner, but they differed in the extent to which firing activity of the population was decreased and the in speed and extent of recovery. At the highest concentration used, both muscimol and tetrodotoxin (TTX) caused an almost complete reduction of firing activity. Lidocaine showed the fastest recovery, but it resulted in a smaller reduction of firing activity of the population. From these results, it can be concluded that whenever during a behavioral experiment a longer lasting, reversible inactivation is required, muscimol is the drug of choice, because it inactivates neurons to a similar degree as TTX, but it does not, in contrast to TTX, affect fibers of passage. For a short-lasting but partial inactivation, lidocaine would be most suitable.