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

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.Until recently, neurophysiological analysis of information processing in the brain was primarily based on the examination of firing activity of single cells during behavior, as measured with repetitive presentations of stimuli (Gerstein and Kiang, 1960). However, this could not provide an answer to the question of how information is represented by the pattern of activity distributed across a population of neurons. With the emergence of techniques to record large numbers of neurons simultaneously ("ensemble recordings"), it became possible to examine information coding at the level of cell populations (Wilson and McNaughton, 1993). However, an issue that has not been addressed thus far is how neurotransmitters influence the activity of these cell populations.To gain more insight in the interaction between neurotransmitters or pharmacological agents and neuronal firing activity, we sought to develop a method in which drugs could be locally administered while performing ensemble recordings in freely moving rats. Because drugs should ideally be delivered with a constant concentration throughout the experimental session within the entire recording area, reverse microdialysis is preferred over either local injections, because with injections additional fluid is introduced into the brain, causing a change in pressure; or iontophoresis,...

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