In vivo analysis for mechanism of drug action by juxtacellular recording

Abstract

Electrophysiological methods are commonly used in neuroscience and pharmacology to reveal the mechanisms of drug action. In vivo analysis of the mechanisms of drug action is a particularly important method in neuropharmacology. Here, we show the juxtacellular recording method to characterize the electrophysiological and neurochemical properties of neurons. Using juxtacellular recording, researchers can record the membrane potential from single neurons, and examine action potential parameters, such as the width and coefficient variance of inter-spike intervals. Additionally, recorded neurons can be labeled using neurobiotin, and neurochemical properties can be revealed by a combination of immunohistochemical staining and in situ hybridization. We introduce an experiment testing the effects of a phosphodiesterase 4 (PDE4) inhibitor on the fronto-striatal circuit using juxtacellular recording. The cerebral cortex-nucleus accumbens (NAcc)-external segment of globus pallidus (GPe)-subthalamic nucleus (STN)-substantia nigra pars reticulata (SNr) pathway is the neurobiological basis of many neuropsychiatric disorders. Several components of this pathway are particularly important for the regulation of motor action and cognitive function: 1) STN-SNr pathway (hyperdirect pathway), 2) NAcc-SNr pathway (direct pathway), and 3) GPe-STN-SNr pathway (indirect pathway). Researchers can record tri-phasic responses reflecting these pathways using electro-stimulation in cerebral cortex. A PDE4 inhibitor, roflumilast, affected the 2) direct pathway as well as the 3) indirect pathway, but not the 1) hyperdirect pathway. The current findings suggest that PDE4 inhibition could be considered as a possible treatment for cognitive deficits related to fronto-striatal disorders such as attention deficit/hyperactivity disorder, and Parkinson’s disease.