A powerful tool for studying the effects of compounds on neuronal circuity.
In vivo electrophysiology in the CNS allows for monitoring of single neuron-level activity or local field potentials in live subjects. PsychoGenics offers in vivo electrophysiological recordings from many defined regions of the brain or spinal cord, including (but not limited to) the hippocampus, basal ganglia, prefrontal cortex, subthalamic nuclei, and spinal cord dorsal horn. This approach enables real time measurements of the pharmacodynamic effects of a compound of interest in an intact biological system. These data can be especially useful when evaluating target engagement or potential rescue of pathological changes in neuronal function in disease-relevant rodent models. Compounds can be dosed systemically or administered locally using microiontophoretic or micropressure drug delivery systems. These techniques can also be combined with serial blood sampling during recordings to establish pharmacokinetic/pharmacodynamic relationships.
Pharmacological modulation of circuit-level inhibition
Globus pallidus (GP) stimulation-induced inhibition of cell firing in substantia nigra (SN). Rhythmically active cells in the SN are briefly inhibited following high intensity stimulation in the GP. The duration of this inhibition is increased after administration of chlordiazepoxide. A) Location of stimulating electrodes (within the GP) and recording electrodes (within the SN). B) Top – example of spike trace recorded in SN showing neuronal firing. Each spike represents a single neuronal firing event. Black arrows indicate stimulus trains delivered to the GP. Middle – raster plot of firing activity from a portion of the spike trace (top), as indicated by dashed lines. Bottom – spike firing binned by time from a portion of the spike trace (top), as indicated by dashed lines. Temporary cessation of activity in the SN is caused by train stimulation of the GP (black arrows). C) Chlordiazepoxide (CDP, 5 mg/kg, i.v.), a positive allosteric modulator of GABA-A receptors, expands the duration of inhibition of SN firing produced by GP stimulation (bottom trace) compared to control (top trace).
Pharmacological modulation of single neuron activity
NMDA-induced activation of a single neuron in rat prefrontal cortex (PFC) is blocked by MK-801. Microiontophoresis can deliver low volume drug administration with a rapid application time while bypassing the blood-brain barrier. This can be combined with in vivo recording to measure modulation of single neuron activity. A) Local iontophoretic administration of NMDA (represented by black bars) produces increases in firing frequency (top) of a single neuron in the PFC of an anesthetized rat. Top – spike frequency (binned), bottom – spike amplitude. B) Systemic administration of the use-dependent NMDA receptor antagonist MK-801 (2 mg/kg, i.v.) blocks increases in neuronal activity produced by iontophoretic NMDA administration. This can be observed in the suppression of spike firing after MK-801 administration (indicated by black arrow).
Correlation of drug efficacy with drug exposure
Pharmacodynamic exposure relationships can be established by monitoring neuronal activity over time and correlating it with drug levels in serially collected plasma samples. This figure demonstrates the relationship between plasma concentration of MP-10 (solid red line), a PDE10 inhibitor, and the single unit firing rates of subthalamic nuclei (STN) neurons (black shading). The i.v. administration of MP-10 (blue arrow) produces a transient increase in STN firing rate. The rate of firing correlates with the increasing plasma concentration of MP-10; as plasma concentrations of MP-10 decrease over time, so does the mean firing rate of STN neurons. The red dotted line represents the baseline firing rate of the STN neurons when no compound is present. The grey shading represents the standard error of STN firing.
