Abstract
Epipial application is one of the approaches for drug delivery into the cortex. However, passive diffusion of epipially applied drugs through the cortical depth may be slow, and different drug concentrations may be achieved at different rates across the cortical depth. Here, we explored the pharmacodynamics of the inhibitory effects of epipially applied ionotropic glutamate receptor antagonists CNQX and dAPV on sensory-evoked and spontaneous activity across layers of the cortical barrel column in urethane-anesthetized rats. The inhibitory effects of CNQX and dAPV were observed at concentrations that were an order higher than in slices in vitro, and they slowly developed from the cortical surface to depth after epipial application. The level of the inhibitory effects also followed the surface-to-depth gradient, with full inhibition of sensory evoked potentials (SEPs) in the supragranular layers and L4 and only partial inhibition in L5 and L6. During epipial CNQX and dAPV application, spontaneous activity and the late component of multiple unit activity (MUA) during sensory-evoked responses were suppressed faster than the short-latency MUA component. Despite complete suppression of SEPs in L4, sensory-evoked short-latency multiunit responses in L4 persisted, and they were suppressed by further addition of lidocaine suggesting that spikes in thalamocortical axons contribute ∼20% to early multiunit responses. Epipial CNQX and dAPV also completely suppressed sensory-evoked very fast (∼500 Hz) oscillations and spontaneous slow wave activity in L2/3 and L4. However, delta oscillations persisted in L5/6. Thus, CNQX and dAPV exert inhibitory actions on cortical activity during epipial application at much higher concentrations than in vitro, and the pharmacodynamics of their inhibitory effects is characterized by the surface-to-depth gradients in the rate of development and the level of inhibition of sensory-evoked and spontaneous cortical activity.
Highlights
The epipial application of pharmacological agents is widely used for drug delivery into the cortex (Pockberger et al, 1984; Andreasen et al, 1989; Hablitz and Sutor, 1990; Kohling et al, 1993; Conti and Minelli, 1994; Ikeda et al, 2002)
We addressed the pharmacodynamics of the ionotropic glutamate receptor antagonists (170–500 μM CNQX and 0.7– 2 mM dAPV) after their epipial administration using linear multisite silicone probe recordings of the local field potentials (LFPs) signals and multiple unit activity (MUA) at different depths of the cortical barrel column
principal whisker (PW) deflection evoked sensory evoked potentials (SEPs) with a characteristic Current-source density (CSD) profile with two early sinks in L4 and the L5/6 border followed by sinks in L2/3 and L5 (Figures 1A, 3A; Di et al, 1990; Castro-Alamancos and Oldford, 2002; Roy et al, 2011; Reyes-Puerta et al, 2015)
Summary
The epipial application of pharmacological agents is widely used for drug delivery into the cortex (Pockberger et al, 1984; Andreasen et al, 1989; Hablitz and Sutor, 1990; Kohling et al, 1993; Conti and Minelli, 1994; Ikeda et al, 2002) This approach appears to be useful for compounds, which are not very permeable through the brain–blood barrier (BBB), and . In keeping with the relatively slow diffusion rates and the thickness of the cortex, drug concentration may develop at different rates and attain different levels at different depths of the cortex This raises the question of the pharmacodynamics of drugs during epipial application. We have chosen a combination of the glutamate ionotropic AMPA/kainate and NMDA receptor antagonists CNQX and dAPV as a model drug, using the spontaneous and sensory-evoked activity in different cortical layers as a readout of their penetration into the cortex
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