Cocaine self-administration in mice with forebrain knock-down of trpc5 ion channels

Matthew B Pomrenze,Donald C Cooper,Lutz Birnbaumer,Brian A Cadle,Michael V Baratta,Kristin C Rasmus,Shinya Nakamura

doi:10.3410/f1000research.2-53.v1

Abstract

Canonical transient receptor potential (TRPC) channels are a family of non-selective cation channels that play a crucial role in modulating neuronal excitability due to their involvement in intracellular Ca2+ regulation and dendritic growth. TRPC5 channels a) are one of the two most prevalent TRPC channels in the adult rodent brain; b) are densely expressed in deep layer pyramidal neurons of the prefrontal cortex (PFC); and c) modulate neuronal persistent activity necessary for working memory and attention. In order to evaluate the causal role of TRPC5 in motivation/reward-related behaviors, conditional forebrain TRPC5 knock-down (trpc5-KD) mice were generated and trained to nose-poke for intravenous cocaine. Here we present a data set containing the first 6 days of saline or cocaine self-administration in wild type (WT) and trpc5-KD mice. In addition, we also present a data set showing the dose-response to cocaine after both groups had achieved similar levels of cocaine self-administration. Compared to WT mice, trpc5-KD mice exhibited an apparent increase in self-administration on the first day of cocaine testing without prior operant training. There were no apparent differences between WT and trpc5-KD mice for saline responding on the first day of training. Both groups showed similar dose-response sensitivity to cocaine after several days of achieving similar levels of cocaine intake.

Highlights

The prefrontal cortex (PFC) supports higher order cognitive functions, such as decision-making, reasoning, and working memory[1]
Genetic and environmental factors can influence PFC excitability[4,5,6], and repeated cocaine alters the excitability of the PFC by biasing neurons towards strong inputs, such as those associated with drug cues, which may diminish cognitive function[7]
Since deep-layer pyramidal neurons of the PFC are known to project to limbic structures that subserve reward, such as the ventral tegmental area, nucleus accumbens, amygdala, laterodorsal tegmentum[14], and the rostromedial tegmental nucleus[15], TRPC5 channels may influence the ability of cortical networks to exert inhibitory control over these structures

Summary

Introduction

The prefrontal cortex (PFC) supports higher order cognitive functions, such as decision-making, reasoning, and working memory[1]. TRPC5 channels a) are one of the two most prevalent TRPC channels in the adult rodent brain[12]; b) are densely expressed in deep layer pyramidal neurons of the PFC12; and c) modulate neuronal persistent activity necessary for working memory and attention[13]. Since deep-layer pyramidal neurons of the PFC are known to project to limbic structures that subserve reward, such as the ventral tegmental area, nucleus accumbens, amygdala, laterodorsal tegmentum[14], and the rostromedial tegmental nucleus[15], TRPC5 channels may influence the ability of cortical networks to exert inhibitory control over these structures. In the present data sets, we gathered data from mice that lack functional TRPC5 channels in their forebrain CaMKII-expressing pyramidal neurons to measure their cocaine self-administration behavior as an index of cocaine reward

Materials and methods

Results

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