Local field potentials in the ventral tegmental area during cocaine-induced locomotor activation: Measurements in freely moving rats

Highlights

• We recorded local field potential (LFP) activity in the ventral tegmental area (VTA).

• Cocaine increased local field potentials in the VTA as well as locomotor behavior.

• VTA changes during locomotion were highest in the delta and theta bands.

• VTA changes were highest directly after cocaine injection.

• Initiation of stimulant induced locomotion can be studied using LFP recording.

Abstract

The ventral tegmental area (VTA) has been established as a critical nucleus for processing behavioral changes that occur during psychostimulant use. Although it is known that cocaine induced locomotor activity is initiated in the VTA, not much is known about the electrical activity in real time. The use of our custom-designed wireless module for recording local field potential (LFP) activity provides an opportunity to confirm and identify changes in neuronal activity within the VTA of freely moving rats. The purpose of this study was to investigate the changes in VTA LFP activity in real time that underlie cocaine induced changes in locomotor behavior. Recording electrodes were implanted in the VTA of rats. Locomotor behavior and LFP activity were simultaneously recorded at baseline, and after saline and cocaine injections. Results indicate that cocaine treatment caused increases in both locomotor behavior and LFP activity in the VTA. Specifically, LFP activity was highest during the first 30 min following the cocaine injection and was most robust in Delta and Theta frequency bands; indicating the role of low frequency VTA activity in the initiation of acute stimulant-induced locomotor behavior. Our results suggest that LFP recording in freely moving animals can be used in the future to provide valuable information pertaining to drug induced changes in neural activity.

Introduction

The ventral tegmental area (VTA) has been established as a critical nucleus for processing the effects of psychomotor stimulants such as cocaine. The VTA is a structure in the mesolimbic system that projects to the nucleus accumbens in the ventral striatum as well as other areas such as the amygdala and hypothalamus (Adinoff, 2004, Sesack and Grace, 2010, Russo and Nestler, 2013). The administration of psychostimulants such as cocaine induces an increase in locomotor behavior in rats (Henry and White, 1992), which is quantifiable (Cornish and Kalivas, 2001, Rebec, 2006). Cocaine-induced locomotor activity has been associated with changes in neural activity of mesolimbic structures including the VTA, which is a critical nucleus for the initiation phase of drug induced changes in behavior (Henry and White, 1992, Pierce and Kalivas, 1997). The administration of cocaine results in transient cellular changes in the VTA which have been extensively studied. Briefly, the VTA is richly innervated with a large population of heterogeneous dopaminergic cell bodies, comprising approximately 60–65% of the cells in the VTA (Sesack and Grace, 2010). Cocaine increases the dopamine at the postsynaptic receptor site by blocking the dopamine transporter (DAT), which results in dopamine failing to reabsorb back into the presynaptic neuron (Adinoff, 2004, Soderman and Unterwald, 2008, Sabeti et al., 2003). Repeated administration of the dopamine re-uptake inhibitor (GBR 12909) into the VTA results in sensitization of the behavioral locmotor effects of cocaine (Cornish and Kalivas, 2001). Thus, alterations in cellular functioning of neurons in the VTA, in part, underlie psychostimulant-induced changes in behavior and increase in dopamine activity in the area (Byrnes et al., 2000).

The VTA also contains approximately 30–35% of GABAergic neurons (Sesack and Grace, 2010). The release of GABA in the VTA is influenced by D₁ receptors; cocaine administration changes the pre-synaptic regulation of GABA transmission (Pierce and Kalivas, 1997). Other cellular mechanisms in the VTA play important roles in the psychostimulant augmentation of locmotion such as: synthesis of the retrograde messenger nitric oxide (Byrnes et al., 2000), orexin A facilitation of VTA neurons (Borgland et al., 2006), endogenous mu opiod receptor activation (Soderman and Unterwald, 2008), brain derived neurotrophic factor support of dopimanergic cells (Horger et al., 1999) and the necessary activation of NMDA receptors in the area (Vanderschuren and Kalivas, 2000). Taken together, many cellular mechanisms are activated during cocaine induced locomotor changes and certainly contribute to the oscillation of electrical activity in the vicinity of the VTA.

Psychostimulant-induced changes in locomotor activity can be impeded by lesions to the VTA (Byrnes et al., 2000), while repeated electrical stimulation of the area results in sensitization of locomotor effects after injection of amphetamine (Ben-Shahar and Ettenberg, 1994). Furthermore, Borgland et al. (2004) found that cocaine induced locomotor behaviors were correlated with synaptic enhancement in the VTA in post-mortem tissue. Although these studies established that the VTA is necessary for the initiation phase of cocaine-induced locomotor activity, our current knowledge of how that activity changes in real time is limited.

Local field potential (LFP) recording is a measure of the low-frequency neuron activity in the vicinity of the tip of the electrode, providing information about activity in real time (Lindén et al., 2011). The LFP measure reflects activity within an average range of 200–400 μm (Katzner et al., 2009, Xing et al., 2009). The development of our custom-designed wireless recording module presents an opportunity to assess LFP changes in the VTA of freely moving rats during the initiation phase of cocaine-induced locomotor activation (Ativanichayaphong et al., 2008, Farajidavar et al., 2012, Zuo et al., 2012).

The purpose of this study was to investigate the changes in VTA LFP activity in real time that underlie cocaine induced changes in locomotor behavior. The hypothesis was that cocaine would provoke changes in VTA LFP activity concomitant with drug induced locomotor displays. Preliminary data were previously presented in abstract form (Harris et al., 2013).