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

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

Brain Research Bulletin 121 (2016) 186–191 Contents lists available at ScienceDirect Brain Research Bulletin journal homepage: www.elsevier.com/loca...

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Brain Research Bulletin 121 (2016) 186–191

Contents lists available at ScienceDirect

Brain Research Bulletin journal homepage: www.elsevier.com/locate/brainresbull

Research report

Local field potentials in the ventral tegmental area during cocaine-induced locomotor activation: Measurements in freely moving rats Amber L. Harris Bozer, Ai-Ling Li, Jiny E. Sibi, Samara A.M. Bobzean, Yuan B. Peng ∗,1 , Linda I. Perrotti ∗,1 Department of Psychology, The University of Texas at Arlington, Arlington, TX 76019, USA

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Article history: Received 17 November 2015 Received in revised form 31 January 2016 Accepted 3 February 2016 Keywords: Ventral tegmental area VTA Locomotion Cocaine Field potential

a b s t r a c t 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. © 2016 Elsevier Inc. All rights reserved.

1. 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;

∗ Corresponding authors at: Department of Psychology, University of Texas at Arlington, Arlington, TX 76019-0528, USA. E-mail addresses: [email protected] (Y.B. Peng), [email protected] (L.I. Perrotti). 1 These two authors contribute equally to this project. http://dx.doi.org/10.1016/j.brainresbull.2016.02.003 0361-9230/© 2016 Elsevier Inc. All rights reserved.

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

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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 lowfrequency 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 ␮m (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).

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mals were monitored each day after surgery for signs of infection or distress. 2.3. Locomotor and local field potential recordings Our custom-built LFP module is a closed-loop digital wireless system that has both stimulating and recording subsystems, although just recording was used in this experiment (Zuo et al., 2012). On the test day, subjects were placed under isoflurane anesthesia (3% isoflurane/97% oxygen induction) and the wireless recording module (weighing less than 20g) was connected to the implanted electrode and mounted on a backpack worn by the rat along with a 3 V lithium battery. The module signal amplifies and transmits to a USB dongle on the host computer. The graphical user interface for displaying recorded activity was custom made through Labview. The rat was disconnected from the isoflurane for a period of 15 min and placed in locomotion test chamber to record LFP and locomotion simultaneously. Locomotor activity was recorded in a single outer chamber of a three-chambered Med Associates Inc. (Georgia, VT) conditioned place preference apparatus (8.25 W × 8.24 H × 26.75 L) that was lit by a single bulb. The chamber was equipped with 16 infrared photo beam detectors evenly spaced along each wall of the apparatus for automated data collection. Consecutive photo beam breaks (movement counts) were automatically recorded using Med Associates IV software (Med Associates; Georgia, VA). Locomotor behavior was regarded as the interruption of an infrared laser beam elicited by movement of the animal. A period of fifteen minutes was allotted for recovery from anesthesia before testing began in the following sequence (Fig. 1): (1) thirty minutes of baseline locomotor and LFP activity was recorded, (2) after an intraperitoneal NaCl injection (0.9% NaCl at 0.1 ml/kg), animals were promptly placed back into the chamber where recording was resumed for another 30 min, (3) following an intraperitoneal cocaine hydrochloride injection (10 mg/kg dissolved in 0.9% saline), animals were returned to the chamber for 60 min of recording.

2. Materials and methods 2.4. Histological confirmation of electrode placement 2.1. Animals Eight adult female Sprague-Dawley rats weighing 247–305 g at 7–8 months of age were taken from the University of Texas at Arlington vivarium. Animals were housed in cages of 3–4 and given access to food and water ad libitum. They were kept on a 12 h light dark cycle from 7:30 a.m. to 7:30 p.m. Testing occurred during the light cycle (the animals active phase). All animal procedures were preapproved by the University of Texas Arlington Institutional Care and Use Committee (IACUC) and were in compliance with AAALAC standards. 2.2. Electrode implantation After placement into a stereotaxic frame under sodium pentobarbital anesthesia (50 mg/kg, i.p.), subjects received a right unilateral VTA implant of a .23 mm bipolar stainless steel electrode (Plastics One, Roanoke VA). The electrode was attached to a plastic threaded pedestal. Electrodes were placed in the VTA using coordinates at 5.8 posterior to bregma, 2.0 mm lateral to the right, and 8.3 mm from the dura at an angle of 10◦ pointing towards the midline (Paxinos and Watson, 1998). Three stainless steel mounting screws (1.57 mm shaft diameter, Plastics One, Roanoke VA) were fixated on the skull and the electrode pedestal was permanently fixed in place by dental cement. The skin was stapled around the implant and animals were single housed after surgery. A period of 4 weeks for recovery was allotted before testing commenced. Ani-

After testing was completed, animals were sacrificed via carbon dioxide euthanasia. Brains were extracted and fixed in 33% formaldehyde for 48 h and then switched to a 30% sucrose solution for 48 h. Brains were sliced with a microtome (American Optical Corporation, Buffalo NY, Model 860) at 80 ␮m (coronal sections) and mounted to gelatin coated slides. Thionine staining was applied and slides were cover slipped with Shur/Mount Toluene based liquid mounting media (Triangle Biomedical Sciences). Electrode placement was analyzed under a microscope. Of the 8 animals that received an implant at the VTA region, 5 were included in the main analysis (see Fig. 2 for electrode placement). Three subjects were not included in the statistical analysis because placement of the electrode in the VTA could not be confirmed. Two observers analyzed placement of the electrodes. 2.5. Statistical analyses Locomotor behavior was recorded as number of beam breaks per minute in the conditioned place preference chamber. The number of beam breaks per minute for each animal was exported from the conditioned place preference chamber MedPC file into Excel. Averages were computed for each time-point (baseline, saline, cocaine 0–30 min, cocaine 30–60 min) and imported into SPSS where a repeated-measures ANOVA was run to analyze locomotor changes over time. A significant effect (p < .05.) was analyzed further using post-hoc LSD test. All data are presented as mean ± SEM.

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Fig. 1. Timeline of procedures. After implantation of electrodes, four weeks of recovery were allotted. On the test day, animals were placed under isoflourane anesthesia and the previously implanted electrode was connected to the LFP recording system carried on the back of the freely moving rat. During testing, animals were placed in a Conditioned Place Preference Chamber (MedPC) where locomotor activity and LFP testing were recorded simultaneously. Thirty minutes of baseline testing was recorded. After an injection of saline, testing resumed for 30 min. Lastly, cocaine was administered at 10 mg/kg, followed by 60 min of testing.

Fig. 2. Schematic summary of electrode placement (blue dots) for in the ventral tegmental area at 5.8 posterior to bregma, 2.0 mm lateral to the right, and 8.3 mm from the dura at an angle of 10◦ pointing towards the midline (N = 5). The figure was adapted from Fig. 41 (bregma −5.20 mm) of The Rat Brain in Stereotaxic Coordinates (Paxinos and Watson, 1998). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

LFP module data are stored by the LabView recording in a text file format depicting LFP amplitude in arbitrary units over time per the LFP module amplifier magnitude. Raw LFP text files for each animal at each time point were imported into Spike 2 (Cambridge Electronic Design) and displayed in spectrogram format. Power spectrum analyses were performed to display the power at predefined frequency components of the LFP waveform (Delta 0–3 Hz; Theta, 4–8 Hz; Alpha, 8–13 Hz; Beta, >13–30 Hz; and Gamma, 30–100 Hz) over time (0–30 min of baseline, 0–30 min after saline injection, 0–30 min after cocaine injection, and 30–60 min after cocaine injection). Spike 2 text files with power spectrum analyses were copied into excel. Averages of activity for all animals in each frequency band were computed. SPSS was used to run ANOVAs for power at each frequency band (delta, theta, alpha, beta, gamma) followed by post-hoc LSD tests when there was a significant effect (p < .05.). All data are presented as mean ± SEM.

2.6. Calculation of Pearson correlation LFP and locomotor data were prepared for a correlation analysis by binning the data according to time-point and measure. Aggregate averages of all locomotor behavior were created across all time-points (baseline, saline, cocaine 0–30 min, and cocaine 30–60 min). Aggregate averages of all frequency bands were also calculated for LFP across the same time points. A Pearson correlation was run to assess the relationship between changes in locomotor behavior and LFP over time. First, the correlation coefficient (r) between these two data sets (Locomotion and LFP) was

calculated by using Excel formula (=CORREL(data set1, data set2)). Second, the t value was calculated by using r in the following formula (t = r*SQRT (n − 2)/SQRT (1 − r2 )), where n was the number of variables in each data set (in this case, 4). Third, the Excel tdist () function was used to find the associated p (=tdist(t, N − 2, tail)), where the value of t was known, the degrees of freedom (N = 4, N − 2 = 2), and the number of tails was (2). 3. Results 3.1. Locomotor behavior is increased following cocaine injection Results from repeated measures ANOVA indicated that there was a significant change in locomotor beam breaks over time, F (3, 12) = 9.37, p =0.002 (Fig. 3). Post-hoc LSD tests revealed that the number of beam breaks was significantly higher during the 30 min following cocaine injection (17.51 ± 5.07 bb/min) than during baseline (2.51, ±0.70, p = 0.037 bb/min) or saline (1.65, ±0.40, p = 0.031 bb/min). Beam break counts were also higher during 30–60 min following cocaine injection (7.82, ±2.30 bb/min) than at baseline (p = 0.038) or saline (p = .036). 3.2. Local field potential is increased following cocaine injection The results of different frequency bands are reported separately. For delta frequency band (0–3 Hz), the repeated measures ANOVA yielded a significant change over time, F (3, 12) = 11.27, p =0.001. Post-hoc LSD tests revealed that the power of delta band LFP was

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significantly higher during the first 30 min following cocaine injection (32.70 ± 8.74 ␮V2 ) than at baseline (14.44 ± 2.87 ␮V2 , p = .018), saline (15.57 ± 5.69 ␮V2 , p = .017), or 30–60 min after cocaine injection (15.45 ± 6.62 ␮V2 , p = .011). For theta frequency band (4 − 7 Hz), the repeated measures ANOVA indicated a significant change of the theta frequency band

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over time, F (3, 12) = 12.25, p = .001. Post-hoc LSD tests revealed that the power of theta band LFP was significantly higher during the first 30 min following cocaine injection (36.48 ± 8.65 ␮V2 ) than at baseline (16.62 ± 5.45 ␮V2 , p = .017), saline (18.54 ± 8.13 ␮V2 , p = .026), and 30–60 min after cocaine injection (17.52 ± 3.74 ␮V2 , p = .008). For alpha frequency band (8 − 13 Hz), the repeated measures ANOVA indicated a significant change over time, F (3, 12) = 8.31, p =0.003. Post-hoc LSD tests revealed that the power of alpha band LFP was significantly higher during the first 30 min following cocaine injection (8.35 ± 2.55 ␮V2 ) than at baseline (4.33 ± 1.55 ␮V2 , p = .033) and 30–60 min after cocaine injection (4.50 ± 0.99 ␮V2 , p = .025). For beta frequency band (14 − 30 Hz), the repeated measures ANOVA indicated a significant change over time, F (3, 12) = 6.62, p =0.007. Post-hoc LSD tests revealed that the power of beta band of saline (1.35 ± 0.48 ␮V2 ) was significantly higher than baseline (1.19 ± 0.46 ␮V2 , p = .007). The power was significantly higher during the first 30 min following cocaine injection (2.14 ± 0.57 ␮V2 ) than at baseline (1.19 ± 0.46 ␮V2 , p = .032). During 30- 60 min after cocaine injection (1.51 ± 0.46 ␮V2 ), the power was significantly higher than baseline (1.19 ± 0.46 ␮V2 , p = .023) and saline (1.35 ± 0.48 ␮V2 , p = 044). For gamma frequency (31–100 Hz), the repeated measures ANOVA indicated a significant change over time, F (3, 12) = 7.25, p =0.004. Post-hoc LSD tests revealed that the power of gamma band of 30–60 min after cocaine injection (0.71 ± 0.21 ␮V2 ) was significantly higher than baseline (0.35 ± 0.13 ␮V2 , p = .027) and saline (0.45 ± 0.15 ␮V2 , p = 002). Results for the 3 subjects with VTA lesions that could not be confirmed showed no significant results from baseline or saline to cocaine time periods in any of the frequency bands, p > .05. 3.3. Correlation of LFP and locomotion Averages of locomotor behavior for all animals were computed for baseline (2.51 bb/min), saline (1.65 bb/min), cocaine 0–30 min (17.51 bb/min), and cocaine 30–60 min (7.82 bb/min). Averages of overall LFP power for all animals were also computed for baseline (7.39 ␮V2 ), saline (8.14 ␮V2 ), cocaine 0–30 min (16.08 ␮V2 ), and cocaine 30–60 min (7.94 ␮V2 ). The Pearson correlation to deter-

Fig. 4. Representative sample of LFP trace spectrograms from Rat #1. Text file data from LabView recording software were imported into Spike 2 software where spectrograms were generated to visualize VTA activity. Sub-figures represent spectrograms for Rat #1 at (A) baseline for 30 min, (B) saline for 30 min, and (C) cocaine for 60 min. AU = arbitrary unit.

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Fig. 5. Summary of power spectrum analysis for each frequency band (Delta 0–4 Hz, Theta 4–8 Hz, Alpha 8–13 Hz, Beta 13–30 Hz, Gamma 30–100 Hz) across time points (baseline recording for 30 min, after saline injection for 30 min, after cocaine injection for 0–30 min, and 30–60 min after cocaine). * Represents a significant difference from baseline, (p < 0.05). + Represents a significant difference from saline, (p < 0.05). Hz = Hertz.

mine if there was a relationship between changes in locomotor behavior and LFP averages over time, however, was not statistically significant, r = +0.93, p = 0.07 (Fig. 6). 4. Discussion We found that cocaine provoked changes in LFP activity in the VTA concomitantly with cocaine-induced changes in locomotion. Drawing conclusions about VTA LFP activity was contingent on the increase of locomotor behavior following cocaine injection. Our behavioral findings are consistent with previous research demonstrating the expected increase in locomotor behaviors after cocaine administration (Guan et al., 1985; Borgland et al., 2004; Soderman and Unterwald, 2008; Henry and White, 1992), thus permitting analysis of LFP data. Specifically, the increase in locomotor behaviors was highest during the first 30 min following cocaine injection (Fig. 3). Local Field Potential activity during baseline and after saline injection differed only at the Beta frequency band, which demonstrates that injections of saline alone do not cause in an overall substantial increase of neural activity in the VTA. Acute cocaine administration increased LFP activity in the VTA and this activity was easily differentiated from the baseline activity. Overall, results from frequency band power analyses indicated a significant increase in LFP activity during the first 30 min after cocaine injection at Delta, Theta, Alpha, and Beta frequency bands, indicating a robust and transient change in low-frequency activity in the VTA (Figs. 4 and 5). Therefore, the overall effects of cocaine injection on LFP were most robust during the first 30 min after injection. However, from 30 to 60 min after cocaine injection, only Beta and Gamma indicated a significant change from baseline. This suggests that the transient changes in VTA LFP activity occur very quickly after administration and are frequency and temporally dependent. The power of the LFP changes were congregated primarily in the Delta and Theta bands, demonstrating that increases in the lower frequency neural events were most powerful after cocaine injection. As LFP primarily measures summed low-frequency synaptic activity nearby to the electrode (Lindén et al., 2011), the changes in activity in the VTA detected in this experiment indicate that neural events occurring at lower frequencies were most prominent during the development of cocaine-induced locomotor activation. We measured LFP changes in the VTA to further examine the knowledge of the role of the VTA in processing cocaine induced locomotor behaviors. Following cocaine injection, there were tran-

Fig. 6. Correlation between locomotor behavior and LFP over time. The relationship between averages of locomotor behavior (label on the left) was run by Pearson correlation to correlate the averages of LFP (label on the right) at each time bin (baseline, saline, cocaine 0–30 min, and cocaine 30–60 min) (r = +0.93, p = .07).

sient increases of LFP in the VTA alongside an increase in locomotor behaviors. The concurrent increase in locomotor behavior alongside the increase in low-frequency VTA LFP after cocaine injection merited a correlation analysis to review the relationship. Although there was a positive, high correlation between increases in locomotion and LFP activity in the VTA overall (r = +0.93), the statistical result was not significant (p =0.07). However, the trend was meaningful and the lack of statistical significance could be explained because there were only 4 time points. The correlation was run with averages for all animals at the 4 times points for locomotor behavior and LFP data (Fig. 6). The purpose of this study was to confirm that the VTA is involved in the initiation of cocaine-induced locomotor behavior and this data expand the field by providing evidence of the activity in real time using our custom built recording device. We have confirmed the role of the VTA in locomotor behavior initiation after cocaine administration as it occurred in real time and revealed the frequency and temporally dependent changes in activity. Specifically, low-frequency VTA activity is increased during the first 30 min following cocaine injection (when locomotor activity is highest) and tapers off 30–60 min after injection. Further, this research has yielded data that supports the use of a wireless recording module to investigate the neural activity during drug induced behavioral changes in freely moving animals. In fact, our custombuilt recording device can be applied in a variety of contexts to reveal information about the behavioral effects of drug administration. Acknowledgements This work benefited from support by the Texas Norman Hackerman Advanced Research Program (003656-0071-2009) and TxMRC Grant. References Adinoff, B., 2004. Neurobiologic processes in drug reward and addiction. Harv. Rev. Psychiatry 12 (6), 305–320, http://dx.doi.org/10.1080/10673220490910844. Ativanichayaphong, T., He, J.W., Hagains, C.E., Peng, Y.B., Chiao, J.C., 2008. A combined wireless neural stimulating and recording system for study of pain processing. J. Neurosci. 170 (1), 25–34, http://dx.doi.org/10.1088/1741-2560/ 9/5/056010. Ben-Shahar, O., Ettenberg, A., 1994. Repeated stimulation of the ventral tegmental area sensitizes the hyperlocomotor response to amphetamine. Pharmacol. Biochem. Beh. 48 (4), 1005–1009, http://dx.doi.org/10.1016/00913057(94)90212-7. Borgland, S.L., Malenka, R.C., Bonci, A., 2004. Acute and chronic cocaine-induced potentiation of synaptic strength in the ventral tegmental area: electrophysiological and behavioral correlates in individual rats. J. Neurosci. 24 (34), 7482–7490, http://dx.doi.org/10.1523/JNEUROSCI.1312-04.2004.

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