Williams_unc_0153M_18733.pdf

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Emily Williams

A thesis submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Master of Arts in the Department of

Psychology and Neuroscience (Behavioral and Integrative Neuroscience)

Chapel Hill 2019

Approved by:

Kathryn J. Reissner

Regina M. Carelli

Todd E. Thiele

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ABSTRACT

Emily Williams: The Effects of Nicotinamide on Reinstatement to Cocaine Seeking (Under the direction of Kathryn Reissner)

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ACKNOWLEDGEMENTS

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TABLE OF CONTENTS

LIST OF FIGURES...vi

LIST OF ABREVIATIONS...vii

Chapter I INTRODUCTION... 1

Oxidative Stress... 1

NAD+ signaling and mitochondrial functioning... 3

II METHODS... 5

Subjects and Reagents... 5

Surgical Procedures... 5

Behavioral Training... 6

Experiment 1 ... 7

Experiment 2 ... 8

Experiment 3 ... 8

Experiment 4 ... 8

Experiment 5 ... 9

III RESULTS... 11

Experiment 1 ... 11

Experiment 2 ... 12

Experiment 3 ... 13

Experiment 4 ... 13

Experiment 5 ... 14

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LIST OF FIGURES

Figure

1 Chronic NAM administration reduces cue- but not cocaine-primed reinstatement in males, but not females... 23

2 The effects of chronic NAM administration are specific to cue-primed reinstatement 25

3 Acute NAM administration did not affect cue- or cocaine-primed reinstatement ... 26

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8-OHG 8-hydroxyguanine ATP adenosine triphosphate BLA basolateral amygdala

CeA central nucleus of the amygdala CPP conditioned place preference

DA dopamine

Dnmt1 DNA methyltransferase FR fixed ratio

IP intraperitoneal injection IV intravenous infusion NAc nucleus accumbens

NAD+ nicotinamide adenine dinucleotide NAM nicotinamide

NADP+ nicotinamide adenine dinucleotide phosphate NAMPT nicotinamide phosphoribosyltransferase NMN nicotinamide mononucleotide

OS oxidative stress PAR poly(ADP-ribose)

PARP-1 poly(ADP-ribose) polymerase ROS reactive oxygen species SAL saline

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CHAPTER 1: INTRODUCTION

Nicotinamide (NAM), a form of vitamin B3, component of crucial coenzymes NAD+ and NADP+, and free radical scavenger, is widely used clinically to treat pellagra (niacin deficiency), bullous pemphigoid, acne and rosacea, atopic dermatitis, and skin photoageing (Mutasim, 2003; Surjana & Damian, 2011). It also shows promise in preserving and enhancing neurocognitive function in a variety disease models such as Alzheimer’s, traumatic brain injury (ischemia and contusion injury), and Parkinson’s disease (Rennie, Chen, Dhillon, Vardy, & Damian, 2015). In addition, NAM has been proposed as an effective treatment for substance abuse (Namazi, 2004; Otte, Borelli, & Korting, 2005); however, empirical scientific evidence for this is lacking. Nevertheless, several cellular functions of NAM indicate that it may be beneficial in opposing cellular adaptations that mediate cocaine seeking in a preclinical rodent model of addiction, including consequences of oxidative stress and compromised cellular metabolic functions.

Oxidative Stress

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Importantly, levels of ROS have been linked to cocaine seeking, as administration of ROS scavengers leads to a reduction in cocaine self-administration as well as attenuation of cocaine-induced enhancement of dopamine (DA) release (Jang et al., 2015). In addition, in comparison to animals who were assigned to a cocaine yoke procedure, animals who voluntarily self-administer cocaine show significantly altered expression of oxidative stress biomarkers in the hippocampus, frontal cortex, and dorsal striatum (Pomierny-Chamiolo et al., 2013).

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NAD+ signaling and mitochondrial functioning

In addition, chronic cocaine also impairs both NAD+ signaling and mitochondrial function (de Oliveira & Jardim, 2016; Logan et al., 2018). NAD+ is important for energy homeostasis and calcium transport in the brain (Liang et al., 2017; Tamsett, Picchione, & Bhattacharjee, 2009; Ying, 2007) and is depleted following DA stimulation (Requardt et al., 2012; Requardt, Wilhelm, Rillich, Winkler, & Hirrlinger, 2010). Within neuronal mitochondria isolated from 9-12 week old rats, cocaine impairs mitochondrial respiration (Cunha-Oliveira et al., 2013), and disrupts the mitochondrial membrane potential of mitochondria in cultured neurons (Cunha-Oliveira et al., 2006; Yao, Allen, Zhu, Callen, & Buch, 2009). Cocaine exposure also results in in disrupted mitochondrial membrane potential within the mitochondria of cultured astrocytes (Yang, Yao, Lu, Wang, & Buch, 2010). As mentioned previously, NAM serves as a means to increase the bioavailability of NAD+ and other coenzymes crucial to mitochondrial functioning (Fricker, Green, Jenkins, & Griffin, 2018). Given that the many mitochondrial processes depend both on NAD+ and its phosphorylated counterpart NADP, the availability and redox state of NAD+ has important influence on all major mitochondrial processes (Dolle, Rack, & Ziegler, 2013). As a precursor to NAD+, NAM administration may therefore combat cocaine dependent disruptions in NAD+ signaling and mitochondrial functioning.

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CHAPTER 2: METHODS AND MATERIALS Subjects and reagents

Male (225-250g upon arrival, Envigo) and female (175-200g upon arrival, Envigo) Sprague-Dawley rats, were housed individually in a temperature-controlled environment (20-21° C) on a 12-h reverse light cycle (7 am off, 7 pm on). Prior to the start of experimental procedures, rats were maintained on ad libitum food and were given unlimited water access throughout the experiment. Treatment and housing of animals was approved by the University of North Carolina Institutional Animal Care and Use Committee and followed the “Guide for the Care and Use of Laboratory Rats” (Institute of Laboratory Animal Resources on Life Sciences, National Research Council, 1996). Cocaine was generously provided by the NIH Drug Supply Program. Nicotinamide was purchased from Sigma-Aldrich (catalog #72340) and prepared in saline.

Surgical Procedures

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(100U/mL) were administered i.v. To check for catheter patency, propofol (1 mg/0.1 mL, i.v.) was administered prior to the onset of self-administration and subsequently as needed.

Behavioral Training

Before surgery, rats were trained to lever press for food pellets (45 mg pellets; Bio Serv, Flemington, NJ) under an FR1 reinforcement schedule. Food training and self-administration sessions were performed in sound attenuated, standard operant conditioning chambers (Med Associates, St. Albans, VT). Each chamber was equipped with two retractable levers divided by a food pellet dispenser. Starting 24 hours prior to food training session, rats received rations of approximately 20g of chow daily. Lever presses on the active lever during training sessions resulting in the delivery of one food pellet (Bio Serv, Flemington, NJ). Presses on the inactive lever had no consequences for the entirety of the training session. Training session continued until animals reached a criterion of 100 active lever presses or 8 hours had elapsed.

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Experiment 1: Effects of Chronic NAM administration on cue- and cocaine-primed reinstatement in males and females

A timeline for the experiment can be seen in Figure 1A. Given the relatively short half-life of NAM (100 mg/kg: 3.4 hours), rats were given daily i.p. injections of NAM (10 mg/kg, 30 mg/kg, 60 mg/kg, or 120 mg/kg; 1 mL/kg) or saline 30 minutes prior to every extinction session and subsequent reinstatement tests (Stratford & Dennis, 1994). Twenty-four hours following the last extinction session, rats were tested on a 2h cue-primed reinstatement session. This session began with a five second presentation of the light and tone cues which had been previously presented during self-administration. All subsequent active lever presses resulted in identical light and tone cue presentations without delivery of cocaine. Inactive lever presses were recorded, but maintained a lack of programmed consequences. Cue-primed reinstatement was followed by a return to extinction sessions for three days to return to baseline extinction pressing. Following the third extinction session, animals were tested on a cocaine-primed reinstatement test. For this reinstatement session, animals received NAM or saline i.p. 30 minutes prior to the session, just as in extinction and cue-primed reinstatement testing. However, immediately before entering the chambers, animals were given a 10 mg/kg i.p. injection of cocaine. Active and inactive lever presses during cocaine-primed reinstatement did not result in the delivery of light or tone cues.

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type identification was made microscopically consulting methods by Cora, Kooistra, and Travlos (2015); Zenclussen, Casalis, Jensen, Woidacki, and Zenclussen (2014)

Experiment 2: Effects of Chronic NAM administration on locomotion

To examine if the effects of effects on responding were due to locomotor sedative effects, open field locomotor activity was assessed in the same cohort of rats used for reinstatement testing. Prior to locomotor testing, animals remained in their home cages 1-5 days following the final reinstatement procedure; injections of NAM or saline were given daily. On the day of locomotor testing, rats were given NAM or saline injections 30 minutes before being placed into standard locomotor chambers (Med Associates, St. Albans, VT). Locomotor behavior was recorded for a total of 2h. At the one-hour time point, all animals were given a 10 mg/kg i.p. injection of cocaine and returned to the chamber to continue locomotor recording for the second hour.

Experiment 3: Effect of chronic NAM administration on cocaine-primed reinstatement alone

In order to control for any possible ordering effects of the reinstatement test sessions, a separate cohort of rats was given only a cocaine-primed reinstatement session following extinction. All other procedures were identical to experiment 1. A timeline for the experiment can be seen in Figure 2A

Experiment 4: Effects of Acute NAM administration on cue- and cocaine-primed reinstatement

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Experiment 5: Effects of Chronic NAM administration on Food Reinstatement

In an effort to determine whether or not the effects of NAM administration on reinstatement are specific to drug reinforcers, a cohort of animals completed a food self-administration, extinction, and reinstatement paradigm as previously described by Cosme, Gutman, and LaLumiere (2015) and McFarland and Kalivas (2001). Briefly described, animals initially pressed on the active lever for an FR1 schedule for delivery of a 45 mg food pellet, followed progressively by sessions on FR3 and FR5 reinforcement schedules. Each rat was required to press for at least 100 food pellets per day for at least three days in order to progress to the next schedule of reinforcement. Completion of each reinforcement schedule also resulted in the presentation of both the light and tone cue for 5 seconds. After these criteria were reached on the FR5 schedule, extinction procedures began. As for cocaine studies, NAM (120 mg/kg) or saline injections began on day 1 of extinction and continued for the remaining duration of the experimental sessions. For food-primed reinstatement, two food pellets were placed in the food hoppers before the session began. During the first 30 minutes of the session, a single food pellet was delivered non-contingently every two minutes; the remaining time proceeded as a typical extinction session. Presses on either lever had no programmed consequences for the entire duration of the session. An experimental timeline can be seen in Figure 4A.

Data Analysis

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compare active lever presses on the last day of extinction and active lever pressing on the tests of reinstatement of NAM and SAL animals. Sidak's multiple comparisons test was used to examine whether each group or dose displayed an increase in active lever pressing in comparison to the final day of extinction. For locomotor tests, two-way repeated measures ANOVA was performed with time (5 minute bins) and group (NAM: 10 mg/kg, 30 mg/kg, 60 mg/kg, 120 mg/kg or SAL) as factors. Tukey’s multiple comparisons test was used to examine whether locomotor behavior increased in all groups due to administration of cocaine at the 1 hour time-point. One-way ANOVAs were performed to examine differences between groups in the total distance traveled (cm) for the first hour and second hour. Data shown are SEM and significance was considered p

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CHAPTER 3: RESULTS

Experiment 1: Chronic NAM administration reduces cue- but not cocaine-primed reinstatement in males but not females

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group also pressed significantly less than the 10 mg/kg group (p < 0.05). Following cue-primed reinstatement, rats underwent three additional extinction sessions, followed by a cocaine-primed reinstatement test. No effect of NAM treatment was observed on subsequent cocaine-primed reinstatement (Fig. 1D; F(4, 49) = 0.331, p = 0.856).

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Experiment 2: Chronic NAM administration has no effects on open-field locomotor or cocaine-primed locomotor

The same cohort of male animals from experiment 1 were tested on open field and cocaine-induced locomotor 30 minutes following a NAM injection; results are shown in Figure 1H-J. There were no differences between groups at any time point during the entire 120 minutes (Fig. 1H, F (4,49) = 1.045, p = 0.394). There was no interaction (F(92, 1127) = 1.07, p = 0.312) and no main effect of group (F(4, 49) = 1.045, p = 0.394) but there was a significant main effect of time (F(23, 1127) = 116.4, p <0.0001). Tukey’s multiple comparison tests revealed that for all groups distance traveled (cm) increased following an injection of cocaine (p < 0.0001). There were no differences between groups in total distance traveled during the first 60 minutes of open field testing (Fig. 1I, F(4,49) = 1.886, p = 0.128) or during the final 60 minutes following experimenter administration of cocaine (Fig. 1J, F(4, 49) = 0.981, p = 0.427).

Experiment 3: Chronic NAM administration had no effect on cocaine-primed reinstatement.

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SAL p = 0.05, NAM p < 0.05); however, treatment groups did not differ on active lever pressing during cocaine-primed reinstatement (Fig. 2C, F(1,11) = 0.134, p = 0.721).

Experiment 4: Acute NAM administration does not affect cue- or cocaine-primed reinstatement

Self-administration and extinction data for experiment 4 are shown in Figure 3B. Prior to receiving any NAM or saline, neither lever pressing behavior nor reinforcers earned differed across future groups (active lever pressing: (F(1, 144) = 0.543; p = 0.462); reinforcers earned: (F(1,144) = 0.695; p = 0.406). In contrast to chronic administration of NAM across extinction, there was no effect of acute 120 mg/kg NAM on active lever responding during cue-primed reinstatement (Fig. 3C, effect of reinstatement: F(1,12) = 39.93, p < 0.0001 SAL p < 0.005, NAM p < 0.005; F(1,12) = 0.092, p = 0.766). Likewise, there was no effect of acute 120 mg/kg NAM on cocaine-primed reinstatement (Fig. 3D, effect of reinstatement: F(1,12) = 26.87, p < 0.001, SAL p < 0.01, NAM p < 0.01; F(1,12) = 0.1213, p = 0.7337).

Experiment 5: Chronic NAM administration did not reduce cue or food-primed reinstatement

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CHAPTER 4: DISCUSSION Discussion

Results of the current study indicate that chronic, but not acute, systemic administration of NAM specifically reduces responding in cue-primed, but not cocaine-primed reinstatement in male rats but not female rats. This effect on cue-primed reinstatement is likely not due to a generalized sedative effect, motor effect, or generalized effect on motivation, as both locomotor activity, cocaine-primed reinstatement, and food reinstatement were unaffected.

Therapeutic Uses of Nicotinamide

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although NAM has been suggested by some to be a potential “anti-addiction weapon,”(Namazi, 2004), to our knowledge, there are no existing empirical scientific studies that examine NAM treatment in the context of drug self-administration, extinction, and reinstatement.

Cocaine Cue-primed Reinstatement Specificity

Our results suggest that the effects of NAM are specific to reducing cue-primed reinstatement. Examination of neural circuitry involved in different modalities of reinstatement unsurprisingly reflects that different stimuli engage overlapping yet distinct circuits. Of particular interest in regard to cue-primed reinstatement are the basolateral amygdala (BLA) and the central amygdala (CeA), as inactivation of these areas reduces cue-primed reinstatement (Feltenstein & See, 2008; See, 2005) but not cocaine-primed reinstatement (Grimm & See, 2000; McFarland & Kalivas, 2001). Though none have examined the effects of NAM, PARP-1 inhibition, or NAD+ supplementation in a reinstatement model, PARP-1 inhibition in the CeA but not the BLA reduces cocaine conditioned place preference (CPP) (Lax et al., 2017). Additionally, Lax et al. (2017) found that while PARP-1 was significantly activated in the CeA, it was not significantly increased in the BLA further implicating the potential specificity of PARP-1 effects in the CeA. The differential circuitry of cue-primed and cocaine-primed reinstatement suggests that the effects of NAM may be primarily influential within the amygdala. The importance and mechanistic effects of NAM within the CeA is yet to be determined and requires further study within a reinstatement model.

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lack of effect of NAM any locomotor activity, this further confirms the lack of any generalized motor or motivational effect of chronic NAM.

Nicotinamide and Sex differences

While NAM dose-dependently reduced cue-primed reinstatement in male rats, it was without effect in females. In order to investigate potential avenues of explanation for the resulting sex differences in NAM treatment, consulting studies relating to ischemia treatment are informative.

Sex differences have been reported in the effects of both NAM administration and PARP-1 inhibition as treatments for ischemia as well as oxidative stress. For example, Siegel and McCullough (2013) found that NAM treatment was effective in reducing oxidative stress induced damage in male mice, but showed no effects in females. Further, when PARP-1 knockout animals were tested, they found that the oxidative stress induced damage was significantly greater in PARP-1 knockout females while it was decreased in knockout males. However, in both PARP-1 knockout males and knockout females, treatment with NAM reduced the oxidative stress induced damage. Similar exacerbations of ischemic damage occur in female neonatal, adult, and aging female rats when PARP-1 is disrupted or inhibited (Hagberg et al., 2004; McCullough, Zeng, Blizzard, Debchoudhury, & Hurn, 2005) These results are similar to ours in such that our NAM treatment reduced cue-reinstatement in males, but had no effect in females indicating that the mechanism by which NAM reduces cue-primed reinstatement is sex dependent.

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ischemic injury (Siegel & McCullough, 2013). This could be due to the fact that females have higher NADH-linked respiration rates in brain mitochondria as NAD+ is reduced to NADH during this respiration (Gaignard et al., 2015). These differences suggest that mediation of PARP-1 or NAD+ may not be a viable treatment option in females; however, others did report that female rats’ infraction volume following ischemic injury was decreased similarly to male rats at the same dose and application method of NAM (Sakakibara, Mitha, Ogilvy, & Maynard, 2000). More research is needed regarding NAM as a viable application in females to reduce reinstatement responding. For example, future studies should investigate a variety of NAM doses in females to determine if the lack of effects on reinstatement could be related to a difference in effective dose.

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Mechanism of Action

Our results are limited to the behavioral effects of NAM. Based upon the broader literature, several functions of NAM could be at play in exerting the effect on cue-primed reinstatement, including: PARP-1 inhibition, NAD+ supplementation, and oxidative stress reduction. There is, however, some disagreement in the literature surrounding NAM’s function as a PARP inhibitor. Specifically, it has been argued that NAM’s ability to inhibit PARP-1 may only exist in in vitro testing and not in vivo (Kirkland, 2009). On the other hand, it has been suggested that NAM’s function may be dependent upon dosing such that only high doses of NAM lead to PARP-1 inhibition (5mM or more) while lower doses result in PARP-1 facilitation through provision of NAD+ (Riklis et al., 1990). Facilitation through NAD+ is thought to be beneficial due to the fact that PARP-1 activation is followed by NAD+ depletion and a resulting ATP depletion due to inhibition of glycolysis (Andrabi et al., 2014; Ying, Garnier, & Swanson, 2003) in cells including astrocytes (Suh et al., 2007; Tang et al., 2010) and overall brain tissue (Cosi & Marien, 1999; Zeng et al., 2007). PARP-1 activation can also lead to mitochondria dysfunction, cell death (David, Andrabi, Dawson, & Dawson, 2009; Fatokun, Dawson, & Dawson, 2014), and inhibition of astrocytic glutamate uptake capacity (Tang et al., 2010) all of which can be prevented by supplicating with NAD+ (Alano, Ying, & Swanson, 2004; Liu, Pitta, & Mattson, 2008; Tang et al., 2010).

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nicotinamide mononucleotide (NMN) which can then be converted to NAD+ (Dahl, Holm, Aukrust, & Halvorsen, 2012), it seems less likely that an increase of NAD+ would decrease cocaine seeking. Although an increase in NAMPT expression reduces ischemic injury in neurons (P. Wang et al., 2011), overexpression of NAMPT in the ventral tegmental area (VTA) of mice prior to cocaine CPP results in facilitation of cocaine-induced CPP (Kong et al., 2018). On the other hand, inhibition of VTA NAMPT prior to each CPP training session decreases cocaine-induced CPP and furthermore, the relative VTA content of NAD following CPP correlates with observed CPP scores (Kong et al., 2018). Interestingly, since NAMPT functions to convert NAM to NMN, inhibition of NAMPT would hypothetically result in an increase of NAM which could be working by unknown mechanisms to reduce cocaine CPP in this situation. The effect of NAMPT manipulation on cocaine CPP suggests that a proposed mechanism focusing on NAM’s role as an NAD+ precursor would not reduce reinstatement, but would rather facilitate reinstatement. Conversely, both deletion of PARP-1 as well as direct inhibition of PARP-1 is linked to increases the cellular content of NAD+ (Bai et al., 2011; Mukhopadhyay et al., 2017), which suggests that NAM’s actions as a PARP-1 inhibitor may be inseparable from its ability to increase NAD+ availability. To our knowledge, however, this has not been directly tested; therefore, future studies may investigate whether direct PARP-1 inhibition or supplementation with NAD+ is sufficient for attenuating reinstatement as well as whether or not the effects of chronic NAM administration are dependent upon either of these mechanisms.

PARP-1 and gene regulation

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Knackstedt, Melendez, & Kalivas, 2010). The reduction in mRNA and protein expression of GLT-1 is associated with increased methylation of the GLT-1 gene, Slcla2 (Kim et al., 2018). PARP-1 has many varied roles in gene regulation including DNA methylation (Kraus & Hottiger, 2013). More specifically, PARP-1 regulates the expression and activity of the DNA methyltransferase Dnmt1 (Caiafa, Guastafierro, & Zampieri, 2009). While the activity of PARP-1 has not been directly linked to Slcla2 expression, PARP-PARP-1 activation is known to impair glutamate uptake activity in cultured astrocytes (Tang et al., 2010)Likewise, interaction of PAR with Dnmt1 following cocaine self-administration has not been examined. Therefore, future studies can examine how PARP-1 activity may change across time and between different self-administration models. In addition, future studies may examine the regulatory nature of PARP-1 on Dmnt1 across time and between different self-administration models.

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B

0 5 10

0 50 100 150 Lever Presses 60 mg/kg 120 mg/kg Saline 30 mg/kg Active Inactive Self-Administration Extinction

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A

Self-administration Extinction

Cue Coc Loco

12d 14-17d 3d 1-5d

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0 10 20 30 40 50 60 70 80 90 100 110 120 0 500 1000 1500 2000 2500 Time (min)

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Figure 1: Chronic NAM administration reduces cue- but not cocaine-primed reinstatement in males, but not females. (A) Experimental Timeline. (B) Active and inactive lever presses across days during self-administration in male rats (left). Active lever presses between treatment groups are shown, right. No differences in active lever presses among treatment groups were seen across extinction. (C) Males who received daily i.p. 120 mg/kg and 60 mg/kg NAM injections throughout extinction pressed the active lever significantly less during a test of cue-primed reinstatement than those who received daily saline injections throughout extinction (p <0.05). Additionally, those in the 120 mg/kg group also pressed significantly less than those in the 10 mg/kg group (p < 0.05). (D) Males treated with 0-120 mg/kg NAM during extinction did not differ significantly when tested with a cocaine-primed reinstatement session. (E) Active and inactive lever presses across days during self-administration in female rats. A main effect of lever was observed between active and inactive lever presses (* p < 0.05). No differences in active lever presses among treatment groups were seen across extinction. (F) Females that received 120 mg/kg NAM did not differ significantly during a tests of cue-primed or (G) cocaine-primed reinstatement. (H) Ambulatory distance (cm) was measured beginning 30 minutes after a saline or NAM i.p. injection and continued for two hours. Arrow indicates 10 mg/kg i.p. cocaine injection given at the 60 minute mark. (I) No significant differences were seen between groups during the open field behavior of the first hour (t = 0-60). (J) No significant differences were seen between groups following the cocaine injection during the second hour (t = 60-120). Data shown in H-J are from the same male rats as in B-D. * indicates significant difference between active and inactive lever pressing (B) and between treatment groups by post-hoc analysis (C).

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Figure 2: The effects of chronic NAM administration are specific to cue-primed reinstatement. (A) Experimental timeline. (B) Lever pressing across self-administration and extinction. A main effect of lever was observed between active and inactive lever presses (* p < 0.05). (C) No significant differences between groups were seen during the cocaine-primed reinstatement.

Figure 2:

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SAL NAM 0 20 40 60 80 100

Cocaine-primed

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7

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Self-Administration Extinction

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Figure 3: Acute NAM administration did not affect cue- or cocaine-primed reinstatement.

(A) Experimental timeline. (B) Active and inactive lever presses across self-administration and extinction. A main effect of lever was observed between active and inactive lever presses (* p < 0.05). (C) No significant differences between groups were seen during a cue-primed reinstatement test after receiving 120 mg/kg injections of NAM thirty minutes prior to the test session. (D) No significant differences between groups were seen during the cocaine-primed reinstatement after receiving 120 mg/kg injections of NAM 30 minutes prior to the test session.

A

Figure: 3

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Cue-primed 7 7 SAL NAM 0 50 100

Cocaine-primed 7 7

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Figure: 4

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Figure 4: Chronic NAM administration did not affect cue- or food-primed reinstatement. (A) Experimental timeline. (B) Animals reliably self-administered food and extinguished responding reliably during extinction. A main effect of lever was observed between active and inactive lever presses (* p < 0.05). There was a significant interaction between group and session during extinction. Multiple comparisons reveled that the NAM group had significantly fewer active lever presses on day 1 of extinction than the saline group (* p <0.0001). Active lever pressing the remaining days was not significantly different between groups (p > 0.9999). (C) No significant differences between groups were seen during a cue-primed reinstatement test after receiving 120 mg/kg injections of NAM 30 minutes prior to the test session. (D) No significant differences between groups were seen during the food-primed reinstatement after receiving 120 mg/kg injections of NAM 30 minutes prior to the test session.

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