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. Author manuscript; available in PMC: 2021 Mar 1.
Published in final edited form as: Psychopharmacology (Berl). 2019 Dec 7;237(3):669–680. doi: 10.1007/s00213-019-05404-y

The Effects of Nicotinamide on Reinstatement to Cocaine Seeking in Male and Female Sprague Dawley Rats

Emily A Witt 1, Kathryn J Reissner 1
PMCID: PMC7039762  NIHMSID: NIHMS1546012  PMID: 31811351

Abstract

Rationale:

Interventions for psychostimulant use disorders are of significant need. Nicotinamide (NAM) is a small molecule that can oppose cellular adaptations observed following cocaine exposure in the rodent self-administration and reinstatement model of addiction. In addition, utility of NAM against symptoms of withdrawal and vulnerability to relapse to cocaine use has been suggested by case studies and anecdotal reports. However, the empirical effects of nicotinamide on drug seeking behaviors have not been examined.

Objective:

The objective of the current study was to investigate the effects of systemic NAM administration on reinstatement to cocaine seeking, using the rat self-administration/extinction/reinstatement model of cocaine addiction.

Methods:

Male and female Sprague-Dawley rats were trained to self-administer i.v. cocaine or food pellets for 2 hrs per day for 12 days, followed by 14-17 days of extinction, during which i.p. NAM injections (0-120 mg/kg) were given 30 minutes prior to each extinction or reinstatement session. Rats were tested on cue-, cocaine-, or food-primed reinstatement, as well as locomotor activity.

Results:

Chronic NAM administered throughout extinction dose-dependently attenuated cue-primed reinstatement in male rats, but not female rats. In contrast, acute NAM given once prior to reinstatement had no effect on reinstatement. Chronic NAM had no effect on locomotor activity or reinstatement to food seeking.

Conclusions:

The specificity of NAM against cue-primed reinstatement indicates that NAM may influence responsiveness to drug-associated cues, specifically in males. Future studies will examine the mechanism(s) by which NAM may exert this effect.

Keywords: Cocaine, Reinstatement, Nicotinamide, NAD/NADH, PARP-1, sex differences

Introduction

Nicotinamide (NAM), a form of vitamin B3, component of crucial coenzymes NAD+ and NADP+, and free radical scavenger (Negi et al. 2010), is widely used clinically to treat pellagra (niacin deficiency), bullous pemphigoid, acne and rosacea, atopic dermatitis, and skin photoageing (Mutasim 2003; Surjana and Damian 2011). It also shows promise in preserving and enhancing neurocognitive function in a variety of disease models such as Alzheimer’s, traumatic brain injury (ischemia and contusion injury), and Parkinson’s disease (Rennie et al. 2015). In addition, NAM has been proposed as an effective treatment for substance abuse (Namazi 2004; Otte et al. 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 the rodent reinstatement model of addiction. For example, NAM is a free radical scavenger that protects against cellular oxidative stress as well as reactive oxygen species (ROS) following oxidative stress (Bayrakdar et al. 2014; Negi et al. 2010; Song et al. 2017). Cocaine exposure in vitro as well as in vivo increases the expression of oxidative stress biomarkers including 8-hydroxyguanine (8-OHG) in the nucleus accumbens (NAc) (Jang et al. 2015), as well as superoxide dismutase and malondialdehyde in the frontal cortex, hippocampus, and dorsal striatum (Pomierny-Chamiolo et al. 2013; Steinmetz et al. 2018). Elevated levels of ROS following oxidative stress induce damage to DNA, lipids, and proteins (Schieber and Chandel 2014). Moreover, 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 response to ROS-induced DNA damage, upregulation of the DNA repair enzyme, poly(ADP-ribose)polymerase (PARP-1) is also found (Jiang et al. 2018; Lonskaya et al. 2005). PARP-1 expression and activity is also upregulated within the rodent brain following both non-contingent cocaine and cocaine self-administration (Lax et al. 2017; Scobie et al. 2014). Beyond the role of PARP-1 as a DNA repair enzyme, PARP-1 serves as a component in transcriptional regulation, poly(ADP-ribosyl)ation (PARylation) of various cellular targets (Gupte et al. 2017; Kraus and Hottiger 2013), and promotes the motivational aspects of chronic cocaine use. For example, overexpression of PARP-1 promotes cocaine conditioned place preference (CPP), increases self-administration of cocaine, and augments locomotor responses to cocaine (Lax et al. 2017; Scobie et al. 2014). As mentioned, NAM attenuates ROS levels and protects against cellular oxidative stress (Bayrakdar et al. 2014; Negi et al. 2010; Song et al. 2017); however, NAM is also an inhibitor of PARP-1 (Javle and Curtin 2011; Riklis et al. 1990). Given that inhibition of PARP-1 is found to reduce cocaine CPP (Lax et al. 2017), this suggests that, as a PARP-1 inhibitor, NAM may impact cocaine seeking.

Based on evidence that chronic i.p. NAM can reduce oxidative stress (Turunc Bayrakdar et al. 2014), PARP-1 activity (Guzyk et al. 2016; Virag and Szabo 2002), and increase protective NAD+ levels (Wang et al. 2017) we sought to determine whether chronic i.p. administration of NAM would influence reinstatement to cocaine seeking. Five experiments were performed in order to test this hypothesis. The first two experiments were designed to investigate the effects of chronic NAM on cue-primed and cocaine-primed reinstatement as well as locomotor behavior or locomotor responses to cocaine first in male and second female rats. Next, the effect of chronic NAM administration on cocaine-reinstatement in isolation was examined. The fourth experiment was to investigate whether chronic NAM was necessary to affect reinstatement in male rats; therefore, NAM was given acutely prior to the cue and cocaine-primed reinstatement sessions following cocaine self-administration and extinction. Finally, the effect of chronic NAM administration on food reinstatement was examined.

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 were 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

Rats were anesthetized with ketamine (100 mg/kg, i.m.) and xylazine (7 mg/kg, i.m.). Custom in-house indwelling catheters for self-administration were then surgically implanted into the right jugular vein to allow for i.v. cocaine delivery, described previously by (Fuchs et al. 2007; Scofield et al. 2016). Catheter tubing ran from the jugular vein subcutaneously and exited between the shoulder blades of the animal to be capped securely with sealed Tygon tubing. At least five days of post-operative care and recovery were allotted for all animals prior to the initiation of cocaine self-administration. Throughout recovery, as well as for the duration of self-administration procedures, 0.1 mL gentamicin (5 mg/mL) and 0.1 mL heparinized saline (100U/mL) were administered daily 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 the food training session, rats received rations of ~20g of chow daily. Active lever presses resulted in the delivery of one food pellet (Bio Serv, Flemington, NJ) and continued until rats reached a criterion of 100 active lever presses or 8 hours had elapsed. Presses on the inactive lever had no consequences.

Criterion for self-administration was a minimum of 10 infusions per day (0.75 mg/kg/infusion, 2 h/day) for 12 days, which varied from 12-14 days total. Active lever presses during cocaine self-administration resulted in delivery of a cocaine infusion, as well as the illumination of a stimulus light above the active lever and a tone presentation, simultaneously for a programed duration of 5 sec. A 20 sec timeout was enacted following the delivery of each infusion during which time active lever presses were recorded, but had no consequences. Inactive lever presses during cocaine self-administration sessions had no programmed responses for the entirety of the session. The self-administration phase was followed by extinction training (2 h/day). Extinction was performed for 14-17 days, such that all rats would reinstate on the same test day. During extinction, presses on the active lever no longer resulted in cocaine infusions, lights, or tone presentation. All sessions were completed during the animals’ dark phase (7am-7pm) at the same time each day, between 7:30am and 5pm daily, depending on the experiment.

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

Given the relatively short half-life of NAM (100 mg/kg: 3.4 hours (Stratford and Dennis 1994)), 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 min prior to every extinction session and subsequent reinstatement tests. Twenty-four hours following the last extinction session, rats were tested on a 2 h cue-primed reinstatement session. This session began with a 5 sec presentation of the light and tone cues that 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. 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 min 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.

Effects of chronic NAM administration on locomotion in males

To examine if the effects of NAM on responding were due to locomotor 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 min before placement into standard locomotor chambers (Med Associates, St. Albans, VT). Locomotor behavior was recorded for a total of 2 h. 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 2: Effects of chronic NAM administration on cue- and cocaine-primed reinstatement in females

A separate dose response of NAM was performed on cue- and cocaine-primed reinstatement in female rats. Saline, 30 mg/kg, 60 mg/kg, 120 mg/kg; 1mL/kg was given 30 min prior to each extinction session and reinstatement test. Although comparisons of the effects of NAM between males and females are limited, doses were selected following consultation with the literature. While some find the effects of NAM to be similar between sexes (Miki et al. 2007; Sakakibara et al. 2000) others find the effective dose in males to be ineffective in females (Batra et al. 1980; Siegel and McCullough 2013; Vital et al. 2006). When effective, NAM doses in females are either the same as in males (Miki et al. 2007; Sakakibara et al. 2000) or higher (Kamat et al. 1980). Pilot examination of a higher dose here (300 mg/kg i.p.) in female rats was found to reduce locomotor behavior and weight gain (data not shown). Growth inhibition and weight loss have been reported at higher doses of nicotinamide (1000 mg/kg and 600 mg/kg) (Cosmetic Ingredient Review Expert 2005; Knip et al. 2000); accordingly, 120 mg/kg was the maximum dose employed for this study. Subjects received vaginal swabs after completion of the reinstatement test sessions, to prevent stressor effects on reinstatement. Vaginal swabs were transferred to glass slides, allowed to dry, and stained with Wright’s Stain (Fisher Chemical W35-25) for later examination. Cell type identification was made microscopically as described (Cora et al. 2015; Zenclussen et al. 2014). Locomotor activity was assessed in the same cohort of female rats used for reinstatement testing in a manner identical to experiment 1.

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

Because we hypothesized that NAM would alter both cue- and cocaine-primed reinstatement, we designed an experiment to control for any possible ordering effects of the reinstatement test sessions. To do this, a separate cohort of male rats was given a single cocaine-primed reinstatement session following extinction. All other procedures were identical to experiment 1.

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

To determine whether or not chronic NAM administration was necessary to produce effects on reinstatement, or whether an acute exposure would be sufficient, rats completed cocaine self-administration and extinction as in experiment 1; however in this case NAM injections were only given once, 30 min prior to cue- or cocaine-primed reinstatement sessions. All other procedures were identical to experiment 1.

Experiment 5: Effects of chronic NAM administration on food reinstatement

To determine whether or not the effects of NAM administration on reinstatement are specific to drug reinforcers, a cohort of male rats completed a food self-administration, extinction, and reinstatement paradigm as previously described by Cosme et al. (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 sec. 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 min of the session, a single food pellet was delivered non-contingently every 2 min; the remaining time proceeded as a typical extinction session. Presses on either lever had no programmed consequences for the entire duration of the reinstatement session.

Statistical Analysis

Statistical analysis was performed using Prism 7 software. For self-administration and extinction measures, two-way repeated measures ANOVA were performed with day and dose as factors. Active lever presses and the number of infusions or food pellets received throughout self-administration were dependent variables. For reinstatement data, a two-way ANOVA was used to compare active lever presses on the last day of extinction to 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. Additionally, Sidak’s multiple comparisons test was used to examine whether between dose differences in active lever pressing existed on reinstatement day or the final day of extinction. For locomotor tests, two-way repeated measures ANOVA was performed with time (5 min bins) and dose 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 ≤ 0.05.

Results

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

Experimental timeline is shown in Figure 1a. Following 12-14 days of cocaine self-administration, male rats were treated with varying doses of NAM prior to each extinction and reinstatement session. Prior to receiving NAM, future treatment groups did not differ across days on active or inactive lever presses (p > 0.05) or interaction between group and day (p > 0.05) (Fig. 1b). Likewise, future treatment groups did not differ on reinforcers earned during self-administration, prior to receiving NAM or SAF (data not shown, (p > 0.05) or interaction between group and day (p > 0.05). There were no significant differences between treatment groups during extinction (Fig. 1b; (p > 0.05). All groups demonstrated significant cue-primed reinstatement (Fig. 1c; F(1,50) = 163, p < 0.0001; 10 mg/kg: p < 0.0001, 30 mg/kg: p < 0.0001, 60 mg/kg: p < 0.001, 120 mg/kg: p = 0.005, SAF: p < 0.0001) and cocaine-primed reinstatement (F(1,49) = 73.1, p < 0.0001, 10 mg/kg: p < 0.01, 30 mg/kg: p < 0.05, 60 mg/kg: p < 0.01, 120 mg/kg: p = 0.0001, SAF: p < 0.001). A dose-dependent effect of NAM on active lever responding was observed during cue-primed reinstatement (Fig. 1c; (F(4, 50) = 3.105, p < 0.05)). Sidak’s multiple comparisons revealed that the 60 mg/kg (p < 0.05) and 120 mg/kg (p < 0.001) treatment groups responded significantly less on the active lever than the saline treatment group. Additionally, the 120 mg/kg group also pressed significantly less than the 10 mg/kg group (p < 0.05). Inactive lever pressing between groups was not significantly different during cue-primed reinstatement (p > 0.05). Following cue-primed reinstatement, rats underwent three additional extinction sessions, followed by a cocaine-primed reinstatement test. As indicated above, all groups demonstrated significant cocaine-primed reinstatement; however, no effect of NAM treatment was observed between groups on cocaine-primed reinstatement (Fig. 1d; p > 0.05). To more closely examine whether or not differences in cue-primed reinstatement may be related to differences in extinction learning, extinction responding was further examined by analyzing extinction pressing in 5 min bins across individual sessions. There were no group differences observed between 5 min binned active lever pressing on any day of extinction in the males (p > 0.05).

Fig. 1: Chronic NAM administration reduces cue- but not cocaine-primed reinstatement in male rats.

Fig. 1:

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(a) Experimental Timeline. (b) Active lever presses between treatment groups (Saline: ◯, 10 mg/kg: Inline graphic, 30 mg/kg: Inline graphic, 60 mg/kg: Inline graphic, and 120 mg/kg: ◆) are shown during self-administration (future groups) and extinction (c) Active lever presses during cue-primed reinstatement tests, (d) Active lever presses during cocaine-primed reinstatement tests. (e) Ambulatory distance (cm) from 2 h locomotor sessions displayed across time (Saline: ◯, 10 mg/kg: Inline graphic, 30 mg/kg: Inline graphic, 60 mg/kg: Inline graphic, and 120 mg/kg: ◆) Arrow indicates 10 mg/kg i.p. cocaine injection given at the 60 min mark. (f) Total distance travelled per group during the first 60 min prior to delivery of i.p. cocaine. (g) Total distance travelled per group during the 60 min following delivery of i.p. cocaine. Data shown in e-g are from the same male rats as in b-d. * indicates significant difference (p < 0.05) between treatment groups by post-hoc analysis (c).

The same cohort of rats was tested on open field and cocaine-induced locomotor 30 min following a NAM injection; results are shown in Figure 1e. There was a significant main effect of time (F(23, 1127) = 116.4, p <0.0001), however there were no differences between groups at any time point across the entire 120 minutes (Fig. 1e, p > 0.05). Tukey’s multiple comparison tests revealed that for all groups, distance traveled (cm) increased following an injection of cocaine (p < 0.0001). Examinations of total distance traveled during the first 60 min of open-field testing using a one-way ANOVA found no significant differences between groups (Fig. 1f, p > 0.05). Likewise, during the final 60 min following experimenter administration of cocaine (Fig. 1g, p > 0.05), no differences were observed.

Experiment 2: Chronic NAM administration has no effects on cue- or cocaine-primed reinstatement in females

Following cocaine self-administration, female rats were treated with varying doses of NAM 30 min prior to each extinction and reinstatement session (Fig. 2a). Prior to receiving NAM or SAL injections, two-way ANOVAs found that future groups did not differ on active or inactive lever presses (p > 0.05) or reinforcers earned (p > 0.05) (Fig. 2b). Two-way ANOVA revealed main effects of session for both cue-primed (F(1,43) = 0.4881, p < 0.0001) and cocaine-primed reinstatement (F(1,43) = 39.82; p < 0.0001) (Fig. 2c, d). Sidak’s multiple comparisons tests revealed that all treatment groups demonstrated significant cue-primed (30 mg/kg: p < 0.0001, 60 mg/kg: p < 0.0001, 120 mg/kg: p = 0.005, SAL: p < 0.005) and cocaine-primed reinstatement (30 mg/kg: p < 0.05, 60 mg/kg: p < 0.005, 120 mg/kg: p < 0.005) with the exception of the saline cocaine-prime group (p > 0.05). There were no significant differences between any dose and the saline group active lever presses during the cue-primed reinstatement session (p > 0.05). Likewise, no significant differences were found between the active lever presses of any dose of NAM or SAL groups during the cocaine-primed reinstatement (p > 0.05).

Fig. 2: Chronic NAM administration does not affect reinstatement in female rats.

Fig. 2:

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(a) Experimental Timeline. (b) Active lever presses between treatment groups (Saline: ◯, 30 mg/kg: Inline graphic, 60 mg/kg: Inline graphic, and 120 mg/kg: ◆) are shown during self-administration (future groups) and extinction. (c) Active lever presses during cue-primed reinstatement. (d) Active lever presses during cocaine-primed reinstatement tests. (e) Ambulatory distance (cm) from 2 h locomotor sessions displayed across time (Saline: ◯, 30 mg/kg: Inline graphic, 60 mg/kg: Inline graphic, and 120 mg/kg: ◆). (f) Total distance travelled per group during the first 60 min prior to delivery of i.p. cocaine. (g) Total distance travelled per group during the 60 min following delivery of i.p. cocaine. Data shown in e-g are from the same female rats as in b-d.

The same cohort of females were tested on open field and cocaine-induced locomotor 30 min following a NAM injection; results are shown in Figure 2e. There was no main effect of group or interaction across the entire 120 min of testing (p > 0.05), during the first 60 min (p > 0.05), or during the final 60 min following cocaine challenge (Fig. 2e; p > 0.05) as revealed by two-way ANOVAs. There was, however, a significant main effect of time (Fig. 2e; F(23, 966) = 57.89; p<0.0001). Tukey’s multiple comparison tests revealed that for all groups, distance traveled (cm) increased following an injection of cocaine (p < 0.05). Examinations of total distance traveled (cm) across the entire first 60 min of open-field testing using a one-way ANOVA, found no significant differences between groups (Fig. 2f; p > 0.05). Likewise, during the final 60 min following cocaine prime (Fig. 2g), no differences were observed (p > 0.05).

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

Experiment 1 indicates that chronic NAM had no effect on a test of cocaine-primed reinstatement when it occurred subsequent to a cue-primed reinstatement. In order to determine whether this lack of effect on cocaine-primed reinstatement might be due to an ordering effect associated with multiple reinstatement tests, a separate cohort of animals was chronically administered 120 mg/kg NAM or saline during extinction and then tested on cocaine reinstatement only (Fig. 3a); results are shown in Figure 3. Prior to receiving NAM injections, two-way ANOVAs revealed that while there was not a main effect of group, there was a significant interaction between session and group for active lever presses (F(11,121) = 2.121, p <0.05) and inactive lever presses (F(11,121) = 1.953, p < 0.05). Sidak’s multiple comparisons tests revealed that on the first day of self-administration the future NAM group pressed significantly more times on the active (p < 0.0005) and the inactive (p < 0.0001) lever (Fig. 3b). Multiple comparisons did not reveal any other significant differences. There were no significant differences in the number of reinforcers earned between groups (p > 0.05). Both groups demonstrated significant cocaine-primed reinstatement behavior (F(1,11) = 15.02, p < 0.005: SAL p = 0.05, NAM p < 0.05); however, treatment groups did not differ on active lever pressing during cocaine-primed reinstatement (Fig. 3c; p > 0.05).

Fig. 3: The effects of chronic NAM administration are specific to cue-primed reinstatement.

Fig. 3:

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(a) Experimental timeline. (b) Lever pressing (Active NAM (●), active Saline (◯) and inactive NAM (◼), inactive saline (◻)) across self-administration. * indicates significant difference (p < 0.05) between NAM and Saline Active presses as well as NAM and Saline inactive presses (c) Active lever presses of male rats during cocaine-primed reinstatement test.

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 4b. Prior to receiving any NAM or saline (timeline: Fig. 4a), neither lever pressing behavior nor reinforcers earned differed across future groups (active & inactive lever pressing: p > 0.05; reinforcers earned: p > 0.05). 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. 4c) Likewise, there was no effect of acute 120 mg/kg NAM on cocaine-primed reinstatement (Fig. 4d).

Fig. 4: Acute NAM administration did not affect cue- or cocaine-primed reinstatement.

Fig. 4:

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(a) Experimental timeline. (b) Active lever presses (NAM (◆); Saline (◯) lever presses across self-administration and extinction. (c) Active lever presses of male rats during cue-primed reinstatement tests (d) Active lever presses of male rats during cocaine-primed reinstatement test.

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

Food self-administration, extinction, and reinstatement data are shown in Figure 5b. Prior to receiving NAM or SAL injections (timeline: Fig. 5a), lever pressing or reinforcers earned did not differ across future groups. A two-way ANOVA revealed a significant interaction between group and session during extinction (F(14, 196) = 6.104; p < 0.0001). Sidak’s multiple comparisons revealed 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 across the remaining days was not significantly different between groups. A two-way ANOVA revealed a significant effect of cue-primed reinstatement in comparison to extinction active lever pressing (F(1,14) = 7.646, p < 0.05); however Sidak’s multiple comparisons revealed that neither group pressed significantly higher in the cue-primed reinstatement session than they did in extinction. There were no differences in active lever presses between groups on the cue-primed reinstatement session (Fig. 5c). There was a significant effect of reinstatement for food-primed reinstatement (F(1,14) = 23.11, p < 0.001), and Sidak’s multiple comparisons revealed that both groups pressed significantly more in the food-primed reinstatement session than during extinction (NAM: p < 0.01, SAL: p < 0.01). There was no effect of group on food-primed reinstatement (Fig. 5d).

Fig. 5: Chronic NAM administration did not affect cue- or food-primed reinstatement.

Fig. 5:

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(a) Experimental timeline. (b) Active lever presses (NAM (◆); Saline (◯) during food self-administration and active lever presses across extinction are shown. (c) Active lever presses of male rats during cue-primed reinstatement test. (d) Active lever presses of male rats during food-primed reinstatement test.

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 but not female rats. The effect on cue-primed reinstatement is likely not due to a generalized motor effect, or generalized effect on motivation, as locomotor activity, cocaine-primed reinstatement, and food reinstatement were unaffected. Additionally, investigation of 5 min bins of lever pressing across extinction days suggests that the effect on cue-primed reinstatement was not the result of facilitated extinction learning.

Therapeutic Uses of Nicotinamide

NAM shows promise as a preventative treament for non-melanoma skin cancers (Surjana et al. 2012) and has neuroprotective effects in animal models of Alzheimer’s, traumatic brain injury (ischemia and contusion injury), and Parkinson’s disease (for full review see: (Rennie et al. 2015)). Within these animal models, NAM is known to produce behavioral changes as well, including improved short-term and long-term memory in Alzheimer’s disease model mice (Green et al. 2008), improved reference memory acquisition and reversal learning in post-cortical contusion injury rats (Peterson et al. 2012), and improved motor functioning in Parkinson’s disease model mice (Xu et al. 2012). When administered in combination with tryptophan, early studies indicated that NAM treatment may improve depression symptomology in humans (Chouinard et al. 1977; Chouinard et al. 1978) and NAM administration alone in rats prevents the development of a subordinate status in animals that were experimentally characterized as ‘highly anxious’ (Hollis et al. 2015). With respect to addiction, 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 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 and See 2008; See 2005) but not cocaine-primed reinstatement (Grimm and See 2000; McFarland and Kalivas 2001). Though none have examined the effects of NAM, PARP-1 inhibition, or NAD+ supplementation in a reinstatement test following extinction, PARP-1 inhibition in the CeA but not the BLA reduces CPP (Lax et al. 2017). Accordingly, it will be of interest to determine whether the effects of NAM within the CeA and/or BLA may contribute to its effects on reinstatement.

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 ischemia-induced damage in male mice, but not female mice. Further, when PARP-1 knockout animals were tested, ischemia-induced damage was significantly greater in PARP-1 knockout females, despite being decreased in knockout males. However, in both PARP-1 knockout males and knockout females, treatment with NAM reduced the 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 et al. 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.

Likewise, there are also known sex-dependent differences in the expression of oxidative stress. For example, measurement of oxidative stress biomarkers in healthy human subjects indicates females to have lower basal levels of oxidative stress than males (Ide et al. 2002; Kander et al. 2017); and, in rodents exposed to chronic or acute cocaine, females exhibit lower DNA damage levels (de Souza et al. 2014). In addition to suggesting that following cocaine exposure females my experience lower levels of oxidative stress or simply less oxidative stress induced damage, it further suggests that females may also experience lower levels of PARP-1 activity in response to oxidative stress. In fact, overall, females seem to be less susceptible to oxidative stress and have more antioxidant potential than males (Kander et al. 2017). However, oxidative stress and PARP-1 activity following cocaine self-administration and extinction have not been examined in female rats. Therefore, future studies may examine sex differences of oxidative stress and PARP-1 responses to cocaine self-administration as well as the sex-dependent divergence of these mechanisms following NAM administration.

Interestingly, we did not observe a difference between sexes in self-administration, as have been reported previously (for full review, see (Becker and Koob 2016)). Female rats have been shown to acquire cocaine self-administration more rapidly than male rats at a 0.2 mg/kg/infusion procedure (Carroll et al. 2002; Lynch and Carroll 1999) and maintain higher levels of intake (mg/kg) under an FR1 schedule (Lynch and Carroll 1999). The lack of differences observed in our experiments may be due to the fact that the male and females for this study were studied in separate cohorts at separate times. It may also be a factor of dose as male rats self-administering a higher dose of cocaine (1.0mg/kg/infusion) acquire cocaine self-administration significantly faster than female rats (Caine et al. 2004). Additionally, there are others, who at an FR1 at 0.75mg/kg/infusion cocaine, as was used in our experiments, did not observe any sex differences, but later observed differences in the same cohort under an FR5 schedule of reinforcement (Jordan and Andersen 2018).

It is certainly possible that an estrous-stage dependent effect of NAM was not revealed by our investigation. For this reason, vaginal swabs were taken and cycle identifications were made for experiment 2. To minimize the effect of stress on reinstatement behavior, swabs were only taken immediately after the reinstatement tests. However, 11-12 animals per dose group does not allow for statistical power to make determinations regarding the effect of estrous stages within dose groups. Further, it is known that cocaine can influence estrous cycling (Broderick and Malave 2014), further complicating efforts to assess a dose-dependent effect between stages. Future studies will be required to investigate this possibility in more detail.

Mechanism of Action

Several functions of NAM could be at play in exerting the effect observed on cue-primed reinstatement, including NAD+ supplementation, as well as inhibition of oxidative stress and/or PARP-1 inhibition. PARP-1 inhibition and NAD+ supplementation 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 et al. 2003) in cells including astrocytes (Suh et al. 2007; Tang et al. 2010) and overall brain tissue (Cosi and Marien 1999; Zeng et al. 2007). PARP-1 activation can also lead to mitochondria dysfunction, cell death (David et al. 2009; Fatokun et al. 2014), and inhibition of astrocytic glutamate uptake capacity (Tang et al. 2010) all of which can be prevented by supplementing with NAD+ (Alano et al. 2004; Liu et al. 2008; Tang et al. 2010). Although, recent studies investigating the mechanism of conversion of NAM to NAD+ within the cocaine CPP context suggest that supplementing with NAD+ may not be beneficial (Kong et al. 2018). However, this has not yet been examined in a reinstatement model. Additionally, although PARP-1 activation has been linked to cell death as previously mentioned, others have shown that the cocaine-induced upregulation of PARP-1 expression did not result in the elicitation of neuronal apoptosis (Dash et al. 2017).

In conclusion, evidence presented herein indicates efficacy of NAM against responsiveness to drug-paired cues in male rats. Further investigation of the circuitry and cellular mechanism of this effect such as PARP-1 inhibition, oxidative stress reduction, and NAD+ supplementation will assist in the elucidation of the cellular mechanisms of addiction. Further, because NAM had no discernable effect on extinction learning, it is likely that its effects on cocaine seeking might also extend to addiction models which employ forced abstinence, such as the incubation of cocaine craving model. Lastly, investigation of these mechanisms in females as well as males will contribute to the understanding of sex differences in both addiction as well as efficacy of treatment options.

Acknowledgements:

This work was supported by DHHS grants R01DA041455 (KJR) and T32 DA007244 (EAW). The authors thank members of the Reissner lab for constructive criticisms on a previous version of this manuscript.

Footnotes

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of a an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

Conflict of interest statement: On behalf of all authors, the corresponding author states that there is no conflict of interest.

References

  1. Alano CC, Ying W, Swanson RA (2004) Poly(ADP-ribose) polymerase-1-mediated cell death in astrocytes requires NAD+ depletion and mitochondrial permeability transition J Biol Chem 279:18895–18902 doi: 10.1074/jbc.M313329200 [DOI] [PubMed] [Google Scholar]
  2. Andrabi SA et al. (2014) Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis Proc Natl Acad Sci U S A 111:10209–10214 doi: 10.1073/pnas.1405158111 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bayrakdar ET, Armagan G, Uyanikgil Y, Kanit L, Koylu E, Yalcin A (2014) Ex vivo protective effects of nicotinamide and 3-aminobenzamide on rat synaptosomes treated with Abeta(1-42) Cell Biochem Funct 32:557–564 doi: 10.1002/cbf.3049 [DOI] [PubMed] [Google Scholar]
  4. Becker JB, Koob GF (2016) Sex Differences in Animal Models: Focus on Addiction Pharmacol Rev 68:242–263 doi: 10.1124/pr.115.011163 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Broderick PA, Malave LB (2014) Cocaine Shifts the Estrus Cycle Out of Phase and Caffeine Restores It J Caffeine Res 4:109–113 doi: 10.1089/jcr.2014.0015 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Caine SB, Bowen CA, Yu G, Zuzga D, Negus SS, Mello NK (2004) Effect of gonadectomy and gonadal hormone replacement on cocaine self-administration in female and male rats Neuropsychopharmacology 29:929–942 doi: 10.1038/sj.npp.1300387 [DOI] [PubMed] [Google Scholar]
  7. Carroll ME, Morgan AD, Lynch WJ, Campbell UC, Dess NK (2002) Intravenous cocaine and heroin self-administration in rats selectively bred for differential saccharin intake: phenotype and sex differences Psychopharmacology (Berl) 161:304–313 doi: 10.1007/s00213-002-1030-5 [DOI] [PubMed] [Google Scholar]
  8. Chouinard G, Young SN, Annable L, Sourkes TL (1977) Tryptophan-nicotinamide combination in depression Lancet 1:249. [DOI] [PubMed] [Google Scholar]
  9. Chouinard G, Young SN, Annable L, Sourkes TL, Kiriakos RZ (1978) Tryptophan-nicotinamide combination in the treatment of newly admitted depressed patients Commun Psychopharmacol 2:311–317 [PubMed] [Google Scholar]
  10. Cora MC, Kooistra L, Travlos G (2015) Vaginal Cytology of the Laboratory Rat and Mouse: Review and Criteria for the Staging of the Estrous Cycle Using Stained Vaginal Smears Toxicol Pathol 43:776–793 doi: 10.1177/0192623315570339 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cosi C, Marien M (1999) Implication of poly (ADP-ribose) polymerase (PARP) in neurodegeneration and brain energy metabolism. Decreases in mouse brain NAD+ and ATP caused by MPTP are prevented by the PARP inhibitor benzamide Ann N Y Acad Sci 890:227–239 [DOI] [PubMed] [Google Scholar]
  12. Cosme CV, Gutman AL, LaLumiere RT (2015) The Dorsal Agranular Insular Cortex Regulates the Cued Reinstatement of Cocaine-Seeking, but not Food-Seeking, Behavior in Rats Neuropsychopharmacology 40:2425–2433 doi: 10.1038/npp.2015.92 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dash S et al. (2017) Poly (ADP-Ribose) Polymerase-1 (PARP-1) Induction by Cocaine Is Post-Transcriptionally Regulated by miR-125b eNeuro 4 doi: 10.1523/ENEURO.0089-17.2017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. David KK, Andrabi SA, Dawson TM, Dawson VL (2009) Parthanatos, a messenger of death Front Biosci (Landmark Ed) 14:1116–1128 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. de Souza MF, Goncales TA, Steinmetz A, Moura DJ, Saffi J, Gomez R, Barros HM (2014) Cocaine induces DNA damage in distinct brain areas of female rats under different hormonal conditions Clin Exp Pharmacol Physiol 41:265–269 doi: 10.1111/1440-1681.12218 [DOI] [PubMed] [Google Scholar]
  16. Fatokun AA, Dawson VL, Dawson TM (2014) Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities Br J Pharmacol 171:2000–2016 doi: 10.1111/bph.12416 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Feltenstein MW, See RE (2008) The neurocircuitry of addiction: an overview Br J Pharmacol 154:261–274 doi: 10.1038/bjp.2008.51 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fuchs RA, Eaddy JL, Su ZI, Bell GH (2007) Interactions of the basolateral amygdala with the dorsal hippocampus and dorsomedial prefrontal cortex regulate drug context-induced reinstatement of cocaine-seeking in rats Eur J Neurosci 26:487–498 doi: 10.1111/j.1460-9568.2007.05674.x [DOI] [PubMed] [Google Scholar]
  19. Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, LaFerla FM (2008) Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau J Neurosci 28:11500–11510 doi: 10.1523/JNEUROSCI.3203-08.2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Grimm JW, See RE (2000) Dissociation of primary and secondary reward-relevant limbic nuclei in an animal model of relapse Neuropsychopharmacology 22:473–479 doi: 10.1016/S0893-133X(99)00157-8 [DOI] [PubMed] [Google Scholar]
  21. Gupte R, Liu Z, Kraus WL (2017) PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes Genes Dev 31:101–126 doi: 10.1101/gad.291518.116 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Guzyk MM, Tykhomyrov AA, Nedzvetsky VS, Prischepa IV, Grinenko TV, Yanitska LV, Kuchmerovska TM (2016) Poly(ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors Reduce Reactive Gliosis and Improve Angiostatin Levels in Retina of Diabetic Rats Neurochem Res 41:2526–2537 doi: 10.1007/s11064-016-1964-3 [DOI] [PubMed] [Google Scholar]
  23. Hagberg H et al. (2004) PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury J Neurochem 90:1068–1075 doi: 10.1111/j.1471-4159.2004.02547.x [DOI] [PubMed] [Google Scholar]
  24. Hollis F, van der Kooij MA, Zanoletti O, Lozano L, Canto C, Sandi C (2015) Mitochondrial function in the brain links anxiety with social subordination Proc Natl Acad Sci U S A 112:15486–15491 doi: 10.1073/pnas.1512653112 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ide T et al. (2002) Greater oxidative stress in healthy young men compared with premenopausal women Arterioscler Thromb Vasc Biol 22:438–442 [DOI] [PubMed] [Google Scholar]
  26. Jang EY et al. (2015) Involvement of reactive oxygen species in cocaine-taking behaviors in rats Addict Biol 20:663–675 doi: 10.1111/adb.12159 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Javle M, Curtin NJ (2011) The role of PARP in DNA repair and its therapeutic exploitation Br J Cancer 105:1114–1122 doi: 10.1038/bjc.2011.382 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Jiang HY, Yang Y, Zhang YY, Xie Z, Zhao XY, Sun Y, Kong WJ (2018) The dual role of poly(ADP-ribose) polymerase-1 in modulating parthanatos and autophagy under oxidative stress in rat cochlear marginal cells of the stria vascularis Redox Biol 14:361–370 doi: 10.1016/j.redox.2017.10.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Jordan CJ, Andersen SL (2018) Working memory and salivary brain-derived neurotrophic factor as developmental predictors of cocaine seeking in male and female rats Addict Biol 23:868–879 doi: 10.1111/adb.12535 [DOI] [PubMed] [Google Scholar]
  30. Kander MC, Cui Y, Liu Z (2017) Gender difference in oxidative stress: a new look at the mechanisms for cardiovascular diseases J Cell Mol Med 21:1024–1032 doi: 10.1111/jcmm.13038 [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kong J et al. (2018) Nicotinamide phosphoribosyltransferase regulates cocaine reward through Sirtuin 1 Exp Neurol 307:52–61 doi: 10.1016/j.expneurol.2018.05.010 [DOI] [PubMed] [Google Scholar]
  32. Kraus WL, Hottiger MO (2013) PARP-1 and gene regulation: progress and puzzles Mol Aspects Med 34:1109–1123 doi: 10.1016/j.mam.2013.01.005 [DOI] [PubMed] [Google Scholar]
  33. Lax E et al. (2017) PARP-1 is required for retrieval of cocaine-associated memory by binding to the promoter of a novel gene encoding a putative transposase inhibitor Mol Psychiatry 22:570–579 doi: 10.1038/mp.2016.119 [DOI] [PubMed] [Google Scholar]
  34. Liu D, Pitta M, Mattson MP (2008) Preventing NAD(+) depletion protects neurons against excitotoxicity: bioenergetic effects of mild mitochondrial uncoupling and caloric restriction Ann N Y Acad Sci 1147:275–282 doi: 10.1196/annals.1427.028 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lonskaya I, Potaman VN, Shlyakhtenko LS, Oussatcheva EA, Lyubchenko YL, Soldatenkov VA (2005) Regulation of poly(ADP-ribose) polymerase-1 by DNA structure-specific binding J Biol Chem 280:17076–17083 doi: 10.1074/jbc.M413483200 [DOI] [PubMed] [Google Scholar]
  36. Lynch WJ, Carroll ME (1999) Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats Psychopharmacology (Berl) 144:77–82 doi: 10.1007/s002130050979 [DOI] [PubMed] [Google Scholar]
  37. McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hum PD (2005) Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection J Cereb Blood Flow Metab 25:502–512 doi: 10.1038/sj.jcbfm.9600059 [DOI] [PubMed] [Google Scholar]
  38. McFarland K, Kalivas PW (2001) The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior J Neurosci 21:8655–8663 [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Mutasim DF (2003) Autoimmune bullous dermatoses in the elderly: diagnosis and management Drugs Aging 20:663–681 [DOI] [PubMed] [Google Scholar]
  40. Namazi MR (2004) Nicotinamide: a potential anti-addiction weapon Med Hypotheses 62:844–845 doi: 10.1016/j.mehy.2004.01.020 [DOI] [PubMed] [Google Scholar]
  41. Negi G, Kumar A, Kaundal RK, Gulati A, Sharma SS (2010) Functional and biochemical evidence indicating beneficial effect of Melatonin and Nicotinamide alone and in combination in experimental diabetic neuropathy Neuropharmacology 58:585–592 doi: 10.1016/j.neuropharm.2009.11.018 [DOI] [PubMed] [Google Scholar]
  42. Otte N, Borelli C, Korting HC (2005) Nicotinamide - biologic actions of an emerging cosmetic ingredient Int J Cosmet Sci 27:255–261 doi: 10.1111/j.1467-2494.2005.00266.x [DOI] [PubMed] [Google Scholar]
  43. Peterson TC, Anderson GD, Kantor ED, Hoane MR (2012) A comparison of the effects of nicotinamide and progesterone on functional recovery of cognitive behavior following cortical contusion injury in the rat J Neurotrauma 29:2823–2830 doi: 10.1089/neu.2012.2471 [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Pomierny-Chamiolo L, Moniczewski A, Wydra K, Suder A, Filip M (2013) Oxidative stress biomarkers in some rat brain structures and peripheral organs underwent cocaine Neurotox Res 23:92–102 doi: 10.1007/s12640-012-9335-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Rennie G, Chen AC, Dhillon H, Vardy J, Damian DL (2015) Nicotinamide and neurocognitive function Nutr Neurosci 18:193–200 doi: 10.1179/1476830514Y.0000000112 [DOI] [PubMed] [Google Scholar]
  46. Riklis E, Kol R, Marko R (1990) Trends and developments in radioprotection: the effect of nicotinamide on DNA repair Int J Radiat Biol 57:699–708 [DOI] [PubMed] [Google Scholar]
  47. Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress Curr Biol 24:R453–462 doi: 10.1016/j.cub.2014.03.034 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Scobie KN et al. (2014) Essential role of poly(ADP-ribosyl)ation in cocaine action Proc Natl Acad Sci U S A 111:2005–2010 doi: 10.1073/pnas.1319703111 [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Scofield MD et al. (2016) Cocaine Self-Administration and Extinction Leads to Reduced Glial Fibrillary Acidic Protein Expression and Morphometric Features of Astrocytes in the Nucleus Accumbens Core Biol Psychiatry 80:207–215 doi: 10.1016/j.biopsych.2015.12.022 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. See RE (2005) Neural substrates of cocaine-cue associations that trigger relapse Eur J Pharmacol 526:140–146 doi: 10.1016/j.ejphar.2005.09.034 [DOI] [PubMed] [Google Scholar]
  51. Siegel CS, McCullough LD (2013) NAD+ and nicotinamide: sex differences in cerebral ischemia Neuroscience 237:223–231 doi: 10.1016/j.neuroscience.2013.01.068 [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Song SB, Jang SY, Kang HT, Wei B, Jeoun UW, Yoon GS, Hwang ES (2017) Modulation of Mitochondrial Membrane Potential and ROS Generation by Nicotinamide in a Manner Independent of SIRT1 and Mitophagy Mol Cells 40:503–514 doi: 10.14348/molcells.2017.0081 [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Steinmetz A et al. (2018) In vitro model to study cocaine and its contaminants Chem Biol Interact 285:1–7 doi: 10.1016/j.cbi.2018.01.017 [DOI] [PubMed] [Google Scholar]
  54. Stratford MR, Dennis MF (1994) Pharmacokinetics and biochemistry studies on nicotinamide in the mouse Cancer Chemother Pharmacol 34:399–404 [DOI] [PubMed] [Google Scholar]
  55. Suh SW, Aoyama K, Alano CC, Anderson CM, Hamby AM, Swanson RA (2007) Zinc inhibits astrocyte glutamate uptake by activation of poly(ADP-ribose) polymerase-1 Mol Med 13:344–349 doi: 10.2119/2007-00043.Suh [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Surjana D, Damian DL (2011) Nicotinamide in dermatology and photoprotection Skinmed 9:360–365 [PubMed] [Google Scholar]
  57. Surjana D, Halliday GM, Martin AJ, Moloney FJ, Damian DL (2012) Oral nicotinamide reduces actinic keratoses in phase II double-blinded randomized controlled trials J Invest Dermatol 132:1497–1500 doi: 10.1038/jid.2011.459 [DOI] [PubMed] [Google Scholar]
  58. Tang KS, Suh SW, Alano CC, Shao Z, Hunt WT, Swanson RA, Anderson CM (2010) Astrocytic poly(ADP-ribose) polymerase-1 activation leads to bioenergetic depletion and inhibition of glutamate uptake capacity Glia 58:446–457 doi: 10.1002/glia.20936 [DOI] [PubMed] [Google Scholar]
  59. Turunc Bayrakdar E, Uyanikgil Y, Kanit L, Koylu E, Yalcin A (2014) Nicotinamide treatment reduces the levels of oxidative stress, apoptosis, and PARP-1 activity in Abeta(1-42)-induced rat model of Alzheimer’s disease Free Radic Res 48:146–158 doi: 10.3109/10715762.2013.857018 [DOI] [PubMed] [Google Scholar]
  60. Virag L, Szabo C (2002) The therapeutic potential of poly(ADP-ribose) polymerase inhibitors Pharmacol Rev 54:375–429 [DOI] [PubMed] [Google Scholar]
  61. Wang C, Zhang Y, Ding J, Zhao Z, Qian C, Luan Y, Teng GJ (2017) Nicotinamide Administration Improves Remyelination after Stroke Neural Plast 2017:7019803 doi: 10.1155/2017/7019803 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Xu J, Xu SQ, Liang J, Lu Y, Luo JH, Jin JH (2012) [Protective effect of nicotinamide in a mouse Parkinson’s disease model] Zhejiang Da Xue Xue Bao Yi Xue Ban 41:146–152 [PubMed] [Google Scholar]
  63. Ying W, Garnier P, Swanson RA (2003) NAD+ repletion prevents PARP-1-induced glycolytic blockade and cell death in cultured mouse astrocytes Biochem Biophys Res Commun 308:809–813 [DOI] [PubMed] [Google Scholar]
  64. Zenclussen ML, Casalis PA, Jensen F, Woidacki K, Zenclussen AC (2014) Hormonal Fluctuations during the Estrous Cycle Modulate Heme Oxygenase-1 Expression in the Uterus Front Endocrinol (Lausanne) 5:32 doi: 10.3389/fendo.2014.00032 [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Zeng J et al. (2007) Pyruvate improves recovery after PARP-1-associated energy failure induced by oxidative stress in neonatal rat cerebrocortical slices J Cereb Blood Flow Metab 27:304–315 doi: 10.1038/sjjcbfm.9600335 [DOI] [PubMed] [Google Scholar]

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