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. Author manuscript; available in PMC: 2015 Jun 2.
Published in final edited form as: Behav Neurosci. 2015 Apr 27;129(3):281–291. doi: 10.1037/bne0000050

A critical role of nucleus accumbens dopamine D1-family receptors in renewal of alcohol seeking after punishment-imposed abstinence

Nathan J Marchant 1,2, Konstantin Kaganovsky 1
PMCID: PMC4451375  NIHMSID: NIHMS673097  PMID: 25914922

Abstract

In humans, places or contexts previously associated with alcohol use often provoke relapse during abstinence. This phenomenon is modeled in laboratory animals using the ABA renewal procedure, where alcohol seeking that is suppressed with extinction training in a context (B) renews when the animal returns to the original training context (A). However, extinction training does not adequately capture the motivation for abstinence in human alcoholics who typically self-initiate abstinence due to the negative consequences of excessive use. We recently developed a procedure to study renewal in laboratory rats after abstinence is imposed by negative consequences (footshock punishment). The mechanisms of renewal of punished alcohol seeking are largely unknown. Here we used the D1-family receptor antagonist SCH 23390 to examine the role of nucleus accumbens (NAc) shell and core dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We trained alcohol preferring ‘P rats’ to self-administer 20% alcohol in context A and subsequently suppressed alcohol taking via response-contingent footshock punishment in context B. We tested the effects of systemic, NAc shell, or NAc core injections of SCH 23390 on renewal of alcohol seeking after punishment-imposed abstinence. We found that both systemic and NAc shell and core injections of SCH 23390 decreased renewal of punished alcohol seeking. Our results demonstrate a critical role of NAc dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We discuss these results in reference to the brain mechanisms of renewal of alcohol seeking after extinction versus punishment.

Keywords: alcohol, relapse, renewal, context, punishment, nucleus accumbens, dopamine D1 receptor

Introduction

In abstinent drug users, exposure to environmental contexts previously associated with drug and alcohol use can provoke relapse (O’Brien, Childress, McLellan, & Ehrman, 1992; Wikler, 1973). This phenomenon has been modeled in laboratory animals using the ABA renewal procedure (Bouton, 1993; Bouton & Bolles, 1979). In this procedure, rats are first trained to perform an operant response that is reinforced with drug or alcohol delivery in one context (A), and that response is subsequently extinguished through non-reinforcement in a different context (B). Renewal, as defined by an increase in the operant response, is observed when the rats are tested in context A under extinction conditions (Crombag & Shaham, 2002). This phenomenon is observed in both pavlovian (Bouton & Bolles, 1979) and instrumental (Baker, Steinwald, & Bouton, 1991; Nakajima, Tanaka, Urushihara, & Imada, 2000) procedures, and also in rats trained to self-administer drugs of abuse (Crombag, Bossert, Koya, & Shaham, 2008). Renewal illustrates the potential that environmental contexts have to control operant behavior and this procedure has potential utility as an animal model of human relapse (Bouton, 2002; Crombag et al., 2008).

From a human relapse perspective, however, the use of operant extinction to suppress drug-reinforced behavior is a potential limitation (Epstein & Preston, 2003; Epstein, Preston, Stewart, & Shaham, 2006; Katz & Higgins, 2003). Human drug users typically self-impose abstinence, often out of a desire to avoid the negative consequences associated with excessive drug use (Blume, Schmaling, & Marlatt, 2006; Burman, 1997; Klingemann, 1991). Based on these considerations, we recently developed a modified renewal procedure that utilizes response-contingent punishment to suppress ongoing alcohol self-administration (Marchant, Khuc, Pickens, Bonci, & Shaham, 2013). Like renewal of extinguished alcohol seeking, we found that punished alcohol seeking renews in context A after punishment-imposed suppression of alcohol taking in context B (Marchant et al., 2013). In addition, renewal of food seeking after punishment-imposed abstinence was recently demonstrated (Bouton & Schepers, 2014).

The neural mechanisms of renewal of punished alcohol seeking are poorly understood. One important question is whether the neural substrates of renewal after punishment differ from those of renewal after extinction. Activity at dopamine D1-family receptors has been implicated in renewal of extinguished drug and alcohol seeking (Marchant, Kaganovsky, Shaham, & Bossert, 2014). For example, systemic injections of the dopamine D1-family receptor antagonist SCH 23390 decreases renewal of extinguished alcoholic beer seeking, and also decreases Fos expression in both lateral hypothalamus (LH) and nucleus accumbens (NAc) shell (Hamlin, Newby, & McNally, 2007). Cell bodies from the ventral tegmental area provide the dopaminergic input to NAc (Fallon & Moore, 1978), which is a heterogeneous brain region commonly divided into the shell and core subregions (Brog, Salyapongse, Deutch, & Zahm, 1993; Zahm & Brog, 1992). This dopaminergic input to NAc is critical for renewal, using SCH 23390 Chaudhri et al., (2009) have shown that blockade of D1-family receptors in either NAc shell or NAc core decreases renewal of extinguished alcohol seeking.

Recently, we reported that projections from NAc shell to LH have increased Fos expression in rats tested for renewal after punishment-imposed abstinence (Marchant, Rabei, et al., 2014). These findings are similar to a previous study looking at the role of LH and NAc shell projections to LH in renewal of extinguished alcohol seeking (Marchant, Hamlin, & McNally, 2009). This suggests that NAc shell may be a common substrate of renewal regardless of the mechanism used to suppress behavior in context B. We also found that renewal of punished alcohol seeking increases Fos expression in NAc core (Marchant, Rabei, et al., 2014), suggesting that NAc core is also potentially important for renewal of alcohol seeking after punishment-imposed abstinence. However, to date there are no studies specifically examining the role of NAc in renewal of punished alcohol seeking. Here, we used SCH 23390 to determine the role of NAc dopamine in renewal of punished alcohol seeking. We also determined the behavioral specificity of the effect of SCH 22390 on renewal by testing whether the drug decreases ongoing alcohol and food self-administration.

Materials and Methods

Subjects and apparatus

We received male alcohol-preferring P rats (~30 days old, n=81) from Indiana University and housed them singly under a reversed 12 h light/dark cycle (8:00 AM light off) with free access to food and water. We performed the experiments in accordance to the “Guide for the care and use of laboratory animals” (8th edition); protocols were approved by the Animal Care and Use Committee. For alcohol and food self-administration, we used standard operant chambers (Med Associates) each enclosed in a ventilated sound-attenuating cubicle and illuminated by a houselight on the opposite side of the lever and cue-light. The chambers were equipped with two levers located 8.5 cm above the grid floor: one retractable lever (designated as ‘active’) and one non–retractable lever (designated as ‘inactive’). Above the active lever were the cue-light (7.5 W white light) and the speaker (2900 Hz, 20 dB above background). The grid floors were connected to shockers. We delivered 20% ethanol (0.1 ml/delivery) into the receptacles via 12-gauge blunt needles connected to 60-ml syringes controlled by Razel pumps. For the food self-administration experiments, we delivered 45 mg food pellets (TestDiet, Catalogue # 1811155) from a pellet dispenser into the same receptacles as previously used for alcohol. We manipulated and counterbalanced contexts A and B as described in Marchant et al. (2013): grid width (narrow/wide), illumination level (white/red houselight), background noise (fan on/off), and background cues (food container present/absent within the operant chamber, cabinet doors closed/open).

Behavioral procedure (4 phases)

Phase 1: Home-cage alcohol intake

We used an intermittent access (3–4 times/week) alcohol procedure (Simms et al., 2008; Wise, 1973). Upon arrival to the animal facility from quarantine, rats were handled for 2 days. We exposed all rats to 12 × 24 h sessions of access to 1 bottle of 20% ethanol v/v in water and 1 bottle of water. We made alcohol solutions (prepared in tap water from 100% (v/v) ethanol) in standard water bottles. Food was freely available. The session started around 9:00 am. After 24 h, we replaced the alcohol bottle with a second water bottle, and the no-alcohol session also lasted for 24 h. The following day, we replaced the second water bottle with a 20% ethanol bottle and alternated location of the alcohol bottle from the previous session. The majority of no alcohol sessions were 24 h; however, some no alcohol sessions were 48 h. The total consumption in grams of ethanol for each session was calculated as the weight difference between the start and end of the sessions, minus 2 grams for spillage, multiplied by 0.97 (density of 20% ethanol).

Phase 2: Operant self-administration: context A

We gave rats two 2 h magazine-training sessions where 0.1 ml of alcohol was delivered non-contingently every 5 min; alcohol delivery was paired with a 2 sec tone-light cue. Subsequently, we trained rats for a total of six 2 h sessions (two days on; one day off) to self-administer 0.1 ml deliveries of alcohol on a fixed-ratio-1 (FR-1) 20 sec timeout reinforcement schedule. Illumination of the house light and insertion of the active lever into the chamber signaled initiation of the session. Presses on the active lever resulted in presentation of the 2 sec tone-light cue and activation of the infusion pump. Lever-presses on the inactive lever had no consequences. Next, we trained rats on a variable-interval 30 sec (VI-30) reinforcement schedule for six 2 h sessions. During these sessions, alcohol delivery was available after an active lever-press at pseudo-random intervals (1–59 sec) after the preceding alcohol delivery.

Phase 3: Punishment: context B

We trained the rats to self-administer alcohol in context B (2 h sessions) under the VI-30 reinforcement schedule. Presses on the active retractable lever activated the infusion pump and the 2 sec tone-light cue. For punishment, only 50% of the reinforced active lever presses resulted in 0.5 sec footshock (0.1–0.7 mA). Punished lever presses resulted in immediate delivery of the footshock, as well as the delivery of alcohol and activation of the 2 sec tone-light cue. Active lever presses during the time-out period were not punished.

Our punishment procedure was different for two cohorts of rats in this study. For the first cohort of rats (n=50), we set the shock intensity at 0.3 mA for the first 3 sessions. We set our “suppression threshold” at 15 active lever presses/session; if a rat was above this threshold, we increased the shock intensity by 0.07 mA in the subsequent context B session. Once all rats were below this threshold for two or more days, we tested all of the rats for renewal of alcohol seeking in context A. The individual variability in the number of days required to reach the suppression threshold led us to update our procedure as described below.

The second cohort of rats (n=19) underwent a different shock procedure. The shock intensity was 0.1 mA for the first day of context B punishment, and we increased the shock intensity by 0.1 mA each successive session for all rats until the final level of 0.7 mA (i.e., all rats had seven sessions of punishment in context B, and the shock intensity was the same for all rats). We stopped after seven sessions (at 0.7 mA), because all rats were below our original “suppression threshold” for two consecutive punishment sessions.

Although these punishment procedures are different, we believe that this procedural difference does not confound data interpretation, because both procedures achieve the same amount of suppression of alcohol intake in context B. We calculated a suppression ratio for each rat by dividing the number of active lever presses on the last day of punishment by the number of active lever presses on the last day of self-administration. We found no significant difference between the suppression ratios of the two cohorts of rats (t-test, p>0.05). Based on this, we combined the data from both cohorts for analysis of renewal tests.

We gradually increased the shock intensity in our experiments because we wanted to observe and illustrate the threshold at which shock punishment can suppress alcohol seeking. There is evidence that prior experience to weak shock can impair acquisition of stronger shock in pavlovian conditioning procedures (Hall & Pearce, 1979). Thus, our procedure may result in retardation of punishment-imposed suppression of alcohol seeking. However, because we continue to increase the shock intensity until we observe almost total suppression of alcohol seeking, any potential retardation effect caused by the weak shock is eventually lost with higher shock intensity.

Phase 4: Relapse tests

We tested rats for alcohol seeking (active lever-presses under extinction conditions) in 90 min sessions without punishment or alcohol in contexts A and B; the order of test context was counter-balanced. During testing, presses on the active lever, under the VI-30 reinforcement schedule, resulted in activation of the 2 sec tone+light cue and the pump, but no alcohol or shock was delivered.

Intracranial surgery

We performed all surgeries after the home-cage drinking phase. We anesthetized rats with either 100 mg/kg ketamine+10 mg/kg xylazine (IP) or sodium pentobarbital (70 mg/kg, IP) + atropine sulfate (0.05 mg/kg, subcutaneous (s.c.)). We implanted guide cannulas (23-gauge, Plastics One) 1 mm above the target site (NAc Shell or NAc Core). The coordinates for NAc shell were (nosebar set at −3.3 mm): AP +1.5, ML ±3.5 (20° angle), and DV −7.0 mm from Bregma; the coordinates for NAc core were (nosebar set at −3.3 mm): AP +1.4, ML ±2.5 (6° angle), and DV −6.5 mm from Bregma. We anchored cannulas to the skull with jeweller’s screws and dental cement. These coordinates are based on previous studies (Bossert, Gray, Lu, & Shaham, 2006; Bossert, Poles, Wihbey, Koya, & Shaham, 2007; Bossert et al., 2012). We gave the rats the analgesic buprenorphine (0.1 mg/ml; 0.1 ml/rat, s.c.) after surgery and allowed them to recover for 3–5 days prior to starting the self-administration phase.

Systemic and intracranial injections

For the systemic experiment, we habituated rats to subcutaneous injections of saline for two days prior to test. We dissolved SCH 23390 hydrochloride (Tocris) in sterile saline fresh each test day. We gave systemic injections (vehicle, 5 μg/kg, or 10 μg/kg; s.c.) 15 min before the test sessions, and we placed the rats in the test chamber without the program running during that time period. The doses are based on previous reports (Bossert et al., 2007; Crombag & Shaham, 2002).

We gave bilateral intracranial injections 5–10 min prior to testing (concentration: 0.6 μg/0.3 μl/side) based on previous studies (Bossert et al., 2007; Bossert, Wihbey, Pickens, Nair, & Shaham, 2009). The injectors extended 1 mm below the guide cannula tip. We injected vehicle or SCH 23390 over 1 min and left injectors in place for 1 min. We used a syringe pump (Harvard Apparatus) connected to 10 μl Hamilton syringes attached via polyethylene-50 tubing to 30-gauge injectors. We habituated rats to the injection procedure, inserting the injectors into the cannulas without infusion, for two days before test. After the final test, we anesthetized the rats, removed their brains, and stored the brains in 10% formalin prior to freezing and sectioning. We verified cannula placements under a light microscope after brain sectioning (40 μm), using a Leica cryostat and staining sections with Cresyl Violet.

Specific experiments

Effect of SCH 23390 on renewal of punished alcohol seeking

In the systemic experiment, we used 25 rats of which we injected 15 rats with an AAV virus into NAc shell, and optic fibers secured by similar headcaps to the cannula surgery prior to self-administration training. We had intended to use these rats for an optogenetics experiment, but based on results from a different group showing that the laser light manipulation non-specifically decreased responding during testing, used them instead for the systemic experiment. We did not apply light to the optic fibers at any point before or throughout the experiment.

For the intracranial experiments, we implanted rats with guide cannulas 1 mm above the NAc shell (n=24) or NAc core (n=20) after the home-cage phase. For NAc shell injected rats, 13 rats that received vehicle and 7 rats that received SCH 23390 on test day underwent the original punishment procedure; 2 rats that received vehicle and 2 rats that received SCH 23390 underwent the modified punishment procedure. For NAc core injected rats, 4 rats that received vehicle and 1 rat that received SCH 23390 on test day underwent the original punishment procedure; 8 rats that received vehicle and 7 rats that received SCH 23390 underwent the modified punishment procedure. We tested all rats in both contexts and the test order was counterbalanced.

Effect of SCH 23390 on alcohol and food self-administration

These experiments were designed to show that the systemic or intracranial SCH 23390 do not decrease operant behaviour non-specifically (see (Bossert et al., 2009; Crombag & Shaham, 2002; Nair et al., 2011)). For the systemic SCH 23390 experiment, we re-trained 10 rats after the relapse tests to self-administer 20% alcohol on the VI-30 schedule. After one re-training session we injected vehicle, 5 μg/kg, or 10 μg/kg SCH 23390 (counterbalanced order) 15 min before the next 3 self-administration sessions. For the food self-administration experiment, we trained 12 alcohol-naïve P rats to self-administer food pellets (45-mg food pellets containing 12.7% fat, 66.7% carbohydrate, and 20.6% protein (Catalogue # 1811155, TestDiet)) for 1 h per day under a VI-30 schedule of reinforcement (5 pellets/delivery). We habituated the rats to subcutaneous saline injections before two of the training sessions. On test, we injected vehicle or SCH 23390 (counterbalanced order) 15 min before the self-administration session.

For the intracranial experiment, after the relapse tests, we re-trained NAc shell (n=9) and NAc core (n=6) cannulated rats to self-administer 20% ethanol on the VI-30 schedule for 3 sessions. We injected vehicle or SCH 23390 (counterbalanced order) over 2 sessions. For the food self-administration experiment, we trained the cannulated rats to self-administer food pellets in context A, under a VI-30 schedule of reinforcement, after the alcohol self-administration tests. After the rats achieved a stable level of food self-administration (3 sessions), we tested the effects of vehicle or SCH 23390 (counterbalanced order) into either NAc shell (n=9) or NAc core (n=7) on ongoing food intake. One rat from the NAc core group was excluded from the alcohol self-administration tests because of illness after the first injection, but recovered for the food self-administration tests.

Statistical analysis

We analyzed the data separately for the 4 phases: home-cage, context A operant self-administration, context B operant punishment, and renewal tests. We analyzed the data with SPSS (version 20) using mixed ANOVAs. We analyzed the homecage intake data using the dependent measures of 20% alcohol preference and g/kg alcohol intake and the within-subjects factor of Homecage Session. We analyzed the operant self-administration data using the dependent measures of number of alcohol deliveries, g/kg consumption, and total number of presses on the active lever. We used the within-subject factors Schedule (FR-1, VI-30) and Training Session (6 per Schedule) for these dependent measures. We analyzed the two cohorts of the operant punishment data separately using the dependent measures number of alcohol deliveries, number of presses on the active lever, and latency to first active lever press. We used the within-subject factor Punishment Session for these dependent measures. For the renewal test, the dependent measures were total (non-reinforced) presses on the active lever, with the inactive lever as a covariate, and latency to first active lever press using the within-subjects factor Context (A, B) and the between-subjects factor SCH 23390 Dose.

We analyzed the food and alcohol self-administration data using the dependent measures number of presses on the active lever, with the inactive lever as a covariate, and number of pellet deliveries. We used the within-subject factor SCH 23390 Dose for these dependent measures. We followed up on significant interactions or main effects by using Fischer PLSD test (p<0.05). We performed the within-session analysis on the active lever pressing data with the within-subject factor SCH 23390 Dose as the dependent measure, and the within-session factor of Time, with 6 time-bins (Food: 10 min; Alcohol 20 min).

Results

Alcohol-preferring P rats consumed high amounts of alcohol in the homecage intermittent-access phase (Fig. 1B) and reliably self-administered alcohol in context A under the FR-1 and VI-30 reinforcement schedules (Fig. 1C). During punishment in context B, the rats decreased alcohol self-administration and longer latency to first lever press with increased shock intensity (Fig. 1D). We present formal statistical results from the training and punishment phases in Table 1.

Figure 1. Homecage intake, context A alcohol self-administration, and context B punishment of alcohol self-administration.

Figure 1

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(A) Outline of the experimental procedure prior to test. FR, fixed-ratio; VI, variable-interval. (B) Mean±SEM preference for 20% alcohol or water and alcohol intake (g/kg) during the homecage access to 20% alcohol. The SEMs for these data points are smaller than the symbol size. (C) Mean active lever presses, alcohol deliveries, and alcohol intake during the alcohol self-administration training in context A (6 sessions with each reinforcement schedule). (D) Mean active lever presses, alcohol deliveries, and latency to the first lever press during punishment in context B. In the first cohort, the shock intensity was 0.3 mA for the first 3 sessions for all rats. Rats with more than 15 active lever-presses in the previous 2 h session were given increased shock intensity (+0.07 mA) in the following punishment session. In the second cohort, the shock intensity began at 0.1 mA and was increased each day by 0.1 mA.

Table 1.

Summary of statistically significant results from training (p<0.05). Main effects not reported if interaction exists.

Training Phase Alcohol Preference g/kg intake Alcohol Deliveries Active Lever Presses Latencies
Homecage Training Session [F(11,748)=34.5] Training Session [F(11,748)=10.1]
Self-administration Schedule x Training Session [F(5,340)=29.9] Schedule x Training Session [F(5,340)=51.7] Schedule x Training Session [F(5,340)=25.9]
Punishment: first cohort Training Session [F(8,392)=48.8] Training Session [F(8,392)=42.4] Training Session [F(8,392)=12.5]
Punishment: second cohort Training Session [F(6,108)=116.6] Training Session [F(6,108)=52.5] Training Session [F(6,108)=25.4]
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Effect of systemic SCH 23390 injections on renewal of punished alcohol seeking

We observed renewal of punished alcohol seeking in context A after punishment of alcohol self-administration in context B, and this effect was blocked by systemic injection of SCH 23390 (Fig. 2B). The ANCOVA of active lever presses using the between-subjects factor of SCH 23390 Dose (0, 5, and 10 μg/kg) and the within-subjects factor of Test Context (A, B), with inactive lever-presses as a covariate, showed a significant interaction between Test Context and SCH 23390 Dose (F(2,20)=4.9, p<0.05). We found no effect of systemic SCH 23390 on latency to the first active lever press. The ANOVA of latency to first active lever press using the between-subjects factor of SCH Dose (0, 5, and 10 μg/kg) and the within-subjects factor of Test Context (A, B) showed a significant effect of Test Context (F(1,22)=22.4, p<0.05) but not SCH 23390 Dose (F(2,22)=0.6, p>0.05), and no significant interaction (F(2,22)=0.4, p>0.05). Post-hoc significant differences are indicated in Figure 2B. The mean±SEM inactive lever presses for the systemic injected rats were Vehicle-Context B: 1.2±0.8, Vehicle-Context A: 0.2±0.1, 5 μg/kg-Context B: 1.6±0.9, 5 μg/kg-Context A: 1.0±0.5, 10 μg/kg-Context B: 0.3±0.2, 10 μg/kg-Context A: 0.4±0.4; there were no significant group effects (p<0.05).

Figure 2. Effect of systemic or nucleus accumbens injection of SCH 23390 on renewal of punished alcohol seeking.

Figure 2

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(A) Outline of the experimental procedure. (B) Mean±SEM active lever presses and latencies to first response after subcutaneous injections of vehicle (n=9), 5 μg/kg SCH 23390 (n=7), or 10 μg/kg SCH 23390 (n=9) prior to the renewal tests. (C) Mean±SEM active lever-presses and latencies to first press on the active lever after injection of vehicle (n=15) or SCH 23390 (n=9) prior to the renewal test. (D) Mean±SEM active lever-presses and latencies to first response after injection of vehicle (n=12) or SCH 23390 (n=8) prior to the renewal test. * indicates significant difference between the drug condition and vehicle as determined by Fisher’s PLSD, p<0.05.

Effect of NAc shell or NAc core injections of SCH 23390 on renewal of punished alcohol seeking

We observed renewal of alcohol-seeking in context A after punishment of alcohol self-administration in context B, and this effect was blocked by NAc shell and core injections of SCH 23390 (Fig. 2C, D). For NAc shell (Fig. 2C), the ANCOVA of active lever presses using the between-subjects factor of SCH 23390 Dose (0, 0.6 μg) and the within-subjects factor of Test Context (A, B), with inactive lever presses as a covariate, showed a significant interaction between Test Context and SCH 23390 Dose (F(1,20)=5.4, p<0.05). The ANOVA of latency to first active lever press using the between-subjects factor of SCH 23390 Dose (0, 0.6 μg) and the within-subjects factor of Test Context (A, B) showed a significant effect of Test Context (F(1,22)=17.5, p<0.05) but not SCH 23390 Dose (F(1,22)=1.5, p>0.05). We did observe a significant interaction of Test Context and SCH 23390 Dose (F(1,22)=7.3, p<0.05), which is explained by a significantly longer latency in the SCH group compared to the vehicle group in the punishment context. The mean±SEM inactive lever pressing for NAc shell injected rats on test were Vehicle-Context B: 1.7±1.1, Vehicle-Context A: 1.7±0.4, SCH-Context B: 0.2±0.2, SCH-Context A: 0.7±0.4; there were no significant group effects (p<0.05).

For NAc core (Fig. 2D), the ANCOVA of active lever presses using the between-subjects factor of SCH 23390 Dose (0, 0.6 μg) and the within-subjects factor of Test Context (A, B), with inactive lever presses as a covariate, showed a significant interaction between Test Context and SCH 23390 Dose (F(1,16)=9.2, p<0.05). The ANOVA of latency to first active lever press using the between-subjects factor of SCH 23390 Dose (0, 0.6 μg) and the within-subjects factor of Test Context (A, B) showed a significant effect of Test Context (F(1,18)=25.4, p<0.05) but not SCH 23390 Dose or interaction (p values>0.05). The mean±SEM inactive lever pressing for NAc core injected rats on test were Vehicle-Context B: 0.8±0.4, Vehicle-Context A: 1.3±0.3, SCH-Context B: 0.8±0.4, SCH-Context A: 1.8±1.1; there were no significant group effects (p<0.05).

Effect of systemic SCH 23390 on food and alcohol self-administration

Food (Fig 4A)

Figure 4. Effect of SCH23390 injection on food and alcohol self-administration.

Figure 4

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(A) Mean±SEM number of pellet deliveries (5 pellets per delivery) and responses on the active lever after subcutaneous injections of vehicle or SCH 23390 (n=12). (B) Mean±SEM number of pellet deliveries and responses on the active lever after NAc shell injection of vehicle or SCH 23390 (n=9). (C) Mean±SEM number of infusions and active lever presses after NAc core injection of vehicle or SCH 23390 (n=7). We did not observe significant statistical effects of NAc injections of SCH 23390. (D) Mean±SEM number of alcohol deliveries and responses on the active lever after subcutaneous injections of vehicle or SCH 23390 (n=10). (E) Mean±SEM number of pellet deliveries and responses on the active lever after NAc shell injection of vehicle or SCH 23390 (n=9). (F) Mean±SEM number of infusions and active lever presses after NAc core injection of vehicle or SCH 23390 (n=7). We did not observe significant statistical effects of NAc injection of SCH 23390. * indicates significant difference between the drug condition and vehicle as determined by Fisher’s PLSD, p<0.05.

We found that SCH 23390 (5 μg/kg and 10 μg/kg, s.c.) caused a modest but statistically significant decrease of food self-administration. The ANCOVA of active lever presses using the within-subjects factor of SCH 23390 Dose (0, 5, and 10 μg/kg), with inactive lever presses as a covariate, showed a significant effect of SCH 23390 Dose (F(2,16)=5.7, p<0.05). The ANOVA of pellet deliveries using the within-subjects factor of SCH Dose (0, 5, and 10 μg/kg) showed a significant effect of SCH 23390 Dose (F(2,22)=12.85, p<0.05). Post-hoc significant differences are indicated in Figure 4A. The within-session analysis on active lever presses revealed significant interaction between SCH 23390 Dose and Time (F(10,110)=2.2; p<0.05). Post-hoc analysis show no effect of SCH 23390 Dose in the first and sixth 10 min time-bins (p>0.05), and significant effects in the second, third, fourth, and fifth 10 min time-bins (p<0.05).

Alcohol (Fig 4D)

We found that SCH 23390 (5 μg/kg and 10 μg/kg, s.c.) significantly decreased alcohol self-administration (Fig. 4D). The ANCOVA of active lever presses using the within-subjects factor of SCH 23390 Dose (0, 5, and 10 μg/kg), with inactive lever presses as a covariate, showed an approaching significant effect of SCH 23390 Dose (F(2,12)=3.7, p=0.054). The ANOVA of alcohol deliveries using the within-subjects factor of SCH 23390 Dose (0, 5, and 10 μg/kg) showed a significant effect of SCH 23390 Dose (F(2,18)=14.2, p<0.05). Post-hoc significant differences are indicated in Figure 4D. The within-session analysis of the active lever presses revealed significant interaction between SCH 23390 Dose and Time (F(2,90)=13.4; p<0.05). Post-hoc analysis showed a significant effect of SCH 23390 Dose in the first 20 min time-bin (p<0.05), and no significant effects in the remaining 20 min time-bins (p>0.05).

Effect of intracranial SCH 23390 on food and alcohol self-administration

Food (Fig 4B, 4C)

We found no effect of NAc shell or NAc core injection of SCH 23390 (0.6 μg) on food self-administration. For NAc shell, the ANCOVA of active lever presses using the within-subjects factor of SCH 23390 Dose (0, 0.6 μg), with inactive lever presses as a covariate, showed no effect of SCH 23390 Dose (F(1,7)=2.4, p>0.05). Likewise, the ANOVA of pellet deliveries using the within-subjects factor of SCH 23390 Dose (0, 0.6 μg) showed no effect of SCH 23390 Dose (F(1,8)=1.6, p>0.05). For NAc Core, the ANCOVA of active lever presses using the within-subjects factor of SCH 23390 Dose (0, 0.6 μg) with inactive lever presses as a covariate showed an approaching significance effect of SCH 23390 Dose (F(1,5)=6.3, p=0.054). Likewise, the ANOVA of pellet deliveries using the within-subjects factor of SCH 23390 Dose (0, 0.6 μg) showed no effect of SCH Dose (F(1,6)=2.9, p>0.05).

Alcohol (Fig 4E, 4F)

We found no effect of NAc shell or NAc core injection of SCH 23390 (0.6 μg) on alcohol self-administration. For NAc shell, the ANCOVA of active lever presses using the within-subjects factor of SCH Dose (0, 0.6 μg), with inactive lever presses as a covariate, showed no effect of SCH 23390 Dose (F(1,7)=1.9, p>0.05). Likewise, the ANOVA of alcohol deliveries using the within-subjects factor of SCH Dose (0, 0.6 μg) showed no effect of SCH 23390 Dose (F(1,8)=3.4, p>0.05). For NAc Core, the ANCOVA of active lever presses using the within-subjects factor of SCH 23390 Dose (0, 0.6 μg) with inactive lever presses as a covariate showed no effect of SCH Dose (F(1,3)=1.6, p>0.05). Likewise, the ANOVA of alcohol deliveries using the within-subjects factor of SCH Dose (0, 0.6 μg) showed no effect of SCH Dose (F(1,5)=3.9, p>0.05).

Discussion

We studied the role of NAc dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We found that systemic blockade of dopamine D1-family receptors decreased renewal of punished alcohol seeking. We also identified an anatomical locus of this effect, showing that blockade of D1-family receptors in both NAc shell and NAc core decreased renewal of punished alcohol seeking. Another finding of this study is that systemic SCH 23390 injections decreased ongoing alcohol self-administration, a finding that is consistent with previous data showing an effect of this drug on alcohol self-administration (Hodge, Samson, & Chappelle, 1997). Finally, using ongoing self-administration of food as a behavioral control, we show that SCH 23390 injections do not cause non-specific motor deficits. These results demonstrate that renewal of alcohol seeking after punishment-imposed abstinence is critically dependent on activity at D1-family receptors in NAc.

Role of nucleus accumbens shell in renewal of alcohol seeking

One main finding in this study is that antagonism of D1-family receptors in NAc shell decreased renewal of punished alcohol seeking. These results share a number of similarities with previous studies on renewal (or context-induced reinstatement) of alcohol seeking after extinction (Bossert, Marchant, Calu, & Shaham, 2013; Marchant, Kaganovsky, et al., 2014). Hamlin et al., (2007) have shown that systemic SCH 23390 injections decrease renewal of extinguished alcoholic beer seeking, as well as the renewal-associated increase in Fos expression in NAc shell (Hamlin et al., 2007). A causal role for NAc shell D1-family receptors in renewal of extinguished alcohol seeking was demonstrated by Chaudhri et al., (2009) who reported that SCH 23390 injection into NAc shell decreases renewal of alcohol seeking after extinction. Furthermore, antagonism of mu-opioid receptors in NAc shell also decreases renewal of extinguished alcoholic-beer seeking (Perry & McNally, 2013a). Thus, there is a converging data set in the literature illustrating the importance of NAc shell in renewal of alcohol seeking.

In addition to alcohol, NAc shell appears to be a critical brain region for renewal (or context-induced reinstatement) of extinguished reward seeking independent of the reward type. For example, renewal of sucrose seeking increases Fos expression in NAc shell, and systemic injection of SCH 23390 decreases both sucrose seeking and Fos expression (Hamlin, Blatchford, & McNally, 2006). Bossert et al., (2007) have demonstrated that SCH 23390 injection into NAc shell decreases renewal of heroin seeking. Finally, NAc shell antagonism of AMPA/kainite glutamate receptors (using CNQX) (Xie et al., 2012), and selective lesion of renewal-associated Fos neurons, using the Daun02 inactivation method (Bossert et al., 2011; Cruz et al., 2013; Koya et al., 2009), in NAc shell decreases renewal of cocaine seeking (Cruz et al., 2014). Based on our data presented here, we tentatively propose that NAc shell is a critical brain site for context-induced reward seeking regardless of the mechanism used to suppress responding in context B (extinction or punishment). However, because there are no studies looking at renewal of punished intravenous drug seeking, future studies are needed to further support this conclusion.

Role of nucleus accumbens core in renewal of alcohol seeking

Another main finding of this study is that antagonism of D1-family receptors in NAc core decreases renewal of punished alcohol seeking. This finding is consistent with previous findings showing that renewal of extinguished alcohol seeking is also decreased by injections of SCH 23390 into NAc core (Chaudhri et al., 2009). Although Hamiln et al., (2007) reported no renewal associated Fos expression in NAc core, Perry and McNally (2013b) recently showed that NAc core projections to ventral pallidum have increased fos expression in rats tested for renewal of alcoholic beer seeking. These data suggest that in addition to NAc shell, NAc core is also a critical brain region for renewal of both extinguished and punished alcohol seeking. However, in contrast to renewal of alcohol seeking, there is conflicting evidence in the literature about the role of NAc core in renewal of extinguished intravenous drug seeking. For example, reversible inactivation of NAc core, with injection of GABA receptor agonists muscimol+baclofen, decreases renewal of extinguished cocaine seeking (Fuchs, Ramirez, & Bell, 2008). In contrast to these findings, NAc core injection of SCH 23390 has no effect on renewal (context-induced reinstatement) of heroin seeking, but did decrease discrete cue-induced heroin seeking (Bossert et al., 2007).

One possible explanation for these differences is the specific procedural differences of the studies. For example, in the Fuchs et al., (2008) study the drug-associated conditioned stimulus was not presented during extinction in context B, but in the Bossert et al., (2007) study the conditioned stimulus was extinguished. Subtle differences like this are important because they can change the underlying psychological (and thus neural) mechanism of renewal (Crombag et al., 2008). A study by Chaudhri et al., (2010) has addressed this point. Using a Pavlovian ABA renewal procedure where a discrete cue is paired with alcohol. They demonstrated that reversible inactivation of NAc core with muscimol+baclofen decreases cue-induced conditioned responding in both alcohol and novel contexts. In contrast, reversible inactivation of NAc shell only decreases cue-induced conditioned responding in the alcohol-associated context. Thus, our finding that NAc core antagonism of D1-family receptors decreased renewal of punished alcohol seeking suggests a possible role of discrete cue processing in our renewal procedure.

There are at least two important procedural differences that might account for a greater role of the alcohol-associated discrete cue during the relapse tests in our punishment procedure compared to what is observed in extinction procedures. The first is that during punishment the discrete cue might undergo counter-conditioning (Dickinson, 1976; Nasser & McNally, 2012; Peck & Bouton, 1990). Because we delivered alcohol and the discrete cue in combination with shock, it is possible that the aversive motivational state induced by the shock becomes associated with the discrete cue. A counter-conditioning account would suggest that in addition to renewal of the operant response, test in context A is associated with renewal of the appetitive motivational state induced by the alcohol-associated discrete cue. The second difference is that during punishment in context B every presentation of the discrete cue is paired with alcohol (and shock on only 50% of presentations), and thus the cue is not extinguished. Therefore, because the discrete cue is never extinguished, it is contributing to promoting alcohol seeking on the renewal test to a greater extent than is seen the extinction procedures. Both of these accounts suggest that the discrete cue has motivational significance on test, and we propose this may be mediated in part by activity in NAc core. This interpretation is consistent with the finding here that NAc core antagonism of D1-family receptors decreased renewal of punished alcohol seeking, as well as previous findings of increased Fos expression in NAc core in renewal of punished alcohol seeking (Marchant, Rabei, et al., 2014), but not extinguished alcohol seeking (Hamlin et al., 2007; Marchant et al., 2009).

Methodological considerations

There are several methodological considerations that need to be taken into account for the interpretation of the present data. The first is the possibility that the effects of SCH 23390 are caused by a generalized motor deficit. We address this concern with the food and alcohol self-administration experiments (Fig. 4). Although systemic SCH 23390 did have a statistically significant effect on both food and alcohol self-administration, we propose that a small reduction in a high rate of responding indicates that systemic SCH 23390 did not cause motor deficits, but likely decreased the motivation to seek rewards. More importantly, we show that NAc shell and NAc core injections of SCH 23390 had no or minimal effect on both food and alcohol self-administration. Thus, the suppression of self-administration by systemic SCH 23390 is likely mediated by its action somewhere other than NAc shell or NAc core. We propose that these data combined show that the reduced alcohol seeking observed after NAc injections of SCH 23390 is specific to renewal of punished alcohol seeking and does not reflect non-specific performance deficits.

Another consideration is that the similar effect of NAc shell or core injection of SCH 23990 is because the drug diffused to one subregion or the other. We think this is unlikely because we used similar dose (0.6 μg) and volume (0.3 μl) as a previous study (Bossert et al., 2007), which reported site-specific effects in NAc shell or core. We think it is likely that in our procedure activity of D1-family receptors in either NAc shell or NAc core is necessary for renewal of punished alcohol seeking.

The other consideration is the possibility that the effects of SCH 23390 observed in this study are mediated by action of the serotonin 5-HT2C receptor. Although most commonly used as a D1-family receptor antagonist, SCH 23390 also has agonist action at 5-HT2C (Briggs et al., 1991; Millan, Newman-Tancredi, Quentric, & Cussac, 2001); in addition, systemic injection of a 5-HT2C receptor agonist (Ro 60-0175) decreases renewal of extinguished cocaine seeking (Fletcher, Rizos, Sinyard, Tampakeras, & Higgins, 2008). However, in recent studies both Bossert et al., (2009) and Nair et al., (2011) found no effect of Ro 60-0175 injections under conditions in which SCH 23390 injections were highly effective in decreasing heroin or food seeking. Thus, we tentatively propose that it is unlikely that 5-HT-related mechanisms contribute to the effects of SCH 23390 injections on renewal of punished alcohol seeking.

Conclusions

Using renewal after punishment-imposed abstinence as a model of context-induced relapse of alcohol seeking (Marchant et al., 2013), we found that antagonism of D1-family receptors in both NAc shell and NAc core decreases renewed alcohol seeking. These results demonstrate the importance of NAc dopamine in renewal of alcohol seeking. The role of NAc shell in renewal (or context-induced reinstatement) of drug, alcohol, and reward seeking after extinction has been consistently demonstrated (Bossert et al., 2013; Marchant, Kaganovsky, et al., 2014). The findings reported here indicate that a general role of NAc shell in context-induced reward seeking, currently only demonstrated for extinguished reward seeking, generalizes to conditions where reward seeking is suppressed by punishment. Our demonstration that NAc core is also critical for renewal of punished alcohol seeking provides a preliminary indication that the neural substrates of renewal of punished alcohol seeking may differ to some degree from those of renewal of alcohol seeking after extinction.

Figure 3. Cannula placement.

Figure 3

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Approximate placements (mm from bregma) of the injector tips (Paxinos & Watson, 2005) and representative photomicrographs of cannula placement; circles indicate location of injector tips. From The Rat Brain in Stereotaxic Coordinates (5th ed.), 53–59, by G. Paxinos & C. Watson, 2005, New York, NY: Academic Press. Copyright 2005 by Elsevier Academic Press. Adapted (or reprinted) with permission.

Acknowledgments

Research was supported by the National Institute on Drug Abuse, Intramural Research Program funds to the Neurobiology of Relapse Section (PI: Yavin Shaham). N.J.M. received support from Early Career Fellowship 1053308 by the National Health and Medical Research Council. We thank Yavin Shaham, Antonello Bonci, and Helen Nasser for their help in the conceptualization of the project and the write-up of the paper.

Footnotes

The authors declare that they do not have any conflicts of interest (financial or otherwise) related to the data presented in this manuscript.

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