BJP

British Journal of Pharmacology

British Journal of Pharmacology (2016) 173 1350–1362 1350

RESEARCH PAPER Daily morphine administration increases impulsivity in rats responding under a 5-choice serial reaction time task Correspondence Charles P. France, Departments of Pharmacology and Psychiatry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78229-3900, USA. E-mail: [email protected]

Received 11 August 2015; Revised 22 December 2015; Accepted 7 January 2016;

DR Maguire1, C Henson1 and CP France1,2 1

Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas USA, and 2Department of Psychiatry,

University of Texas Health Science Center at San Antonio, San Antonio, Texas USA

BACKGROUND AND PURPOSE Repeated administration of a μ opioid receptor agonist can enhance some forms of impulsivity, such as delay discounting. However, it is unclear whether repeated administration alters motor impulsivity.

EXPERIMENTAL APPROACH We examined the effects of acute administration of morphine and amphetamine prior to and during daily morphine administration in rats responding under a five-choice serial reaction time task. Rats (n = 5) were trained to detect a brief flash of light presented randomly in one of five response holes; responding in the target hole delivered food, whereas responding in the wrong hole or responding prior to illumination of the target stimulus (premature response) initiated a timeout. Premature responding served as an index of motor impulsivity.

KEY RESULTS Administered acutely, morphine (0.1–10 mg·kg 1, i.p.) increased omissions and modestly, although not significantly, premature responding without affecting response accuracy; amphetamine (0.1–1.78 mg·kg 1, i.p.) increased premature responding without changing omissions or response accuracy. After 3 weeks of 10 mg·kg 1·day 1 morphine, tolerance developed to its effects on omissions whereas premature responding increased approximately fourfold, compared with baseline. Effects of amphetamine were not significantly affected by daily morphine administration.

CONCLUSIONS AND IMPLICATIONS These data suggest that repeated administration of morphine increased effects of morphine on motor impulsivity, although tolerance developed to other effects, such as omissions. To the extent that impulsivity is a risk factor for drug abuse, repeated administration of μ opioid receptor agonists, for recreational or therapeutic purposes, might increase impulsivity and thus the risk for drug abuse.

Abbreviations 5-CSRTT, 5-choice serial reaction time task

DOI:10.1111/bph.13434

© 2016 The British Pharmacological Society

Daily morphine and impulsivity in rats

BJP

Tables of Links TARGETS

LIGANDS

GPCRs

Amphetamine

μ opioid receptor

Morphine

These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www. guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 (Alexander et al., 2015).

Introduction Impulsivity is a complex behavioural trait, encompassing many neuro-biologically and behaviorally distinct processes (Evenden, 1999), that has been associated with numerous problematic behaviours including excessive gambling, risky sexual behaviour and drug abuse (Perry and Carroll, 2008; De Wit, 2009; Jentsch and Taylor, 1999; Pattij and De Vries, 2013; Bickel et al., 2014; Weafer et al., 2014). Impulsive choice reflects a tendency to choose small, immediately available, reinforcers over large, delayed reinforcers (delay discounting; Madden and Bickel, 2010), whereas impulsive action or motor impulsivity reflects a failure to inhibit or withhold inappropriate responses (Moeller et al., 2001; Dougherty et al., 2008). Opioid abusers tend to discount delayed rewards more rapidly than non-users, often preferring small, immediately available, reinforcers over large reinforcers delivered after a delay (Madden et al., 1997). Moreover, studies in non-human subjects such as rats and non-human primates indicate that acute (Kieres et al., 2004; Pitts and Mckinney, 2005; Pattij et al., 2009) and repeated (Harvey-Lewis et al., 2012; Schippers et al., 2012; Maguire et al., 2012; Maguire et al., 2015) administration of opioids such as morphine or heroin can increase choice of small immediately delivered reinforcers. Although there are some exceptions to the general relationship between opioid administration and discounting (see Harty et al., 2011; Eppolito et al., 2013; Maguire et al., 2015), studies to date support the view that increased delay discounting might be one consequence of repeated opioid use. Enhanced delay discounting could increase vulnerability for drug abuse insofar as it predisposes an individual to prefer the immediately available effects of drug-taking rather than the delayed effects of remaining abstinent, such as improved health, additional income, and positive social interactions. Opioid use is also associated with other types of impulsivity (Clark et al., 2006; Verdejo-García et al., 2007; Passetti et al., 2008; Baldacchino et al., 2012), which might further increase vulnerability to abuse drugs. However, the extent to which repeated opioid administration modifies these other types of impulsivity is less well known. The current study examined the effects of daily morphine administration in rats responding under a five-choice serial reaction time task (5-CSRTT). The 5-CSRTT is commonly used to study attentional capacity and impulsivity (Carli et al., 1983; Bari et al., 2008; Higgins and Breysse, 2008). Rats are trained to detect a brief flash of light presented randomly in one of five response holes; responding in the target hole delivers food, whereas responding in the wrong hole or responding prior to illumination of the

target stimulus initiates a timeout. Thus, food delivery is dependent upon waiting until the target stimulus is presented to make a response and attending to its location. Impulsivity is indexed by the number of responses emitted before presentation of the target stimulus, known as premature responses (Robbins, 2002). When administered acutely, drugs such as amphetamine, cocaine and nicotine increase premature responding under the 5-CSRTT (Cole and Robbins, 1987; Harrison et al., 1997; Stolerman et al., 2000; Paine and Olmstead, 2004; Pattij et al., 2007). Morphine also increases premature responding, although its effects are modest compared with the effects of some other drugs (Pattij et al., 2009; Wiskerke et al., 2011). Very few published studies have examined the effects of repeated opioid administration on responding under a 5-CSRTT, and it is unclear whether repeated opioid administration or its discontinuation changes motor impulsivity. In the current study, the acute effects of morphine were assessed prior to and during daily morphine administration. For comparison, the effects of amphetamine, a drug that is reported to increase premature responding under the 5-CSRTT (Cole and Robbins, 1987; see also Wiskerke et al., 2011), were also determined prior to and during daily morphine administration. Understanding whether repeated opioid administration alters impulsivity will further elucidate factors that contribute to the development and maintenance of drug abuse. Under the 5-CSRTT, the duration of the target stimulus can affect response accuracy; increasing the stimulus duration improves accuracy, whereas decreasing the stimulus duration reduces accuracy (Grottick and Higgins, 2002). In the current study, the target stimulus duration varied within and across sessions for individual rats based on response completion and accuracy; correct responses decreased, whereas incorrect responses increased the target stimulus duration by a fixed increment (see also Martin et al., 2015). This adjusting feature was implemented in order to maintain relatively high levels of correct responding, and thus reinforcement rate, under conditions such as repeated drug administration that might produce prolonged disruptions in behaviour. This study also assessed the feasibility of the adjusting procedure as a tool for studying the effects of repeated drug administration on impulsivity.

Methods Animals Five adult male Sprague–Dawley rats (Harlan Sprague–Dawley, Inc., Indianapolis, IN, USA) that were approximately 6 months British Journal of Pharmacology (2016) 173 1350–1362

1351

BJP

D R Maguire et al.

old at the beginning of the experiment served as subjects. Rats were housed individually in 45 × 24 × 20 cm plastic cages containing rodent bedding (Sani-chips; Harlan Teklad, Madison, WI, USA) in a colony room maintained on a 12:12 light/dark cycle; experiments were conducted during the light period. Rats received chow (Harlan Teklad) postsession to maintain their body weights at approximately 360 g. Water was available continuously in the home cage. Rats were initially trained to respond under a standard (fixed stimulus duration) 5-CSRTT (see “Behavioural Procedure”) and were tested with acute administration of caffeine and ethanol as part of an unpublished study. They did not receive any drugs for 6 weeks before the beginning of the current study. All animal care and experimental procedures nimals were carried out in accordance with the Institutional Animal Care and Use Committee, The University of Texas Health Science Center at San Antonio and with the 2011 Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources on Life Sciences, National Research Council, and the National Academy of Sciences). Rats were handled, weighed, and inspected daily for signs of illness or distress. This study did not require the use of anesthesia, analgesia or any surgical procedures; rats were not euthanized as part of this study. All procedures were conducted as humanely as possible and are reported in compliance with the ARRIVE guidelines (Kilkenny et al., 2010; McGrath & Lilley, 2015). Behavioural procedures in non-human subjects are highly predictive of effects in humans and provide an appropriate alternative for studying the effects of repeated drug administration on complex behavioural processes, such as those relating to impulsivity, when such a study in humans is not feasible or ethical. Rodents have been used extensively for studying the effects of drugs of abuse on impulsivity using a procedure similar to the one employed in this study (Robbins, 2002). Moreover, the current study used a withinsubjects design, in which all subjects experienced all treatment conditions; this type of design provides a powerful tool for assessing the behavioural effects of drugs that reduces the number of animals required to complete the study (Sidman, 1960).

Behavioural procedure Rats were initially trained under a 5-CSRTT procedure according to published protocols (Bari et al., 2008). Sessions were conducted at approximately the same time each day, 5–7 days·week 1. The beginning of the session was signalled by illumination of the house light and the food light as well as delivery of a food pellet. The food light remained on until a head entry in the food aperture was detected; at which point, the food light was turned off, and the inter-trial interval began. During the inter-trial interval, only the house light was on. Once the inter-trial interval lapsed, one response hole was illuminated for a fixed period of time (stimulus duration). A response in the illuminated hole (correct response; Figure 1, A) immediately turned off the target stimulus, turned on the food light and delivered one food pellet. Collection of the food pellet turned off the food light and started the inter-trial interval. This sequence of events repeated for up to 30 min or 100 stimulus presentations, whichever occurred first. The location of the target stimulus varied unpredictably from trial to trial with the constraint that each hole was the target once for each five-trial block. Responses in one of the other four holes following presentation of the target stimulus (incorrect response; Figure 1, B) or failure to respond within the limited hold (omission; Figure 1, C) initiated a 5-s timeout during which all lights including the houselight were turned off; timeouts were followed by illumination of the house light and initiation of the inter-trial interval. Responses prior to illumination of a target hole (i.e. during the inter-trial interval) initiated a timeout and were counted as premature responses (Figure 1, D). Responses during a timeout reset the timeout and were counted as timeout responses (Figure 1, E). Responses after a correct response and before food collection had no programmed consequence and were counted as perseverative responses (Figure 1, F).

Apparatus Sessions were conducted in sound-attenuating, ventilated enclosures containing rat operant-conditioning chambers designed for the 5-CSRTT (MED-NP5L-B1; Med-Associates, Inc., Georgia, VT, USA) with an interior space measuring 31 × 25 × 29 cm. Two opposing sides were made of Plexiglas; the other two sides were aluminium instrument panels. One panel contained a house light centrally located near the top of the chamber and a 5 × 5 cm aperture through which 45 mg grain-based food pellets (Bio-Serv, Frenchtown, NJ, USA) were delivered. The other panel contained fivehorizontally aligned response holes, each measuring 2.5 × 2.5 cm and located 5 cm from the floor. The five response holes and the food aperture could be illuminated individually and were equipped with an infrared beam that detected head entries. Experimental events were arranged, and data were collected by a PC-compatible interface and software (Med-PC IV; Med-Associates). 1352

British Journal of Pharmacology (2016) 173 1350–1362

Figure 1 Outline of the five-choice serial reaction time task (5-CSRTT) procedure. Adapted from Bari et al. (2008; “Behavioural Procedure” for details).

Daily morphine and impulsivity in rats

Initially, the stimulus duration, limited hold and intertrial interval were 30, 30, and 5 s, respectively. The stimulus duration and limited hold decreased progressively for each rat according to its performance and in a manner described by Bari et al. (2008). Once the stimulus duration and limited hold decreased to 2.5 and 5 s, respectively, the limited hold remained constant at 5 s for the remainder of the experiment. The stimulus duration was further adjusted for each rat in 0.25-s increments until performance was maintained at 70 ± 5% correct (see “Data and statistical Analyses”) with no more than 20 omissions per session for three consecutive sessions in order to determine performance with a fixed stimulus duration. After approximately 4 months of responding under a fixed stimulus duration procedure, the experimental parameters were modified such that the target stimulus duration adjusted during the session based on performance. Sessions were divided into 20 blocks of five trials each, and the stimulus duration for each block varied based on the number of correct responses made during the previous block. If at least four correct responses were made in a block, then the stimulus duration for the subsequent block decreased by 0.25 s; if three or fewer correct responses were made in a block, the stimulus duration increased by 0.25 s. The stimulus duration for the first block of each session was determined based on performance during the last block of the immediately preceding session. Following acute drug tests, the stimulus duration was set to the stimulus duration for the first block of the previous (no drug) session.

Pharmacological procedure Rats responded under the adjusting procedure for at least 10 sessions, and until responding was stable; at which point, the effects of acute administration of saline (vehicle), morphine, and amphetamine were determined. Morphine was administered 30 min and amphetamine 15 min prior to the start of sessions. Tests with drug or saline occurred so long as the percentage of correct responses did not vary by more than 10%, and the number of omissions did not exceed 20 for the three most recent baseline sessions; at least two baseline (no drug) sessions occurred between tests. Effects of amphetamine were studied first followed by morphine; doses were studied in an irregular order across rats (Figure 2, Phase A). Daily treatment with morphine began at least 2 weeks after the acute effects of morphine and amphetamine were determined (Figure 2, Phase B); 10 mg·kg 1 of morphine was

BJP

administered once daily 30 min prior to each session for 5weeks. After 5 weeks of daily morphine treatment, the acute effects of saline, morphine, and amphetamine were redetermined, while daily morphine treatment continued (Figure 2, Phase C). On test days, the daily morphine injection was omitted, and a test injection was given 30 min (saline and morphine) or 15 min (amphetamine) before the session. When the dose of morphine administered prior to the session was less than 10 mg·kg 1 (i.e. tests with saline, amphetamine, and smaller doses of morphine), the remainder of the daily dose of morphine was administered 30 min after the session. For example, if the test dose was 3.2 mg·kg 1 of morphine, an injection of 6.8 mg·kg 1 of morphine was administered post-session ensuring that a cumulative dose of 10 mg·kg 1 of morphine was administered that day. Tests with drug or saline occurred so long as responding was stable, as assessed by visual inspection of the data, and at least two baseline (daily morphine treatment) sessions occurred between tests. Data used to indicate the acute effects of 10mg·kg 1 of morphine for re-determination of the morphine dose-effect curve were obtained from the last day of week 5 of daily treatment. Tests with 17.8 mg·kg 1 of morphine and saline occurred during week 6; the test with 3.2 mg·kg 1 of morphine occurred during week 7; tests with 1.0 mg·kg 1 of morphine and 0.32 mg·kg 1 of amphetamine occurred during week 8; tests with 1.0 and 3.2 mg·kg 1 of amphetamine occurred during week 9; and the test with 0.1 mg·kg 1 of amphetamine occurred on the first day of week 10. Following re-determination of the dose-effect curves for morphine and amphetamine, daily morphine treatment continued for 7 days before saline injections were substituted for daily morphine injections (i.e. discontinuation; Figure 2, Phase D). During daily morphine treatment, all rats were treated identically, including the order of testing with saline, morphine, and amphetamine.

Data and statistical analyses The data and statistical analysis comply with the recommendations on experimental design and analysis in pharmacology (Curtis et al., 2015). The primary dependent measures were the number of trials initiated (i.e. the number of target stimulus presentations), correct responses, incorrect responses, omissions, premature responses, timeout responses, and perseverative responses. Response accuracy was expressed as a percentage by dividing the number of correct

Figure 2 Timeline of experimental phases before, during and following discontinuation of daily morphine treatment. Rats received daily injections of saline 1 (open boxes; Phases A and D) or 10 mg·kg of morphine (filled box; Phases B and C). On occasion during Phase C, the daily dose of morphine was omitted and a test injection of saline, morphine, or amphetamine was administered prior to the session (see “Pharmacological Procedure” for details). Values shown in the bottom row are the number of days in each phase. British Journal of Pharmacology (2016) 173 1350–1362

1353

BJP

D R Maguire et al.

responses by the total number of responses, excluding omissions, and multiplying by 100. Comparison of baseline performance between the fixed and adjusting stimulus durations procedures was conducted using a repeated-measures t-test. Dose-effect data within each treatment condition (before or during daily morphine treatment) were analysed using one-way repeated-measures ANOVA with dose entered as a within-subject variable. Post hoc comparisons were conducted using Dunnett’s test, which compares effects of all levels of the independent variable (dose) to a single control (saline) and corrects for multiple comparisons (Dunnett, 1955). A separate analysis was conducted for each drug and each treatment condition. Interactions between acutely administered dose and daily treatment condition were analysed using two-way repeatedmeasures ANOVA with dose and treatment condition entered as within-subject variables; only data from saline and doses that were tested before and during daily morphine treatment were included in the analysis. Post hoc comparisons were conducted using Dunnett’s test by comparing the effect of each dose (and saline) determined during daily morphine treatment to its effect determined prior to daily morphine treatment. In order to examine the effects of daily morphine treatment across time, data for each rat were averaged across all sessions for a week (defined as Monday through Sunday, inclusive); data from acute drug tests were excluded from the weekly averages. Group means were then obtained by taking the mean of these weekly averages. Data from the last 3 weeks prior to daily morphine treatment were averaged to obtain a grand baseline mean. Weekly data were analysed using a one-way repeated-measures ANOVA with week entered as a within-subject variable. Post hoc comparisons were conducted using Dunnett’s test by comparing effects of each week during daily morphine treatment and following discontinuation of treatment with the grand baseline mean. Analyses were conducted using Microsoft Excel (Redmond, WA, USA) and NCSS 9 (Kaysville, UT, USA) and plotted using GraphPad Prism (San Diego, CA, USA). The significance level for all tests was set at P < .05.

Materials Morphine sulphate (National Institute on Drug Abuse Drug Supply Program, Bethesda, MD, USA) and d-amphetamine sulphate (Sigma, St. Louis, MO, USA) were dissolved in a sterile 0.9% saline solution and injected i.p. in a volume of 1.0 mL·kg 1.

Results Baseline performance Under the standard (fixed stimulus duration) procedure, the stimulus duration ranged from 1 to 2 s across rats (Table 1). Upon implementation of the adjusting procedure, responding in all subjects stabilized within 10–14 sessions; mean-adjusting stimulus durations for the three sessions preceding the first saline test ranged from 1.03 to 1.54 s across rats (Table 1). Comparison of performance between procedures indicates that there were no differences except for a 1354

British Journal of Pharmacology (2016) 173 1350–1362

Table 1 Stimulus duration under the fixed and adjusting stimulus durations procedures for individual rats

Procedure Rat

Fixed

Adjusting

R01

2.00

1.03 (0.1)

R02

1.25

1.03 (0.1)

R03

1.50

1.37 (0.1)

R04

1.00

1.54 (0.0)

R05

1.00

1.28 (0.1)

a

a

Mean (± SEM) for three sessions of stable responding (see “Methods” for further details.).

modest, statistically significant, decrease in the number of correct responses under the adjusting procedure, compared with the fixed procedure (Table 2).

Effects of acute morphine before daily morphine treatment When administered acutely prior to daily morphine treatment, morphine (Figure 3, open symbols) significantly decreased perseverative responding (one-way ANOVA with dose as a within-subject factor; F5,30 = 27.1, P < 0.001; Figure 3C) with doses ranging from 1 to 10 mg·kg 1 producing significant decreases as compared with saline (Dunnett’s test). Morphine significantly increased omissions (F5,30 = 28.6, P < 0.001; Figure 3D) with doses ranging from 1 to 10 mg·kg 1 producing significant increases as compared with saline. Morphine also significantly increased mean stimulus duration (F5,30 = 15.8, P < 0.001; Figure 3F) with doses of 3.2 and 10mg·kg 1 producing significant increases as compared with saline. Morphine did not significantly affect premature responding (F5,30 = 0.83, P = 0.54; Figure 3A), timeout responding (F5,30 = 0.89, P = 0.50; Figure 3B) or response accuracy (F5,30 = 2.1, P = 0.11; Figure 3E).

Effects of acute amphetamine before daily morphine treatment When administered acutely prior to daily morphine treatment, amphetamine (Figure 4) significantly increased premature responding (one-way ANOVA with dose as a within-subject factor; F3,20 = 11.2, P < 0.001; Figure 4A) with doses of 0.32 and 1 mg·kg 1 producing significant increases, compared with saline (Dunnett’s test). Amphetamine also significantly increased timeout responding (F3,20 = 9.5, P = 0.002; Figure4B) with doses of 0.32 and 1 mg·kg 1 producing significant increases as compared with saline. Amphetamine did not modify perseverative responding (F3,20 = 0.95, P = 0.45; Figure 4C), omissions (F3,20 = 0.7, P = 0.57; Figure 4D), response accuracy (F3,20 = 1.0, P = 0.43; Figure 4E) or mean stimulus duration (F3,20 = 0.82, P = 0.51; Figure 4F).

Daily morphine treatment Daily treatment with 10 mg·kg 1 morphine significantly increased premature responding (one-way ANOVA with week as a within-subject factor; F12,65 = 3.1, P = 0.003; Figure 5A);

Daily morphine and impulsivity in rats

BJP

Table 2 Comparison of performance of rats (n = 5) responding under the fixed- and adjusting-stimulus duration procedures

Procedure Measure Session duration (min) Trials initiated

Fixed 19.9 (0.5)

a

t-test result Adjusting

b

20.4 (0.7)

t

c

P

2.71 —

d

0.053 —

d

100.0 (0.0)

100.0 (0.0)

Correct responses (#)

71.7 (1.1)

67.9 (1.0)

8.08

0.001

Incorrect responses (#)

22.6 (0.7)

24.2 (1.0)

1.56

0.193 0.177

Omissions (#)

5.7 (1.3)

7.9 (1.6)

1.64

76.0 (0.6)

73.8 (0.8)

2.64

0.057

8.9 (1.2)

6.5 (0.6)

2.07

0.107

Timeout responses (#)

10.2 (1.3)

7.1 (1.3)

1.44

0.222

Perseverative responses (#)

23.3 (7.6)

22.5 (7.6)

0.18

0.864

0.9 (0.1)

0.9 (0.0)

Accuracy (% correct) Premature responses (#)

Correct latency (s)

—

d

—

d

Incorrect latency (s)

1.8 (0.1)

1.9 (0.1)

0.83

0.450

Reward latency (s)

2.5 (0.3)

3.3 (0.6)

1.94

0.124

Data from the last three sessions under the fixed stimulus duration and the last three sessions prior to the first drug test under the adjusting stimulus duration procedure. b values in parentheses indicate SEM. c df = 4. d T-test statistic could not be calculated. a

premature responding was significantly increased during weeks 3, 4 and 6 of daily morphine treatment, compared with the grand baseline mean (Dunnett’s test). Daily morphine treatment also significantly increased omissions (F12,65 = 2.6, P = 0.010; Figure 5D), response accuracy (F12,65 = 2.8, P = 0.006; Figure 5E) and mean stimulus duration (F12,65 = 4.4, P < 0.001; Figure 5F). Omissions and response accuracy were significantly increased for the first week of treatment but not thereafter. Mean stimulus duration was significantly increased during the first 3 weeks of treatment but not thereafter. Daily morphine treatment significantly decreased perseverative responding (F12,65 = 13.1, P < 0.001; Figure 5C), which was significantly lower during most weeks of treatment as compared with baseline, except for weeks 5, 8 and 9.

Effects of morphine during daily morphine treatment After at least 5 weeks of daily morphine treatment, acute administration of morphine (Figure 3) significantly increased premature responding (one-way ANOVA with dose as a within-subject factor; F4,25 = 4.0, P = 0.020; Figure 3A) with a dose of 3.2 mg·kg 1 producing a significant increase when compared with saline (Dunnett’s test). Morphine significantly increased omissions (F4,25 = 3.1, P = 0.046; Figure 3D); post hoc analysis revealed that no individual dose was significantly different from saline. Morphine decreased perseverative responding (F4,25 = 8.3, P < 0.001; Figure 3C) with doses of 10.0 and 17.8 mg·kg 1 producing significant decreases as compared with saline. Morphine did not alter timeout responding (F4,25 = 1.4, P = 0.29; Figure 3B), response accuracy (F4,25 = 1.6, P = 0.24; Figure 3E) or mean stimulus duration (F4,25 = 2.7, P = 0.07; Figure 3F).

A two-way ANOVA with morphine dose and treatment condition (before and during daily morphine treatment) entered as within-subject factors indicated a significant main effect of morphine dose on premature responding (F3,40 = 6.0, P = 0.01) but no main effect of daily treatment (F1,40 = 0.41, P = 0.56) and no dose by treatment interaction (F3,40 = 2.0, P = 0.17). For timeout responding, there was no main effect of morphine dose (F3,40 = 1.4, P = 0.30) or daily treatment (F1,40 = 2.5, P = 0.19) and no interaction (F3,40 = 0.97, P = 0.44). For perseverative responding, there was a significant main effect of morphine dose (F3,40 = 19.2, P < 0.001), a significant main effect of daily treatment (F1,40 = 39.6, P = 0.003) and a significant dose by daily treatment interaction (F3,40 = 5.6, P = 0.012); the effects of 1 and 3.2 mg·kg 1 differed significantly between treatment conditions (Dunnett’s test). For omissions, there was a significant main effect of morphine dose (F3,40 = 15.5, P < 0.001) and a significant main effect of daily treatment (F1,40 = 23.5, P = 0.008), but no dose by daily treatment interaction (F3,40 = 1.6, P = 0.23); effects of doses ranging from 1 to 10 mg·kg 1 differed significantly between treatment conditions. For response accuracy, there was no main effect of morphine dose (F3,40 = 0.29, P = 0.83) or daily treatment (F1,40 = 0.07, P = 0.80), and no dose by treatment interaction (F3,40 = 0.73, P = 0.55). For mean stimulus duration, there was a significant main effect of morphine dose (F3,40 = 5.7, P = 0.012), but no main effect of daily treatment (F1,40 = 0.43, P = 0.55) and no dose by treatment interaction (F3,40 = 3.0, P = 0.07).

Effects of amphetamine during daily morphine treatment After at least 5 weeks of daily morphine treatment, acute administration of amphetamine significantly increased British Journal of Pharmacology (2016) 173 1350–1362

1355

BJP

D R Maguire et al.

Figure 3 Morphine dose-effect curves for (A) premature responding, (B) timeout responding, (C) perseverative responding, (D) omissions, (E) accuracy, and (F) 1 mean stimulus duration determined before and during daily administration of 10 mg·kg morphine in rats (n = 5) responding under a five-choice serial reaction time task (5-CSRTT). Morphine or saline (S) was administered 30 min prior to the session. Data points indicate the mean (± SEM). * P < 0.05; significantly different from saline, within a treatment condition; # P < 0.05; significant difference between treatment conditions; ANOVA with Dunnett’s test.

premature responding (one-way ANOVA with dose as a withinsubject factor; F4,25 = 7.6, P = 0.001; Figure 4A) with doses of 1 and 3.2 mg·kg 1 producing significant increases as compared with saline (Dunnett’s test). Amphetamine did not significantlymodify timeout responding (F4,25 = 2.8, P = 0.06; Figure 4B), perseverative responding (F4,25 = 1.8, P = 0.18; Figure 4C), omissions (F4,25 = 2.1, P = 0.13; Figure 4D), response accuracy (F4,25 = 2.8, P = 0.06; Figure 4E) or mean stimulus duration (F4,25 = 1.3, P = 0.31; Figure 4F). A two-way ANOVA with amphetamine dose and treatment condition entered as within-subject factors indicated there was a main effect of amphetamine dose on premature 1356

British Journal of Pharmacology (2016) 173 1350–1362

responding (F3,40 = 19.7, P < 0.001) and no main effect of daily treatment (F1,40 = 0.42, P = 0.55), but there was a significant dose by treatment interaction (F3,40 = 10.5, P = 0.001); the effects of doses ranging from 0.1 to 1 mg·kg 1 differed significantly between treatment conditions (Dunnett’s test). For timeout responding, there was a significant main effect of amphetamine dose (F3,40 = 6.2, P = 0.009), but no main effect of daily treatment (F1,40 = 2.3, P = 0.21) and no dose by treatment interaction (F3,40 = 2.8, P = 0.09); effects of 1 mg·kg 1 were significantly different between treatment conditions. For perseverative responding, there was no main effect of amphetamine dose (F3,40 = 1.6, P = 0.24), but there was a main

Daily morphine and impulsivity in rats

BJP

Figure 4 Amphetamine dose-effect curves for (A) premature responding, (B) timeout responding, (C) perseverative responding, (D) omissions, (E) accu1 racy, and (F) mean stimulus duration determined before (open symbols) and during (filled symbols) daily administration of 10 mg·kg morphine in rats (n = 5) responding under a five-choice serial reaction time task (5-CSRTT). Amphetamine was administered 15 min prior to the session. Saline (S) was tested once during daily morphine administration; saline data during daily morphine treatment in this figure are also shown in Figure 3. Data points indicate the mean (± SEM). * P < 0.05; significantly different from saline, within a treatment condition; # P < 0.05; significant difference between treatment conditions; ANOVA with Dunnett’s test.

effect of daily treatment (F1,40 = 11.7, P = 0.027); however, there was no dose by treatment interaction (F3,40 = 2.1, P = 0.15). Effects of 0.32 and 1 mg·kg 1 on perseverative responding were significantly different between treatment conditions. For omissions, there was no main effect of amphetamine dose (F3,40 = 0.65, P = 0.60) or daily treatment

(F1,40 = 4.6, P = 0.10) and no dose by treatment interaction (F3,40 = 0.57, P = 0.65). For response accuracy, there was a significant main effect of amphetamine dose (F3,40 = 3.9, P = 0.038), but no main effect of daily treatment (F1,40 = 1.1, P = 0.35) and no dose by treatment interaction (F3,40 = 0.58, P = 0.64). For mean stimulus duration, there British Journal of Pharmacology (2016) 173 1350–1362

1357

BJP

D R Maguire et al.

Figure 5 1

Effects of daily administration of saline or 10 mg·kg morphine on (A) premature responding, (B) timeout responding, (C) perseverative responding, (D) omissions, (E) accuracy, and (F) mean stimulus duration plotted by week of treatment. Data points indicate the mean (± SEM) across rats for each week. * P < 0.05; significantly different from the grand baseline mean, which is the average of the last 3 weeks prior to the start of daily morphine administration (labelled as weeks -3, -2 and -1; see “Methods” for details).

was no main effect of amphetamine dose (F3,40 = 0.65, P = 0.60) or daily treatment (F1,40 = 0.85, P = 0.41) and no dose by treatment interaction (F3,40 = 1.9, P = 0.19).

Discontinuation of daily morphine treatment Upon discontinuation of daily morphine treatment (Figure 5, weeks 11 and 12), all measures of responding returned to baseline levels and were not significantly different from the baseline established prior to daily morphine treatment (Dunnett’s test).

Discussion and conclusion Research in non-human subjects indicates that repeated administration of a μ opioid receptor agonist can enhance some types of impulsivity such as delay discounting. However, it is unclear whether repeated opioid administration modifies other types of impulsivity. Understanding whether repeated opioid administration affects impulsivity will further elucidate factors contributing to the development and maintenance of opioid abuse. This study examined the effect 1358

British Journal of Pharmacology (2016) 173 1350–1362

of daily morphine administration on motor impulsivity (premature responding) in rats responding under a modified version of a 5-CSRTT. Rats were trained to detect a brief flash of light presented randomly in one of five response holes, and the duration of the target stimulus varied with trial completion and accuracy. Under the adjusting procedure, performance was comparable with that maintained under a standard (fixed stimulus duration) procedure (Tables 1, 2; Martin et al., 2015). Consistent with previous studies, amphetamine markedly increased premature responding at doses that did not substantially modify trial completion or accuracy (Cole and Robbins, 1987; Grottick and Higgins, 2002). In most rats, morphine also increased premature responding; however, prior to daily morphine administration, the effect at the group level was small and not statistically significant. Taken together, these data indicate that the current (adjusting) procedure is sensitive enough to detect increases in premature responding, for instance, the effects of amphetamine, and confirm that acute administration of opioids such as morphine produced modest increases in premature responding (Pattij et al., 2009). Morphine also dose dependently increased trial omissions

Daily morphine and impulsivity in rats

and, consequently, mean stimulus duration. Despite increased omissions, acute administration of morphine did not significantly affect response accuracy. Maintenance of relatively high levels of response accuracy might be due, in part, to the adjusting nature of the procedure insofar as omissions also increased stimulus duration, making the task less difficult. However, morphine did not reliably modify response accuracy under a procedure in which the stimulus duration was fixed (Boyette-Davis et al., 2008). When administered acutely, morphine typically does not increase premature responding (Pattij et al., 2009) to the same degree as some other drugs, including amphetamine (current study; Wiskerke et al., 2011). In the current study, a relatively small dose of morphine (0.32 mg·kg 1) modestly increased premature responding in most rats; however, larger doses of morphine did not produce further increases. One possibility is that opioids do not induce high levels of motor impulsivity. On the other hand, it is possible that effects on premature responding are limited by other effects that interfere with responding, as reflected by increased omissions. Morphine also decreased perseverative responding, which could be interpreted as reducing compulsive behaviour (Robbins, 2002). However, consistent with an earlier study (Pattij et al., 2009), the range of doses of morphine that decreased perseverative responding also increased omissions, suggesting that the reduction in perseverative responding reflects a non-selective decrease in responding. Daily morphine administration significantly increased premature responding. The levels of premature responding maintained after 3 weeks of daily morphine administration were nearly twofold higher than the level of effect produced by the maximally effective dose of morphine administered acutely, and the morphine dose-effect curve for premature responding appeared to be shifted upwards. For some individual rats, the increase in premature responding was as much as fourfold higher as compared with the acute administration of morphine. In contrast, other effects of morphine (omissions and perseverative responding) were diminished following daily morphine administration, as indicated by rightward shifts in the dose-effect curve. Given the aforementioned relationship between premature responding and omissions it might be the case that premature responding increased during daily morphine administration, in part, because other effects of morphine (i.e. increased omissions) were attenuated. Although effects on premature responding eventually diminished with continued daily morphine administration, possibly reflecting the development of tolerance, these data demonstrate that while repeated administration attenuates some effects of opioids, such as increased omissions, it enhances other effects, such as increased premature responding. Repeated opioid administration also enhances choice of small reinforcers delivered immediately over large reinforcers delivered after a delay (delay discounting; Harvey-Lewis et al., 2012; Schippers et al., 2012; Maguire et al., 2012). Taken together, these data suggest that repeated opioid administration enhances multiple types of impulsive behaviour. Increased premature responding is often interpreted as enhanced impulsivity insofar as responding before the target stimulus is presented reflects reduced behavioural inhibition (Robbins, 2002). Increased premature responding under the 5-CSRTT might also reflect effects on other processes. For

BJP

example, it is possible that morphine increased locomotor activity (Babbini and Davis, 1972) or disrupted stimulus control (Ward and Odum, 2005), which in turn, increased the probability of responding irrespective the prevailing stimulus conditions or regardless of whether the target stimulus had been presented. However, in the current study, morphine and amphetamine increased premature responding without similarly increasing the responding during other periods of the session, such as timeouts. Amphetamine increased timeout responding significantly when administered acutely; however, the magnitude of effect was far smaller than the effect on premature responding (Figure 4). The house light remained on during the inter-trial interval, but was turned off during a timeout; otherwise, both periods were identical, with the same duration (i.e. 5 s) and the same consequence of making a response (i.e. initiating a timeout). If morphine and amphetamine increased premature responding by increasing locomotor activity or reducing stimulus control, they might be expected to increase responding throughout the session including during timeouts. Rather, the selective increase in premature responding, as compared with timeout responding, supports the notion that these drugs increase premature responding by altering processes related to changes in behavioural inhibition or motor impulsivity. Repeated administration of a μ opioid receptor agonist, such as morphine, can lead to the development of physical dependence, which is revealed by the emergence of withdrawal upon discontinuation of treatment. In rats, opioid withdrawal can decrease rates of food-maintained operant behaviour (Babbini et al., 1972; Gellert and Sparber, 1977). Thus, in the current study, discontinuation of daily morphine administration might be expected to increase trial omissions. However, all measures of performance returned to baseline levels within 1–3 days of discontinuation, and there were no effects indicating the emergence of opioid withdrawal. In a previous study that used rats and a 5-CSRTT (Dalley et al., 2005), discontinuation of heroin self-administration sessions decreased response accuracy and increased trial omissions without increasing premature responding. Taken together, these data suggest that discontinuation of repeated administration of opioids might not affect motor impulsivity. Although daily opioid administration increases delay discounting and motor impulsivity, it might be the case that discontinuation of repeated opioid administration selectively increases delay discounting (Harvey-Lewis et al., 2015; Giordano et al., 2002) but not motor impulsivity. In a previous study (Wiskerke et al., 2011), increased premature responding produced by amphetamine was blocked by the opioid receptor antagonist naloxone but not the selective κ opioid receptor antagonist nor-BNI or the selective δ opioid receptor antagonist naltrindole, suggesting that μ opioid receptors might play a role in the effects of amphetamine on premature responding. In the current study, amphetamine was tested before and during daily morphine treatment to determine whether repeated opioid treatment changed the effects of amphetamine. Given that μ opioid receptor blockade attenuated the effects of amphetamine on premature responding (Wiskerke et al., 2011), it might be expected that other manipulations, which attenuate opioid receptor function, such as repeated treatment with a μ opioid receptor agonist, might also alter the effects of amphetamine. Despite changes in the effects of morphine following daily morphine treatment, effects of amphetamine on premature responding British Journal of Pharmacology (2016) 173 1350–1362

1359

BJP

D R Maguire et al.

were not substantially different. The effects of two doses (0.1 and 1 mg·kg 1) were enhanced following daily morphine treatment as compared with their effects prior to daily treatment, although the effect of an intermediate dose (0.32 mg·kg 1) was diminished. These data suggest that repeated treatment with morphine under the conditions employed in the current study does not substantially modify the effects of amphetamine on premature responding under the 5-CSRTT. It is possible that changes in the parameters of repeated opioid treatment, such as treatment dose, frequency, and duration, might reveal an interaction between the opioid and dopaminergic systems with regard to the relationship between repeated drug administration and impulsivity. Finally, the rats used in the study were trained initially under a standard version of the 5-CSRTT in which the stimulus duration was fixed during and across sessions. During that time, rats were tested acutely with caffeine and ethanol. The doses of each drug, ranging from 32 to 100 mg·kg 1 (i.p.) of caffeine and from 1 to 1.78 g·kg 1 (i.p.) of ethanol, were tested acutely once, with at least 6 weeks intervening between the last drug test and the beginning of this study. It is unclear how the history of responding under the fixed stimulus duration procedure and relatively low levels of exposure to ethanol or caffeine would influence the results of the current study. It is unlikely that such limited testing with ethanol and caffeine would have any effects on baseline responding or would change sensitivity to other drugs more than 6 weeks later. Baseline responding in this group of rats was nearly identical to other groups of rats trained in this laboratory with diverse (or even no) pharmacological histories (unpublished data) and performance in studies from other laboratories (Bari et al., 2008; Higgins and Breysse, 2008; Martin et al., 2015). Moreover, sensitivity to acute administration of morphine and amphetamine in this study was similar to previous studies in terms the potency of both drugs to change behaviour and the qualitative nature of effects. Certainly, the consequences of a history with ethanol and caffeine administration, prior to treatment with other drugs such as amphetamine or opioids might be of interest, particularly with regard to impulsivity. In summary, rats responded under a modified version of the 5-CSRTT in which the duration of the target stimulus varied with trial completion and accuracy. Performance under the adjusting procedure was comparable with that maintained under a standard (fixed stimulus duration) procedure. Administered acutely, amphetamine and, to a much lesser extent, morphine increased premature responding. After several weeks of daily morphine administration, tolerance developed to its effects on omissions while premature responding increased. These data suggest that repeated administration of a μ opioid receptor agonist increases the effects of μ opioid receptor agonists on motor impulsivity. To the extent that motor impulsivity increases risk for drug abuse, repeated use of opioids, for recreational or therapeutic purpose, might increase impulsivity and thus the risk for drug abuse.

Acknowledgements The authors thank Elise Rush for excellent technical assistance. This study was supported, in part, by United States Public Health Service grants F32DA035605, R25NS080684 and K05DA017918. 1360

British Journal of Pharmacology (2016) 173 1350–1362

Author contributions D.R.M. designed the study, performed the research, analysed the data and wrote the paper. C.H. designed the study and performed the research. C.P.F. designed the study and wrote the paper.

Conflict of interest The authors declare no conflicts of interest.

Declaration of transparency and scientific rigour This Declaration acknowledges that this paper adheres to the principles for transparent reporting and scientific rigour of preclinical research recommended by funding agencies, publishers and other organizations engaged with supporting research.

References Alexander SPH, Davenport AP, Kelly E, Marrion N, Peters JA, Benson HE et al. (2015). The Concise Guide to PHARMACOLOGY 2015/16: G Protein-Coupled Receptors. Br J Pharmacol 172: 5744–5869. Babbini M, Davis WM (1972). Time-dose relationships for locomotor activity effects of morphine after acute or repeated treatment. Br J Pharmacol 46: 213–224. Babbini M, Gaiardi M, Bartoletti M (1972). Changes in operant behavior as an index of a withdrawal state from morphine in rats. Pyschonomic Sci 29: 142–144. Baldacchino A, Balfour DJK, Passetti F, Humphris G, Matthews K (2012) Neuropsychological consequences of chronic opioid use: a quantitative review and meta-analysis. Neurosci Biobehav Rev 36: 2056–2068. Bari A, Dalley JW, Robbins TW (2008). The application of the 5-choice serial reaction time task for the assessment of visual attentional processes and impulse control in rats. Nat Protoc 3: 759–767. Bickel WK, Koffarnus MN, Moody L, Wilson AG (2014). The behavioral-and neuro-economic process of temporal discounting: a candidate behavioral marker of addiction. Neuropharmacology 76: 518–527. Boyette-Davis JA, Thompson CD, Fuchs PN (2008). Alterations in attentional mechanisms in response to acute inflammatory pain and morphine administration. Neuroscience 151: 558–563. Carli M, Robbins TW, Evenden JL, Everitt BJ (1983). Effects of lesions to ascending noradrenergic neurones on performance of a 5-choice serial reaction time task in rats: Implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal. Behav Brain Res 9: 361–380. Clark L, Robbins TW, Ersche KD, Sahakian BJ (2006). Reflection impulsivity in current and former substance users. Biol Psychiatry 60: 515–522. Cole BJ, Robbins TW (1987). Amphetamine impairs the discriminative performance of rats with dorsal noradrenergic bundle

Daily morphine and impulsivity in rats

BJP

lesions on a 5-choice serial reaction time task: new evidence for central dopaminergic-noradrenergic interactions. Psychopharmacology (Berl) 91: 458–466.

Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010). Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8: e1000412.

Curtis MJ, Bond RA, Spina D, Ahluwalia A, Alexander SPH, Giembycz MA et al. (2015). Experimental design and analysis and their reporting: new guidance for publication in BJP. Br J Pharmacol 172: 3461–3471.

Madden GJ, Bickel WK (eds.) (2010) Impulsivity: The Behavioral and Neurological Science of Discounting. American Psychological Association: Washington, D.C..

Dalley JW, Laane K, Pena Y, Theobald DE, Everitt BJ, Robbins TW (2005). Attentional and motivational deficits in rats withdrawn from intravenous self-administration of cocaine or heroin. Psychopharmacology (Berl) 182: 579–587. De Wit H (2009). Impulsivity as a determinant and consequence of drug use: a review of underlying processes. Addict Biol 14: 22–31. Dougherty DM, Marsh-Richard DM, Hatzis ES, Nouvion SO; Mathias CW (2008). A test of alcohol dose effects on multiple behavioral measures of impulsivity. Drug Alcohol Depend 96: 111–120. Dunnett C (1955). A multiple comparison procedure for comparing several treatments with a control. J Am Stat Assoc 50: 1096–1121. Eppolito AK, France CP, Gerak LR (2013). Effects of acute and chronic morphine on delay discounting in pigeons. J Exp Anal Behav 99: 277–289. Evenden JL (1999). Varieties of impulsivity. Psychopharmacology (Berl) 146: 348–361. Gellert VF, Sparber SB (1977). A comparison of the effects of naloxone upon body weight loss and suppression of fixed-ratio operant behavior in morphine-dependent rats. J Pharmacol Exp Ther 201: 44–54. Giordano LA, Bickel WK, Loewenstein G, Jacobs EA, Marsch L, Badger GJ (2002). Mild opioid deprivation increases the degree that opioiddependent outpatients discount delayed heroin and money. Psychopharmacology (Berl) 163: 174–182. Grottick AJ, Higgins GA (2002). Assessing a vigilance decrement in aged rats: effects of pre-feeding, task manipulation, and psychostimulants. Psychopharmacology (Berl) 164: 33–41. Harrison AA, Everitt BJ, Robbins TW (1997). Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms. Psychopharmacology (Berl) 133: 329–342. Harty SC, Whaley JE, Halperin JM, Ranaldi R (2011). Impulsive choice, as measured in a delay discounting paradigm, remains stable after chronic heroin administration. Pharmacol Biochem Behav 98: 337–340. Harvey-Lewis C, Brisebois AD, Yong H,Franklin KBJ (2015). Naloxoneprecipitated withdrawal causes an increase in impulsivity in morphine-dependent rats. Behav Pharmacol 26: 326–329. Harvey-Lewis C, Perdrizet J, Franklin KBJ (2012). The effect of morphine dependence on impulsive choice in rats. Psychopharmacology (Berl) 223: 477–487. Higgins GA, Breysse N (2008) Rodent model of attention: the 5choice serial reaction time task. Curr Protoc Pharmacol 5: 5.49.1–5.49.20. Jentsch JD, Taylor JR (1999). Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology (Berl) 146: 373–390. Kieres AK, Hausknecht KA, Farrar AM, Acheson A, De Wit H, Richards JB (2004). Effects of morphine and naltrexone on impulsive decision making in rats. Psychopharmacology (Berl) 173: 167–174.

Madden GJ, Petry NM, Badger GJ, Bickel WK (1997). Impulsive and self-control choices in opioid-dependent patients and non-drugusing control patients: drug and monetary rewards. Exp Clin Psychopharmacol 5: 256–262. Maguire DR, Gerak LR, France CP (2015). Effect of daily morphine administration and its discontinuation on delay discounting of food in rhesus monkeys. Behav Pharmacol Published ahead of print. doi:10.1097/FBP.0000000000000194 Maguire DR, Li J-X, France CP (2012). Impulsivity and drugs of abuse: a juice-reinforced operant procedure for determining within-session delay discounting functions in rhesus monkeys. J Pharmacol Toxicol Methods 66: 264–269. Martin TJ, Grigg A, Kim SA, Ririe DG, Eisenach JC (2015). Assessment of attention threshold in rats by titration of visual cue duration during the five choice serial reaction time task. J Neurosci Methods 241: 37–43. McGrath JC, Lilley E (2015). Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP. Br J Pharmacol 172: 3189–3193. Moeller FG, Barratt ES, Dougherty DM, Schmitz JM, Swann AC (2001). Psychiatric aspects of impulsivity. Am J Psychiatry 158: 1783–1793. Paine TA, Olmstead MC (2004). Cocaine disrupts both behavioural inhibition and conditional discrimination in rats. Psychopharmacology (Berl) 175: 443–450. Passetti F, Clark L, Mehta MA, Joyce E, King M (2008). Neuropsychological predictors of clinical outcome in opiate addiction. Drug Alcohol Depend 94: 82–91. Pattij T, De Vries TJ (2013). The role of impulsivity in relapse vulnerability. Curr Opin Neurobiol 23: 700–705. Pattij T, Janssen MC, Vanderschuren LJMJ, Schoffelmeer ANM, VanGaalen MM (2007). Involvement of dopamine D(1) and D(2) receptors in the nucleus accumbens core and shell in inhibitory response control. Psychopharmacology (Berl) 191: 587–598. Pattij T, Schetters D, Janssen MC, Wiskerke J, Schoffelmeer ANM (2009). Acute effects of morphine on distinct forms of impulsive behavior in rats. Psychopharmacology (Berl) 205: 489–502. Pawson AJ, Sharman JL, Benson HE, Faccenda E, Alexander SPH, Buneman OP et al., NC-IUPHAR (2014) The IUPHAR/BPS Guide to PHARMACOLOGY: an expert-driven knowledge base of drug targets and their ligands. Nucl. Acids Res. 42 (Database Issue): D1098-1106. Perry JL, Carroll ME (2008). The role of impulsive behavior in drug abuse. Psychopharmacology (Berl) 200: 1–26. Pitts RC, Mckinney AP (2005). Effects of methylphenidate and morphine on delay-discount functions obtained within sessions. J Exp Anal Behav 83: 297–314. Robbins TW (2002). The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology (Berl) 163: 362–380. Schippers MC, Binnekade R, Schoffelmeer ANM, Pattij T, DeVries TJ (2012). Unidirectional relationship between heroin self-

British Journal of Pharmacology (2016) 173 1350–1362

1361

BJP

D R Maguire et al.

administration and impulsive decision-making in rats. Psychopharmacology (Berl) 219: 443–452. Sidman M (1960). Tactics of scientific research: evaluating experimental data in psychology. Authors Cooperative: Boston. Stolerman IP, Mirza NR, Hahn B, Shoaib M (2000). Nicotine in an animal model of attention. Eur J Pharmacol 393: 147–154. Verdejo-García AJ, Perales JC, Pérez-García M (2007). Cognitive impulsivity in cocaine and heroin polysubstance abusers. Addict Behav 32: 950–966.

1362

British Journal of Pharmacology (2016) 173 1350–1362

Ward RD, Odum AL (2005). Effects of morphine on temporal discrimination and color matching: General disruption of stimulus control or selective effects on timing?. J Exp Anal Behav 84: 401–415. Weafer J, Mitchell SH, De Wit H (2014). Recent translational findings on impulsivity in relation to drug abuse. Curr Addict Rep 1: 289–300. Wiskerke J, Schetters D, Van Es IE, Van Mourik Y, Den Hollander BRO, Schoffelmeer ANM et al. (2011). μ-Opioid receptors in the nucleus accumbens shell region mediate the effects of amphetamine on inhibitory control but not impulsive choice. J Neurosci 31: 262–272.