Drug and Alcohol Dependence 163 (2016) S19–S24

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Drug and Alcohol Dependence

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Full length article

Cocaine withdrawal alters the reward omission effect and enhances

traits of negative urgency in rats across multiple days of testing

∗

Alan T. Barker, G.V. Rebec

Program in Neuroscience, Department of Psychological and Brain Sciences, Indiana University, 1101 E. 10th St., Bloomington, IN 47405-7007, United States

a r t i c l e i n f o a b s t r a c t

Article history: Background: The personality trait of negative urgency, characterized as behaving rashly when emotionally

Received 1 June 2015

perturbed, is gaining attention as an indicator for susceptibility to problematic substance use. How this

Received in revised form

trait is inﬂuenced by exposure to drugs of abuse is still unclear. Using an animal model of binge cocaine

18 November 2015

consumption, we tested this relationship in a reward-omission task across multiple days.

Accepted 21 November 2015

Methods: Adult, male, Sprague-Dawley rats received seven daily (ip) injections of saline, cocaine

(10–20 mg/kg), or cocaine (20–40 mg/kg). Cocaine doses increased linearly each day from the lower to the

Keywords:

higher dose. A separate group received RTI-113 (3.0 mg/kg), a selective dopamine transporter inhibitor,

Binge cocaine

Urgency for 7 days. Fifteen days after their ﬁnal injection, rats were trained on a reward-omission task with an

operant component to earn further rewards.

Reward omission

Rats Results: Previous exposure to cocaine resulted in dose-dependent increases in negative urgency in sepa-

Dopamine reuptake inhibition rate behavioral variables across days of testing. The lower dose range increased negative urgency on the

dimension of decreased reaction time to press a lever, while the higher dose range increased the rate of

increase in lever presses made per trial. Rats receiving RTI-113 did not resemble either cocaine group

and instead showed a decrease in lever pressing across days.

Conclusions: Our results indicate that previous binge cocaine consumption enhances behavioral markers

of negative urgency in a dose-dependent, time-sensitive manner on discrete behavioral dimensions. The

results with RTI-113 suggest the relationship between cocaine exposure and negative urgency is unlikely

to be explained solely by inhibition of dopamine reuptake.

Ireland Ltd. This is an open access article under the CC BY-NC-ND license

(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction nent that goes beyond lack of behavioral inhibition or forethought

(Settles et al., 2012); individuals with high degrees of urgency tend

Personality variables have long been associated with individual to behave impulsively when in emotionally elevated states, but are

risk of substance abuse (Whiteside and Lynam, 2003). The trait of not otherwise volatile. Negative urgency is the tendency to make

impulsiveness, once thought to be a well-deﬁned construct, can be poor choices when in an emotionally distressed state, such as drink-

sub-factored into the traits of disinhibition, sensation seeking, and ing to ameliorate stress (Settles et al., 2012; Whiteside and Lynam,

urgency (Whiteside and Lynam, 2001). Each of these sub-factors 2001). This form of urgency is particularly interesting because it

interacts differentially with drug-consumption tendencies, with serves as a predictor of problem drinking and smoking in chil-

urgency showing the strongest relationship to developing prob- dren as young as ﬁfth grade (Settles et al., 2012), and is associated

lematic substance use (Bardo et al., 2007; Ersche et al., 2012; Gunn with cocaine dependence (Albein-Urios et al., 2012; Verdejo-Garcia

et al., 2013). An individual high in urgency is characterized as one et al., 2008; Whiteside and Lynam, 2003). The neural mechanisms

who scores low in the personality trait of conscientiousness, high in underlying negative urgency are purported to involve an imbal-

impulsivity, and high in disagreeableness (Bardo et al., 2007; Ersche ance of functional connectivity between cortical, striatal, and limbic

et al., 2012; Gunn et al., 2013). Urgency is distinct from general areas (Cyders and Smith, 2008; Gipson et al., 2012; Judice-Daher

impulsivity by the inclusion of an emotional response compo- and Bueno, 2013; Judice-Daher et al., 2012; Tavares et al., 2014).

Repeated cocaine use impairs global functioning of frontal cor-

tex, which manifests as hypofrontality, but also causes damage

locally in orbito-frontal cortex, resulting in impairments in judg-

∗

Corresponding author. Fax: +1 812 8554691. ment and cognitive ﬂexibility, as well as in increased impulsivity

E-mail address: [email protected] (G.V. Rebec).

http://dx.doi.org/10.1016/j.drugalcdep.2015.11.040

license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

S20 A.T. Barker, G.V. Rebec / Drug and Alcohol Dependence 163 (2016) S19–S24

(Albein-Urios et al., 2013; Stalnaker et al., 2007a, 2007b, 2007c; days: Saline, Cocaine (10–20 mg/kg), Cocaine (20–40 mg/kg), and

Zuo et al., 2011). Imaging of cocaine addicts revealed an increase because cocaine binds rather indiscriminately to monoamine

in urgency in patients with comorbid personality disorders, and transporters, we also assessed the behavioral effects produced

was accompanied by a decrease of temporal gray matter, indicating by 2␤-carbophenoxy-3␤-(4-chlorophenyl) tropane (RTI-113), an

further possible involvement of the limbic forebrain (Albein-Urios ultra-selective dopamine transporter inhibitor with similar behav-

et al., 2013). ioral effects to cocaine to help identify the relative contribution of

Considering the association of human cocaine abuse with neg- dopamine uptake inhibition (Carroll et al., 2004; Kuhar et al., 1999).

ative urgency, we adopted a dosing schedule to mimic the binge Rats in the RTI-113 group received 3.0 mg/kg, which is based on DAT

consumption and dosage escalation common to human addicts binding afﬁnities such that an equal saturation of DAT would occur

(Ahmed and Koob, 1998; Ahmed et al., 2002, 2003). Each day for with RTI-113 as in the Cocaine (20–40 mg/kg) group (Dworkin et al.,

seven consecutive days of cocaine administration, the dosage was 1998). USP grade cocaine HCl and RTI-113 provided by Research

increased in a linear fashion so that the dose on the ﬁnal day was Triangle Institute, were dissolved in USP saline at a concentration

twice the dose of the initial day. A similar dosage escalation is that maintained a constant injection volume of 1.0 mL/kg. To sim-

also seen in rats self-administering cocaine, and demonstrates the ulate the escalating dosage schedule observed in human cocaine

maintenance of a particular desired subjective state that requires dependence, cocaine doses escalated each day in a linear fashion

an increasing amount of drug (Ahmed and Koob, 1998; Ahmed et al., such that on the ﬁnal day of injections the dose had doubled. Due

2002, 2003; Fischer et al., 2013; Knackstedt and Kalivas, 2007). After to lack of safety data on high doses of RTI-113, this escalation of

withdrawal, craving for the drug increases (Conrad et al., 2008; dose was limited to the two cocaine groups (see below for further

Grimm et al., 2001), marked by enhanced drug-seeking behavior, discussion). Injections (ip) were administered once daily for seven

but also manifests at the cellular level as structural and functional days. After injection, subjects were returned to their home-cage

changes largely in the pre-frontal cortex (PFC) and nucleus accum- for monitoring before returning to the colony room. Following the

bens (NAcc) (Conrad et al., 2008; Fischer et al., 2013; Grimm et al., ﬁnal day of injections, subjects remained in their home cages in

2001; Sun and Rebec, 2006). The role of these mechanisms in the colony room with food and water available ad libitum for 15

re-establishing drug-seeking behavior and a subsequent loss of cog- days.

nitive ﬂexibility is well established. Here, we assessed the effects

of binge cocaine withdrawal on negative urgency as manifested in 2.3. Apparatus

a reward-omission task. Because cocaine inhibits dopamine reup-

take, we also examined the effects of withdrawal from RTI-113, For training and data collection operant chambers were used.

a highly-selective dopamine transporter (DAT) inhibitor (Carroll They were operated by a Med-PC SG-6510D controller using MED-

et al., 2004; Kuhar et al., 1999). PC IV (ver. 4.0.1.47) software from Med Associates, Inc. (St. Albans,

VT). The boxes measure 31.75 cm W × 31.75 cm D × 41.9 cm H, and

2. Methods are equipped with a central food hopper with a lever and cue-light

positioned to either side. Opposite the food-hopper is a house light

2.1. Subjects and an embedded speaker. The food-hopper is attached to an exter-

nal pellet dispenser that dispenses 48 mg TestDiet Sucrose Pellets

Adult, male, Sprague-Dawley rats, weighing approximately (Richmond, Indiana).

300 g provided by Harlan Industries (Indianapolis, IN), were single-

housed in clear plastic cages. Water was provided ad libitum 2.4. Reward omission training

throughout the course of study. During periods of training and

testing, food intake was restricted to maintain 85% of free-feeding After their ﬁnal day of injections, rats remained in their home

weight. Prior to training, during drug administration days and dur- cages for a 15-day withdrawal period before they began training

ing the drug withdrawal portion of the experiment, food and water on a reward omission test. Training consisted of three phases prior

were available ad libitum. The rats were housed on a 12:12 light to data collection.

cycle, with all testing and drug administration conducted during

the lights-on portion of the day. All housing and animal-use proce-

2.4.1. Phase I. Subjects are conditioned to anticipate a free-food

dures followed NIH guidelines and were approved by the Indiana

pellet delivered immediately following the presentation of a cue

University Institutional Animal Care and Use Committee.

light and tone. The session begins with illumination of the house

light for 60 s. When the house light turns off, one of the two cue

2.2. Drugs lights is illuminated on a randomly determined counterbalance for

each light. The light is illuminated for 5 s, and is accompanied by a

The rats were divided into four treatment groups for 400 Hz, 50 dB, 0.5 s tone along with the release of a single sucrose

injections, which occurred once daily for seven consecutive pellet into the food hopper. A 2 s dark period ensues followed by

Fig. 1. (A) Mean (±SEM) latency for reaction time on the lever after presentation with all groups represented together. A clear strong trend of increasingly shorter reaction

times on omission trials conﬁrms the presence of a test-wide negative urgency effect. (B) Mean (±SEM) lever presses per trial after lever presentation. While a main effect

of trial-type was observed, there was no interaction of trial-type-by-day as was observed with latency. This demonstrates latency as a greater marker of negative urgency in

our particular task. (C) Mean (±SEM) rate of lever pressing (LP). *p < 0.05, compared to reward trials.

A.T. Barker, G.V. Rebec / Drug and Alcohol Dependence 163 (2016) S19–S24 S21

illumination of the house light for a semi-random 45, 60, 75, or (20–40 mg/kg) (n = 10), and RTI-113 (3.0 mg/kg) (n = 16). Responses

90 s signaling the inter-trial period. Phase I consists of 32 trials and on the inactive lever were recorded and constituted less than 1% of

occurs once daily for 3 days. During Phase I training, animals are responding for all rats. Trials in which no response occurred were

observed to ensure conditioning has taken place as indicated by less than 1% of all trials.

hopper approach on presentation of cue.

3.1. Omission versus reward

2.4.2. Phase II. Rats are trained to press a lever for food pellets on

an FR10 schedule. Rats begin by autoshaping overnight in the oper- To conﬁrm the presence of negative urgency, we monitored

ant chamber with an available lever that dispenses a single 48 mg Phase IV behavior on omission trials compared to rewarded trials

sucrose pellet reward on an FR1 schedule of reinforcement with 100 across days for all groups. To ﬁt a normal distribution, latency and

rewards possible. Each subsequent training session is conducted rate data underwent a log transformation. The lever press data sim-

during daylight hours. After earning all 100 available awards within ilarly underwent a square root transformation for it to ﬁt a normal

3 h at the FR1 lever, the rats progress to FR3 the next day, followed distribution.

by FR5, and ﬁnally FR10. Animals continue to press at FR10 each day Our ﬁxed-effects model revealed a trial-type-by-day interaction

until 3 consecutive days of consistent performance is observed, at in latency to lever press. (F(6,306.40) = 24.87, p < 0.05). On rewarded

which time Phase II is complete. trials, latency was consistently higher than on omission trials. Addi-

tionally, omission trials displayed a consistent decline in reaction

2.4.3. Phase III. The two previous phases are combined into a single time across days while rewarded trials remained relatively con-

session. Rats are placed into the operant box and a 60 s pre-session stant. These data are summarized in Fig. 1a. Our lever-pressing data

begins with the house light illuminated. The house light shuts off, (number of lever presses and rate of lever pressing) did not show

and one of the two cue lights switch on in a counter-balanced man- a trial-type-by-day interaction, and are presented in Fig. 1b and

ner for 5 s. At the offset of the cue light, a 500 ms tone is emitted c. Collectively, these data demonstrate latency to lever press as a

along with delivery of a pellet. This is followed by a 2 s dark period, reliable marker of negative urgency.

at the end of which the right-hand lever is presented. The lever is

present for 45 s, during which time the rat can earn as many food

3.2. Group analysis

pellets as possible on an FR10 schedule. After 45 s, the levers retract

and the house light is illuminated for a semi-random 45, 60, 75, or

Next we examined pairwise comparisons. Consistent with our

90 s inter-trial interval. Each session is composed of 32 trials, with

expectations, pairwise comparisons collapsed across days revealed

one session per day for 3 consecutive days.

that all groups displayed shorter reaction times on omission trials

compared to reward trials. Lever-pressing data displayed a trial-

2.4.4. Phase IV. Reward omission is introduced. Phase IV is identical type difference for the RTI-113 condition, but the others remained

to Phase III with the exception that on a random 33% of the trials relatively constant. Pairwise comparison data are presented in

the free-food pellet that follows the cue lights + tone is omitted. Table 1.

Data are collected on the following parameters: latency to lever-

press after cue presentation, rate of lever pressing (presses/s), and

3.3. Group-by-day analysis

total number of lever presses. Phase IV data are collected for 4 days

with 3 days of Phase III inserted between each day of Phase IV to

A slope analysis based on a ﬁxed-effects linear model was used

decrease the frequency of omission sessions overall and maintain

to analyze differences between groups. This allowed day to be a

their “surprising” nature.

categorical variable, which ﬁts a slope to the linear trajectory of

adaptation to the test across days.

2.5. Data analysis Analysis of reward trials during Phase IV testing indicated nearly

ﬂat slopes for latency across days in all groups. Slopes for lever

Trials with no response were excluded from analysis. The data presses on reward trials also failed to show a cocaine effect. In

were then analyzed in SPSS22 (IBM Corp. Released 2013. IBM SPSS omission trials analyzed for latency, we detected a condition-

Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.) using by-day interaction (F(1793.28) = 2.89, p < 0.05) that shows how

a generalized linear model of ﬁxed effects. Such an analysis allows each of the groups adapt to the omission trials across days of

subject to be accounted for as a random variable and day treated as Phase IV testing. Post hoc analysis revealed that the cocaine

a numerical rather than ordinal variable to allow for slope rather (10–20 mg/kg) group had a signiﬁcantly different slope (m = −0.09)

than means comparison across days. than saline (m = −0.05; t(1800.83) = −2.95, p < 0.05)) and RTI-113

(m = −0.05, t(6316.49) = −4.19, p < 0.05)). As shown in Fig. 2a,

3. Results these data demonstrate a time-based behavioral shift toward

greater negative urgency in the low-dose binge cocaine group.

Group sizes after training and data collection were as fol- Interestingly, the higher dose binge cocaine (20–40 mg/kg) group

−

lows: Saline (n = 16), Cocaine (10–20 mg/kg) (n = 10), Cocaine (m = 0.07) showed a trend toward greater negative urgency with

Table 1

Mean (±SEM) rate of lever pressing, latency for reaction time on the lever after presentation, and mean (±SEM) number of presses. Data are cumulative across four days of

collection. Analysis was within groups comparisons of reward to omission trials.

Rate (±SEM) Reaction time (s ± SEM) Lever presses (±SEM)

Reward Omission Reward Omission Reward Omission

Saline 1.04(±0.02) 1.03(±0.01) 4.91(±0.20) 4.32(±0.33) 41.89(±0.75) 42.26(±0.75)

Cocaine (10–20 mg/kg) 1.03(±0.02) 1.03(±0.01) 4.48(±0.22) 3.59(±0.23) 42.20(±0.78) 43.10(±1.05)

Cocaine (20–40 mg/kg) 1.05(±0.02) 1.05(±0.01) 5.41(±0.28) 4.58(±0.45) 39.46(±0.98) 40.72(±1.48)

* *

RTI-113 1.11(±0.02) 1.12(±0.01) 5.00(±0.22) 4.24(±0.25) 37.12(±0.76) 38.60(±1.13)

p < 0.05.

S22 A.T. Barker, G.V. Rebec / Drug and Alcohol Dependence 163 (2016) S19–S24

Fig. 2. (A) Mean (±SEM) latency for reaction time on the lever during omission trials across days. Trends across days are depicted as a slope analysis using a ﬁxed-effects

linear model with day as a numerical variable. The cocaine (10–20 mg/kg) group compared to all others has a more negative slope (t(1800.83) = 2.95, p < 0.05). This suggests

an increase in negative urgency in the low-dose cocaine groups compared to the others on the variable of latency. (B) Mean (±SEM) number of lever presses during omission

trials across days. Trends across days are depicted as a slope analysis using a ﬁxed-effects linear model with day as a numerical variable. The cocaine (20–40 mg/kg) group

displays a steeper slope compared to the other groups (t(1,801.10) = 2.51, p < 0.05), suggesting a growth in negative urgency on the variable of lever pressing. The RTI-113

group, however, shows an opposite effect with a shallower slope than the others, suggesting a reduction in negative urgency. (C) Mean (±SEM) rate of lever pressing (LP)

during omission trials across days. The cocaine (10–20 mg/kg) group has a more negative slope than saline, (t(1801.04) = −2.04).

a steeper negative slope than saline, but did not reach signiﬁcance because of DAT inhibition, actually showed opposite effects on lever

(t(1802.14) = −1.41, p = 0.16). These results demonstrate a dose- pressing than both cocaine groups.

dependent effect of cocaine on negative urgency on reaction time Our extended period of withdrawal ensured that no drug was on

latency such that the low-dose binge exerts a greater effect on board during behavioral testing. Additionally, analysis of inactive

behavior than the high-dose binge. lever presses during Phases III–IV showed the rats unambiguously

Analysis of omission trials for lever pressing revealed an inter- chose the active lever throughout, arguing against a cocaine-

action of condition-by-day (F(4,455.49) = 6.41, p < 0.05). Analysis induced generalized increase in behavioral activation.

of slope values showed that both the high-dose binge cocaine Other than negative urgency, one possible interpretation of

(20–40 mg/kg) group (t(1801.10) = −2.51, p < 0.05) and the RTI-113 the ﬁndings for the low-binge cocaine (10–20 mg/kg) group could

group (t(1800.59) = −1.38, p < 0.05) have a signiﬁcantly different relate to adaptive learning processes rather than frustration. The

slope than saline (see Fig. 2b), conﬁrming an alteration of negative decrease in reaction times was present in all groups, but dispropor-

urgency on a different behavioral variable and in different treat- tionately so in the cocaine (10–20 mg/kg) group perhaps because

ment conditions compared to reaction time latency. The slope of the rats were less tolerant for delay once the lever was presented,

the cocaine (20–40 mg/kg) group (m = 0.32), was greater than saline but they could also be adaptively moving toward the lever once

(m = 0.19) (see Fig. 2a and b). The slope for RTI-113 (m = 0.13) is sig- they detected no reward was delivered. If that is the case, then a

niﬁcantly different from saline, and interestingly has a non-linear shorter delay on the lever is beneﬁcial and would suggest that the

quadratic curve; this was taken into account during the analysis. low-dose range of binge cocaine promotes reward-related learn-

It appears that while both cocaine and RTI-113 block DAT, their ing. The lack of similar effects with the high-dose range may be

effects on negative urgency are quite different. due to the neurotoxic effects of high doses of cocaine, which fall

Analysis of the rate data on omission trials, shown in into our 20–40 mg/kg dosage range (Stalnaker et al., 2007a). This

Fig. 2c, revealed a steeper negative slope in the cocaine interpretation is consistent with the ability of cocaine to enhance

(10–20 mg/kg) group (m = −0.04) compared to saline (m = −0.02), activation of dorsal striatum (White et al., 1998), which mediates

(t(1801.04) = −2.04). stimulus-response learning (Takahashi et al., 2007), and induce

neurotoxicity to the orbitofrontal cortex which impairs associa-

tive learning (Stalnaker et al., 2007a). Thus, our dose range of

10–20 mg/kg may have been sufﬁcient to generate greater plas-

4. Discussion

ticity in associative structures while still low enough to not cause

functional damage in frontal cortex. Interpreting the data within

Our results indicate that an increase in negative urgency fol-

the context of a learning paradigm could also help account for the

lowing withdrawal from binge cocaine is dependent on adaptation

day effect that we observed such that the curve across days could be

across multiple days of testing. Thus, although the groups appear

viewed as learning the associations of reward versus no-reward in

similar when days are pooled together, a clear emergence of an

an attempt to minimize delay between rewards. This may explain

omission effect is manifested across days as in Fig. 1a. When each

as well why the cocaine (10–20 mg/kg) group was the only group

group is represented across all 4 days of Phase IV testing, differ-

showing differences in rate of pressing across days. The change in

ences appear in the rate of adaptation to the testing. Interestingly,

rate for this group was actually a decrease, which is inconsistent

each cocaine group differed on either lever pressing or latency

with an explanation of negative urgency, but would still ﬁt this

to press the lever. Low-dose binge cocaine resulted in a greater

explanation if these rats are learning to press more quickly but

rate of decrease in reaction time on the lever as days progressed,

do not earn a larger number of rewards, which in fact is what we

while all other groups were unaffected. Similarly, high-dose binge

observed.

cocaine increased the rate of increase in number of lever presses as

The decrease in lever pressing in the RTI-113 group is suggestive

days progressed. These ﬁndings demonstrate an increase in nega-

of a decrease in negative urgency, but could also be interpreted as

tive urgency in both cocaine groups by the escalation of behavior

an increase in reward sensitivity, which would be consistent with

prompted by surprise omission of an expected reward (Amsel and

low responding on both reward and omission trials. This effect is

Ward, 1965; Dudley and Papini, 1995) . The cocaine (10–20 mg/kg)

interesting because RTI-113 was chosen as an active psychostimu-

group increased responding with a faster reduction in reaction

lant that isolates the relative contribution of DAT alone on behavior

time, while the cocaine (20–40 mg/kg) group increased the num-

with a chosen dose that simulates the degree of DAT occupancy

ber of presses per trial more quickly. The RTI-113 group, which

seen with the cocaine (20–40 mg/kg) dose range. If DAT inhibition

we expected to resemble either one or both of the cocaine groups

A.T. Barker, G.V. Rebec / Drug and Alcohol Dependence 163 (2016) S19–S24 S23

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Both authors have read and approve of this submission.

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