Yosef Amrami
The use of exercise and atomoxetine to decrease cocaine reinstatement in female rats selected for high or low
impulsivity
Drug relapse is a primary concern regarding the clinical treatment of drug addiction. Unfortunately, cocaine
relapse is a common phenomenon amongst cocaine addicts. In fact, a study conducted by Simpson and colleagues found
that about 23% of individuals who seek treatment for cocaine addiction relapse within a year after treatment, and an
additional 18% reenter treatment (1999). An explanation for the high rate of relapse is that drug addicts are prone to drug
cravings in the presence of cues that elicited memories of the drug, such as drug paraphernalia, and may act on those
cravings (Tolliver, et. al., 2010). This effect has been seen in rats in a drug reinstatement (relapse) study in which both
adult and adolescent rats expressed more drug seeking behavior in the presence of cues associated with the drug, such as
cue light (Anker & Carroll, 2010).
In addition, an innate individual difference, high impulsivity is related to drug-seeking behavior (Economidou,
Pelloux, Robbins, Dalley & Everitt, 2009; Perry, Nelson & Carroll, 2008). Impulsive choice, which is the variant of
impulsivity that our lab studies, is characterized as the preference of a small immediate reward over of large delayed
reward (Broos, et. al., 2012; Perry & Carroll, 2008). In order to investigate the role that impulsive choice has on the
acquisition, maintenance, extinction and reinstatement (relapse) of drugs, Perry et al. conducted a study where rats that
were selected for high (HiI) and low impulsive choice (LoI) self-administered cocaine. Her findings suggest that HiI rats
were more prone to drug abuse, and more likely to show greater drug seeking behaviors during reinstatement (2008).
Since high impulsivity is related to drug seeking behavior, logic would suggest that inhibiting impulsivity would
also decrease drug-seeking behavior. Atomoxetine, a norepinephrine reuptake inhibitor that is FDA approved for the
treatment of attention hyperactivity disorder (ADHD), has been shown to reduce impulsive choice in rats (Broos, et. al.,
2012; Economidou, et. al., 2009; Robbinson, et. al., 2008). Furthermore, findings from Economidou’s study imply that
atomoxetine also decreases drug reinstatement behaviors (2009).
In addition to the pharmaceutical treatment of drug relapse, we also need to consider behavioral interventions.
One considerable behavioral intervention is exercise. Zlebnik and colleagues conducted a study that investigated the
potential that exercise, characterized as wheel running, has on reducing drug-seeking behaviors in female rats during
reinstatement (2010). It was concluded that compared to rats that did not have access to exercise during reinstatement,
wheel-running rats exhibited reduced drug-seeking behavior during reinstatement (2010).
Yosef Amrami
In this study, we will be testing the effects that atomoxetine and exercise have on drug seeking behavior during
cue and cocaine primed reinstatement. We hypothesize (hypothesis 1) that combination of atomoxetine and exercise will
decrease cue and cocaine primed reinstatement in female rats. Furthermore, (hypothesis 2, and 3) this combination will
attenuate reinstatement greater than either atomoxetine or exercise individually. We also hypothesize (hypothesis 4) that
HiI rats will be more sensitive to the effects of atomoxetine than LoI rats and exhibit less reinstatement behavior after
atomoxetine is administered.
Method
Adult female rats will be screened for high (HiI) and Low (LoI) impulsive choice using a delayed discounting
(DD) task. Rats will be given a choice between an immediate small reward, which is the impulsive choice, and a delayed
larger reward. The DD task contains 60 trials per daily session. Rats can choose to press a lever that delivers a small (1
pellet) immediate award or a lever that delivers a large (3 pellets) delayed award. Impulsive rats are more likely to press
the lever that administers the small award. Both HiI and LoI rats will be subjects in our experiment.
After being screened for HiI or LoI, rats will be transferred to an octagonal operant conditioning box, which
serves as the rats’ housing unit. Each operant conditioning box will have an attached running wheel that allows rats free
access to concurrent self-administration levers and wheel running during experimental sessions. Rats will become
acclimated to wheel running conditions within a running wheel that is adjacent to their housing unit. After three days of
sufficient wheel running, rats will then undergo a catheterization surgery, in which an IV catheter will to placed into their
right atrium via their jugular vein. After the surgery, rats will recover for three days within their housing unit. During
these three days rats will be administered pain medication.
Once rats have recovered from surgery, they will start self-administering cocaine. Self-administration sessions are
daily and last for 6 hours. Rat will be conditioned to press a lever that signals a drug infusion pump to administer cocaine
at a dose of 0.4 mg/kg/infusion. Every chamber contains two levers: one lever signals the pump to administer an infusion
(an active lever), and one lever is an inactive control lever. Also, each lever press contingently activates a cue lights above
each lever. Once rats have achieved over 60 infusions per session for 10 days, they will enter the extinction phase of this
study for 2 weeks, during which all cues are turned off, and drug self-administration is discontinued. Rat will not have
access to their wheel during the self-administration and extinction phases of this study.
Subsequently, rats enter the reinstatement phase of this study. Cocaine self-administration will remain
unavailable as during the extinction phase, and lever-pressing on the lever that previously delivered cocaine will be the
Yosef Amrami
measure of reinstatement of cocaine seeking or relapse. To prime animals to resume drug seeking, intraperitoneal (IP)
injections of cocaine will be delivered or cues previously paired with cocaine (i.e., stimulus lights, drug pump) will be
presented. Thirty minutes prior to session onset, rats will be given IP injections of either saline (control) or atomoxetine
(3 mg/kg), and at session onset, the door to the adjacent running wheel will be opened. Rats will have access to either a
locked (control) or unlocked running wheel, depending on the experimental condition assigned for that day. To
investigate the effects of atomoxetine (ATO), wheel running (W), and atomoxetine + wheel running (ATO+W) on
cocaine- and cue-primed reinstatement, the following priming conditions and treatment combinations will be given in
random sequence to all rats in a within-subjects design: ATO+cocaine, W+cocaine, ATO+W+cocaine, ATO+cues,
W+cues, ATO+W+cues..
Experimental Design/Variables of Interest
We will be using a similar design a similar design to the one used by Zlebnik et al (2010). The major dependant
variables of interest are active lever presses, inactive lever presses, and wheel rotations. We are interested in
understanding how the experimental manipulations will affect drug-seeking behavior, as measured by responses on the
active lever that was previously paired with cocaine self-administration. Our major experimental manipulations are
priming with cocaine and/or cue lights, the administration of atomoxetine as a reinstatement medication, and wheel
running.
Implications
We hope to discover a new treatment for drug relapse. If our research implies that atomoxetine attenuates drugseeking behavior during drug relapse, perhaps it may eventually become an FDA approved treatment for cocaine
addiction and relapse. Also, this study has a large behavioral component, which is exercise. Although exercise has already
been associated with reduced drug seeking in female rats (Zlebnik, et. al., 2010), our study will investigate whether
exercise plus atomoxetine has a propagating effect on drug seeking reduction. As stated in our second hypothesis,
atomoxetine plus exercise may attenuate reinstatement behavior greater than either treatment alone.
Yosef Amrami
References
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