Transcript No Slide Title

Delay discounting and sensitization to the locomotor-activating effects of d-amphetamine
Jennifer L. Perry & Michael T. Bardo
Department of Psychology, University of Kentucky
Results
Introduction
Research has suggested that delay discounting, a measure of impulsivity, and drug abuse are
related. In humans, opioid users1, problem drinkers2, crack cocaine users3, and cigarette smokers4,5
discounted delayed rewards to a greater extent (i.e., were more impulsive) than nonusers. Impulsivity
on a delay discounting task was associated with age of first alcohol, nicotine, and marijuana use6, and
it was associated with reduced likelihood of maintaining smoking cessation7,8. While these studies
suggest a relationship between delay discounting and drug abuse, they do not address whether
impulsivity predicts enhanced vulnerability to drug abuse or, conversely, whether exposure to drugs of
abuse increases impulsivity.
In rats, impulsive choice on delay discounting tasks predicted elevated ethanol consumption9,
greater acquisition of cocaine self-administration10, and greater reinstatement of cocaine-seeking
behavior11. Additionally, mice screened for high impulsivity on a delay discounting task showed a lower
locomotor response to an acute ethanol injection; however, they showed greater locomotor
sensitization following repeated ethanol administration12. Combined, these results suggest that
impulsive choice predicts enhanced vulnerability to drug abuse.
Summary/Discussion
Locomotor Activity
B
A
Day 1
LoI Saline
HiI Saline
LoI d-AMPH
HiI d-AMPH
LoI Saline
HiI Saline
LoI d-AMPH
HiI d-AMPH
4000
Distance Traveled (cm)
4000
Distance Traveled (cm)
Day 10
3000
2000
1000
Figure 1. Mean
adjusted delays
(MAD, s) for each
group during the
baseline,
sensitization, and
washout periods.
3000
2000
1000
0
0
0
0
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90
The goals of the present experiment were:
1. To determine whether delay discounting predicts the locomotor response to acute or
repeated d-amphetamine (d-AMPH).
2. To determine whether repeated d-AMPH exposure alters impulsive choice.
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90
Time (min)
Time (min)
C
Distance Traveled (cm)
Subjects: Twenty-nine experimentally-naïve adult female Sprague Dawley rats
Procedure: Briefly, rats were screened for high (HiI) or low (LoI) impulsivity based on a median split of
stable mean adjusted delays (MADs) on an adjusting delay task (see procedure outline below). Over
the subsequent 10 days, rats continued to perform the adjusting delay task, and they were also given
1.0 mg/kg d-amphetamine (d-AMPH) or saline (i.p.). Locomotor activity in an open field was monitored
for 90 min following each d-AMPH or saline injection. Delay discounting continued to be measured for
14 days following repeated d-AMPH exposure. On the 14th day, all rats were administered a challenge
injection of 1.0 mg/kg d-AMPH and locomotor activity was measured for the subsequent 90 min.
Previous studies of the acute effects of d-AMPH on delay discounting have produced mixed
results13,14,15,16,17,18, and it is possible that differences in baseline levels of impulsivity have contributed
to the discrepancies in these results. Therefore, future studies should consider the role of individual
differences in impulsivity when studying the effects of psychostimulants.
Figure 1. Total distance traveled (cm) over a 90
min locomotor testing period on Day 1 (A), Day
10 (B), and the d-AMPH challenge day (C) in LoI
and HiI d-AMPH and saline groups.
3000
2000
• In HiI rats, repeated d-AMPH administration increased MADs (decreased impulsivity).
Similarly, in humans with attention deficit hyperactivity disorder (ADHD), a disorder characterized by
excessive impulsivity, d-AMPH also reduces impulsivity. Thus, HiI rats could potentially be used as an
animal model of ADHD.
LoI Saline
HiI Saline
LoI d-AMPH
HiI d-AMPH
1000
0
0
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90
• The MAD-altering effects of d-AMPH in HiI and LoI rats persisted after discontinuation of dAMPH administration. However, MADs in the HiI and LoI saline groups were no longer significantly
different during the washout period. The change in MADs in the saline groups may have been due to
weight gain, aging, or long-term experience performing the adjusting delay task, and future studies are
needed to clarify this issue.
Adjusting Delay Task
Lever 2
(initially 6 s)
Mean Adjusted Delay (MAD) = quantitative measure of impulsivity
Experimental Outline
AM: Adjusting Delay Task
LoI Saline
HiI Saline
LoI d-AMPH
HiI d-AMPH
†
60000
References
*
#
#
50000
*#
**
30000
Sensitization (10 days)
Washout (14 days)
1.0 mg/kg d-AMPH/saline
d-AMPH
challenge
15
*
*
# #
10
10000
1.
2.
3.
4.
5.
6.
7.
8.
#
9.
10.
11.
12.
13.
5
14.
Day 1
Day 10
d-AMPH
Challenge Day
* = different than Day 1
PM: Locomotor Sensitization
20
20000
0
Baseline
*
*
#
40000
LoI Saline
HiI Saline
LoI d-AMPH
HiI d-AMPH
25
#
MAD (s)
Delay
Total Distance Traveled (cm)
Adjusting Delay
Immediate
70000
• On the d-AMPH challenge day (2 weeks after washout of chronic d-AMPH/saline
administration), there were no differences in HiI and LoI groups that previously received saline.
This suggests that the novelty of the locomotor chamber may have played a role in the HiI/LoI
differences in d-AMPH-induced locomotor activity on Day 1 of the sensitization period. Future studies
should be conducted to characterize the relationship between novelty, delay discounting, and the
response to drugs of abuse.
Delay Discounting
• In LoI rats, repeated d-AMPH administration decreased MADs (increased impulsivity).
Time (min)
Lever 1
• HiI rats showed faster sensitization to the locomotor-activating effects of d-AMPH compared
to LoI rats. By Day 10 of locomotor testing, HiI rats had significantly greater locomotor activity
compared to Day 1. Sensitization to the locomotor-activating effects of d-AMPH occurred in LoI rats;
however, this did not occur until d-AMPH induced locomotor activity was tested following a 14-day
washout period. These findings extend previous research12 showing that HiI mice had greater
locomotor sensitization following chronic ethanol administration compared to LoI mice.
d-AMPH Challenge Day
4000
Method
• HiI rats showed less locomotor activity following acute d-AMPH administration compared to
LoI rats. This is similar to other research12 showing that HiI mice showed lower locomotor activity
following a single injection of ethanol.
Figure 2. Total
traveled
(cm) on Day 1,
# =distance
different than
SAL group
† = d-AMPH
HiI/LoI difference
Day 10, and the
challenge day in LoI and
HiI d-AMPH and saline groups. # significantly
higher than the saline group; * significantly higher
than Day 1; † significant LoI/HiI difference.
15.
0
Baseline
Sensitization
*
Washout
HiI/LoI delays
difference
Figure 3. Mean =
adjusted
(MAD, s) during the
baseline, sensitization,
and washout
periods in LoI and
# = different
than baseline
HiI d-AMPH and saline groups. * significant LoI/HiI
difference; # significantly different from baseline
16.
17.
18.
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Acknowledgements
The authors would like to thank Jason T. Ross, M.S. and Matthew Wethington for their technical
assistance. Supported by USPHS grants DA05312 (MTB) and DA007304 (JLP).