Methylphenidate Self-Administration in High- and Low-Impulsive Sensation Seekers

1
Methylphenidate Self-Administration in High- and
Low-Impulsive Sensation Seekers Using a
Progressive-Ratio Procedure Lee, D.C., Robbins,
G., Martin, C.A., Lile, J.A., and Kelly, T.H.
University of Kentucky
Abstract Previous studies have demonstrated that
methylphenidate is self-administered in both
human and non-human models. This ongoing study
examines methylphenidate self-administration
among high- and low-impulsive sensation-seekers
using a modified progressive-ratio procedure. It
is hypothesized that the reinforcing effects of
methylphenidate will be greater in high- than in
low-impulsive sensation seekers, as evidenced by
higher break points on a progressive ratio task.
Eighteen of twenty healthy, non-stimulant abusing
volunteers scoring in the top and bottom
quartiles of gender-adjusted population norms on
the impulsive-sensation seeking scale of the
Zuckerman-Kuhlman Personality Questionnaire (8
high- an 10 low-impulsive sensation seekers) have
completed the 8-session study consisting of four
2-session test blocks. During the first session
of each test block, subjects receive 8 capsules,
each containing 1/8th of a test dose. During the
second session, subjects are permitted to earn up
to 8 test capsules by completing progressively
increasing response requirements. Verbal reports
of drug effect, task performance and
cardiovascular measures are assessed before and
at 1-hour intervals for 3 hours after capsule
administration. Test doses (0, 16, 32 mg) are
presented under randomized, double-blind
conditions. Preliminary analyses with a
mixed-model repeated measures ANOVA demonstrate
significant stimulant-like effects on
cardiovascular measures including diastolic blood
pressure, task performance, and multiple
verbal-report measures, including those
associated with drug-taking behavior (e.g., Like
Drug Effects, ARCI MBG Scale). However,
methylphenidate self-administration on the
progressive ratio task is not related to dose.
In general, methylphenidate effects do not vary
as a function of impulsive sensation-seeking
status, although on several measures, the
magnitude of effects are greater in low impulsive
sensation-seekers. Supported by DA-05312 and
RR-15592
Method Subjects Eighteen healthy adults, ages 18
to 38, have completed medical screening and given
written consent to participate. Eight have been
classified as High Impulsive Sensation Seekers,
and ten have been classified as Low Impulsive
Sensation Seekers. All subjects receive task
training and practice prior to the study until
stable performance is observed. Three subjects
were excluded from the progressive ratio task
data for either responding maximally across all
drug conditions (2 subjects, 1 high SS and 1 low
SS) or not responding during any drug condition
(1 high SS subject). Impulsive Sensation-Seeking
Status All subjects complete the impulsive
sensation-seeking scale of the Zuckerman-Kuhlman
Personality Questionnaire. Those who score in
the upper and lower 25 of the population, based
on established gender-specific norms, are
classified as High and Low Sensation Seekers,
respectively. Procedure Each participant
completes an eight-session study consisting of
four two-session testing occasions. On the first
sample session of each two-day testing
occasion, subjects receive 8 capsules, each
containing 1/8 of the test dose. On the second
self-administration session, subjects earn up
to 8 of the capsules administered on the previous
day by completing a progressive-ratio task.
Daily Schedule After successfully completing
intake evaluations, including urine pregnancy and
drug-use testing, subjects complete assessments
before (I.e., baseline) and at hourly intervals
for three hours after consuming capsules
administered (sample sessions) or earned
(self-administration sessions). Drug Testing
Across the four two-session testing occasions,
the effects of 0, 16 and 32 mg doses of
methylphenidate are examined under randomized,
double-blind conditions. Each active dose is
tested once, and the placebo dose is tested on
two occasions. Data Analysis Mixed-model ANOVAs
have been conducted with between- (sensation
seeking status) and within-group (e.g., seeking
status by dose).
Background Methylphenidate is a drug used
effectively to treat individuals with ADHD and
problems of impulse control. However, the drug
is misused and diverted, and further study of the
reinforcing effects of the drug is warranted.
Previous studies have demonstrated that
methylphenidate is self-administered in both
human and non-human models. Moreover,
differences in self-administration of a stimulant
drug (d-amphetamine) have been demonstrated in a
related progressive-ratio study (see Figure 1,
Panel A). The purpose of this study was to
examine methylphenidate self-administration as a
function of sensation-seeking status among
healthy adults. Progressive-Ratio
Task Participants could earn up to eight drug
capsules by completing progressively increasing
ratio button click requirements on a computer
mouse. The first capsule could be earned by
completing 50 responses, and the response
requirement for each subsequent capsule was
systematically doubled, such that 12,750
responses were required to earn all 8
capsules. Secondary Assessment Tasks Addiction
Research Center Inventory (ARCI) The 49-item
short form of the true-false ARCI provides
reports of drug effects on five scales LSD,
Amphetamine (A), Benzedrine Group (BG),
Morphine-Benzedrine Group (MBG) and
Pentobarbital, Chlorpromazine, Alcohol Group
(PCAG). Profile of Mood States (POMS) An
experimental 72-adjective version of the POMS
yields scores on ten mood clusters Anxiety,
Depression, Anger, Vigor, Fatigue, Confusion,
Friendliness and Elation, Arousal, and Positive
Mood. Each adjective was rated along a five
point scale, from 'Not at all' to
'Extremely.' Visual-Analog Rating Scales (VAS)
Ratings of Drug Effect, High, Like Effect,
Stimulated and Sedated are obtained by
placing marks on a 100-unit line anchored with
"Not at all" on the left and "Extremely" on the
right. Digit-Symbol Substitution Task (DSST - 2
minutes) Nine random 3-row by 3-column arrays of
asterisks and dashes (one asterisk per row),
labeled 1-9 from left to right, are displayed at
the top of the computer monitor. A randomly
generated number, between 1 and 9, is displayed
in the center of the monitor, indicating which of
the nine arrays should be reproduced on a given
trial. Subjects reproduce an array by pressing
the buttons on a 3-row by 3-column keypad that
corresponded to the positions of the asterisks in
the screen array. Repeated Acquisition Task (3
minutes) Subjects are required to learn a new
randomly assigned ten-response sequence of
responding on four buttons. Correct responses in
the sequence increase a position counter, while
incorrect responses engender a 1-second time out
(blank screen). The tenth correct response in
the sequence increases a point counter and resets
the position counter to 0. Rapid Information
Processing Task (5 minutes) Single digits are
presented in the center of the monitor, and
subjects are instructed to press a key whenever
three consecutive even or odd digits are
presented. Following correct responses, the
speed of digit presentation is increased, and
following incorrect responses or missed signals,
the speed of digit presentation is decreased.
Cued Reaction Time T ask (15 minutes) Subjects
are required to respond as quickly as possible
when green rectangles are presented on the
screen, and to make no response when blue
rectangles are presented. Horizontal and
vertical white rectangles predicting the
subsequent color presentation on 60 of trials
are presented prior to the color
cue. Cardiovascular Heart rate and blood
pressure were recorded immediately after
completing computer tasks.
Results Table 1 summarizes demographic and
drug-use variables among the low and high
impulsive sensation seeker groups. Significant
group differences are observed on the ZKPQ
impulsive sensation-seeking scale. Groups do not
differ in a significant manner on other
demographic or drug-use variables. Figure 1
Displays number of capsules earned in the
progressive-ratio task in a previous
d-amphetamine study (top panel) compared to the
current methylphenidate study (bottom panel).
High impulsive sensation-seekers earned
significantly more capsules in the d-amphetamine
study for the active doses. In contrast, there
are no significant effects of dose or sensation
seeking for the number of capsules earned in the
current methylphenidate study. Figure 2 presents
data relevant to the stimulant effects of
methylphenidate. Dose by time effects occur in
VAS Stimulated and Feel Drug, ARCI Amphetamine
group, and POMS Vigor. Simple effects tests
indicate dose-related increases in VAS Stimulated
and Feel Drug occurring 120 and 180 minutes post
dose. Moreover, dose-related increases in ARCI
Amphetamine group are present 60, 120 and 180
minutes post dose. Simple effects tests for POMS
Vigor indicate increases in the 32mg dose at 120
minutes post dose. Additionally, sensation
seeking effects are present in VAS Stimulated and
Feel Drug. The magnitude of responses is greater
for low sensation seekers. Figure 3 presents
measures associated with drug-taking behavior.
Significant dose by time interactions are
obtained for ARCI Morphine-Benzedrine group and
VAS like drug. Simple effects tests indicate
dose-related increases in ARCI MBG occurring 60,
120 and 180 minutes post dose and also in VAS
like drug occurring 60 and 120 minutes post dose.
No differences in drug effect are apparent
between low and high impulsive sensation-seeking
subjects. In contrast, a three way dose by time
by sensation seeking level interaction is
obtained for VAS High. Dose-related increases in
ratings are apparent only among low sensation
seekers 60 and 120 minutes post dose. Figure 4
presents the effects of methylphenidate on
diastolic blood pressure and proportion of
correct responses during the Rapid Information
Processing Task. Simple effects tests indicate
dose-related increases in diastolic blood
pressure occurring 60 and 120 minutes post dose
and also in proportion correct occurring 60, 120
and 180 minutes post dose.

• Conclusions
• Methylphenidate engenders prototypical
  stimulant-like effects among both low and high
  impulsive sensation seekers
• Verbal Reports of drug effects
• Cardiovascular measures
• Task performance
• Methylphenidate did not function as a reinforcer
  in this study
• Discordance among the direct (progressive-ratio
  procedure) and indirect (verbal report) measures
  of the reinforcing effects of methylphenidate are
  apparent.
• Methylphenidate effects do not vary as a function
  of impulsive sensation-seeking status, although
  the magnitude of effects are greater in low
  impulsive sensation-seekers on several measures,
  including VAS High, Stimulated and Feel Drug.

Figure 4 Methylphenidate dose and time effects
on diastolic blood pressure (panels A, B) and
proportion correct in the Rapid Information
Processing Task (panels C, D) among low (top row)
and high (bottom row) impulsive sensation
seekers. Error bars represent 1 SEM.