Transcript Methylphenidate Self-Administration in High

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
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180 min
Baseline
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Pre-Drug
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Baseline
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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).
ARCI – Amphetamine
Group
VAS - Stimulated
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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 lowimpulsive 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 1hour 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 sensationseeking status, although on several measures, the magnitude of effects are greater in low
impulsive sensation-seekers.
Method
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Abstract
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Post-Drug
Supported by DA-05312 and RR-15592
Table 1
Impulsive Sensation Seeking
d-Amphetamine Study
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 selfadministered 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.
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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.
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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.
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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.
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RIP – Proportion Correct
Diastolic Blood Pressure
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a) Verbal Reports of drug effects
b) Cardiovascular measures
c) Task performance
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Conclusions
1) Methylphenidate engenders prototypical stimulant-like effects among both low
and high impulsive sensation seekers:
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Percent Correct
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.
High Impulsive
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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.
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Placebo
Percent Correct
Repeated Acquisition Task (3 minutes): Subjects are required to learn a new randomly assigned tenresponse 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.
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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.
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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.
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Methylphenidate Study
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.'
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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.
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), MorphineBenzedrine Group (MBG) and Pentobarbital, Chlorpromazine, Alcohol Group (PCAG).
VAS – Like Drug
ARCI - MBG
Progressive-Ratio Task
Secondary Assessment Tasks
Figure 3 (below): Methylphenidate dose and time effects on
verbal report measures associated with drug-taking behavior
(Panels A-F) among low (top row) and high (bottom row)
impulsive sensation seekers. Error bars represent + 1 SEM.
Figure 2 (above): Methylphenidate dose and time effects on
verbal report measures associated with a stimulant effect of the
drug (Panels A-H) among low (top row) and high (bottom row)
impulsive sensation seekers. Error bars represent + 1 SEM.
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Background
Figure 1 (below): Mean number of capsules earned on the progressive-ratio
task as a function of dose for high and low impulsive sensation seekers.
Panel A displays previous findings from a d-amphetamine study (Stoops et
al., 2007). Panel B displays data from the current methylphenidate study.
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2) Methylphenidate did not function as a reinforcer in this study
3) Discordance among the direct (progressive-ratio procedure) and indirect
(verbal report) measures of the reinforcing effects of methylphenidate are
apparent.
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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.
4) Methylphenidate effects do not vary as a function of impulsive sensationseeking status, although the magnitude of effects are greater in low impulsive
sensation-seekers on several measures, including VAS High, Stimulated and
Feel Drug.