Effects Of Raclopride And SCH23390 On Cognitive Performance in Rhesus Monkeys
Stefani N. Von Huben, Sophia A. Davis, Amber J. Kirsten, Christopher C. Lay, Simon N. Katner and Michael A. Taffe
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA
Self-Ordered Spatial Search
80%
60%
Touch each box once per trial
2, 3, and 4 box difficulty levels
Inase et al., 1997; Weed and Gold, 1998
*
*
20%
Raclopride (µg/kg)
SOSS findings suggest that raclopride impairs spatial
working memory to a greater extent than SCH23390. This
was inconsistent with some prior reports of effects on spatial
delayed-response tasks. Arnsten et al., 1994; Sawaguchi and
56.0
32.0
17.8
10.0
3.2
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Base
56.0
32.0
17.8
10.0
0%
56.0
32.0
17.8
10.0
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Base
56.0
32.0
17.8
40%
SCH23390 (µg/kg)
SCH23390 (µg/kg)
Incorrect
*
20%
SCH23390 (µg/kg)
*
2003; Goldsmith and Joyce, 1994; Joyce et al., 1998
Raclopride (µg/kg)
56.0
32.0
17.8
10.0
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Veh
56.0
32.0
0%
17.8
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32.0
17.8
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40%
*
Base
Raclopride (µg/kg)
Base
56.0
32.0
0
60%
10.0
* *
vsPAL findings suggest that raclopride impairs spatial
working memory to a greater extent than SCH23390. This
is consistent with an association of object-location memory
with parahippocampal cortex, an area rich in D2 receptors
which are depleted in Alzheimer s brains. Malkova and Mishkin,
80%
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15
5
100%
Base
20
10
Completion
Percent Task Completed
Correct
25
SCH23390: Significantly reduced the percent of task
completed.
SCH23390 (µg/kg)
10.0
30
17.8
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10.0
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Base
56.0
32.0
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Base
Raclopride (µg/kg)
Total Responses
10.0
Raclopride and SCH23390
significantly slowed choice latency.
60%
Goldman-Rakic, 1994; Arnsten et al., 1995
Base
*
4000
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Base
0
80%
Veh
1000
BMS and RTT findings suggest equivalent impact of
raclopride and SCH23390 on motor function. This finding is
consistent with prior reports of effects on motor tasks.
SCH23390 (µg/kg)
Raclopride:
Reduced trial completion (and choice accuracy) on
initial attempt but did not impair incremental learning.
Responses to sample but not choice patterns were
slowed. The total number of correct responses and
the percent of task completed were reduced.
6000
100%
Percent Correct Choices
2000
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3.2
3000
*
8000
*
Raclopride (µg/kg)
Initial Attempt Choice Accuracy
Choice
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Raclopride (µg/kg)
32.0
10000
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12000
Base
0%
17.8
Initial Attempt
Overall Completion
Milliseconds
*
10.0
20%
56.0
4-box
*
32.0
3-box
40%
SCH23390- A statistically unreliable
trend for a reduction in the percentage
of trials completed was observed.
*
5000
Base
2-box
60%
Raclopride: significantly decreased
the percentage of trials completed.
Sample
6000
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10.0
3.2
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Base
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32.0
17.8
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Base
Latency
SCH23390 (µg/kg)
Latency
Base
80%
*
Raclopride (µg/kg)
Choice
1991; Campbell et al., 1999; Nader et al., 2002
10.0
20%
PR findings suggest equivalent impact of raclopride and
SCH23390 on reinforcer efficacy. This outcome is
consistent with prior reports of effects on schedulecontrolled responding. Woolverton and Virus, 1989; Bergman et al.,
100%
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40%
0
The wide behavioral repertoire of macaque monkeys makes them ideal for
investigating the behavioral selectivity of dopaminergic signaling in
multiple aspects of complex cognition.
Sample
Accuracy
2000
Disruptions of DA neurotransmission are associated with adverse
cognitive symptoms in mental disorders such as schizophrenia,
Attention Deficit/Hyperactivity Disorder, Parkinson s Disease, and
Huntington s Disease as well as mediating some aspects of acute
and chronic exposure to many drugs of abuse.
Discussion
Choose the stimulus in same location as sample
2 - 4 stimuli presented per trial
2 - 4 choice locations
Up to 5 additional attempts allowed following initial failure
4-box
10.0
3-box
3.2
2-box
Number of Responses
Introduction
100%
Accuracy
0%
Milliseconds
The contributions made by dopamine receptor subtypes to the reinforcing
and discriminative properties of various drugs of abuse have been extensively
characterized. In contrast, less is known about the contributions these systems
may make to a breadth of normal cognitive and behavioral functions. Motivation
for the present work is therefore twofold. First, chronic exposure to drugs of
abuse may permanently modify learning, mnemonic or other mechanisms
essential for academic or vocational performance. Second, acute effects of
drugs of abuse on dopaminergic signaling may enhance the development of
repeated / compulsive intake by co-opting associative or other learning
mechanisms. Further study of dopaminergic mechanisms of cognition will
therefore contribute to understanding the functional impact of drug abuse as well
as elucidate possible mechanisms supporting excessive intake. Monkeys were
trained on a cognitive tests adapted from a human neuropsychological
assessment battery (CANTAB; CAmbridge Neuropsychological Test Automated
Battery; Cambridge Cognition, Ltd, Cambridge, UK). The battery included tests
of spatial working memory (self-ordered spatial search task, SOSS), visuospatial associative memory and learning (visuo-spatial paired associates learning
task, vsPAL) and motivation (progressive ratio task, PR). Tests of motor function
(bimanual motor skill task, BMS; rotating turntable task, RTT) were also included.
Animals were trained to asymptotic performance in all tasks and then were
tested on combinations of tasks rotating across weekdays (e.g., RTT/BMS/PR;
vsPAL/BMS; SOSS/RTT/BMS). The effect of acute administration of the
dopamine D2-like antagonist raclopride (Rac; 0.01-0.056 mg/kg, i.m.) and the
D1-like antagonist SCH23390 (SCH; 0.0032-0.056 mg/kg, i.m.) on performance
were then determined. Rac and SCH each interfered with PR, RTT and BMS
performance. SOSS accuracy was suppressed to a greater extent by Rac than
by SCH. Finally Rac suppressed vsPAL performance where SCH did not. These
results therefore illustrate the relative contributions of D1-like and D2-like
dopamine receptors to a range of cognitive functions.
Supported by DA13390.
Percent Correct Trials
Abstract
Visuo-Spatial Paired-Associates Learning
SCH23390 (µg/kg)
Prior work in monkeys has focused on schedule-controlled responding for
appetitive or drug reinforcers. Work on DA involvement in learning,
memory or associative processes in monkeys has been limited.
SCH
RTT
BMS
PR
SCH23390 (µg/kg)
*
10
32.0
17.8
10.0
3.2
Veh
56.0
32.0
17.8
10.0
SCH23390 (µg/kg)
160%
*
*
140%
120%
Raclopride (µg/kg)
56.0
32.0
17.8
10.0
3.2
Veh
56.0
32.0
17.8
80%
10.0
100%
Veh
(Retrieval Latency)
17.8
32.0
10.0
3.2
*
Veh
50%
32.0
60%
56.0
*
56.0
70%
Percent of Baseline
80%
180%
SCH23390 (µg/kg)
*
0
Raclopride (µg/kg)
90%
Raclopride (µg/kg)
56.0
20
100%
17.8
30
110%
10.0
40
120%
Veh
(Retrieval Threshold)
Percent of Baseline
56.0
32.0
17.8
10.0
3.2
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50
Base
Raclopride (µg/kg)
Base
56.0
32.0
17.8
Base
0
60
Veh
BMS
*
SCH23390 (µg/kg)
70
Base
Rac
RTT
The time-to-last-response
100
Responses per Minute
Session 3
SOSS
BMS
*
56.0
SCH
vsPAL
The response rate
60
32.0
Rac
50
17.8
Session 2
40
56.0
SCH
30
200
32.0
Rac
20
* *
17.8
10
300
10.0
Test Session Timeline
400
Veh
The total number of responses
Raclopride (µg/kg)
500
Base
Raclopride (0.01 - 0.056 mg/kg, i.m); D2-like (D2/D3/D4) antagonist
Total Responses
The number of reinforcers acquired
*
*
*
*
Raclopride and SCH23390 significantly decreased:
SCH 23390 (0.0032 - 0.56 mg/kg, i.m); D1-like (D1/D5) antagonist
Session 1
5
0
Acute Drug Challenge
M,W: Baseline (no injection)
Th: Vehicle injection
T, F: Drug challenge doses
0
*
10.0
Battery Test
visuo-spatial Paired Associates
Self-Ordered Spatial Search
Bimanual Motor Skill
Rotating Turntable Task
Progressive Ratio
Cognitive Domain
Associative Learning
Spatial Working Memory
Fine Motor Coordination
Unimanual Motor Coordination
Reinforcer Efficacy
Minutes
Terminates 3 minutes after last response
10
10.0
Concurrent performance on 5 behavioral tests
10 minute session
15 raisins in Lexan holeboard
Latency to extract raisins
Bimanual strategy universally used
58 cm opaque plastic disk
Radial slots containing pellets at edges
Rheostat control of speeds 0-150 rpm
Pass : 6/10 retrieved pellets at a given speed; speed increased
Fail : 5/10 failure to retrieve or dropped pellets; speed reduced
15
3.2
6 young adult male rhesus monkeys (Macaca mulatta) (3-4 yrs old; 3.8-6.4 kg)
Touch screen response for food reinforcer with moderate food restriction
Tested unrestrained in transport cage
20
Bimanual Motor Skill
Rotating Turntable Task
Reinforcers Acquired
Time of Last Response
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FR 1,2,3...8,10,12...24,28,32...
25
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Methods
Minutes / Reinforcers
Progressive Ratio
Base
Objective:
The present study was conducted to identify possible differential
contributions made by DA receptor classes to multiple aspects of
cognitive performance in rhesus monkeys.
SCH23390 (µg/kg)
Raclopride and SCH23390 both slowed the threshold speed at which
animals could retrieve 6/10 reinforcers from the turntable.
Raclopride and SCH23390 both impaired bimanual
coordination, slowing the speed of raisin retrieval in
the BMS task