The CANTAB Intradimensional/Extradimensional Attentional Shift Procedure in Rhesus Monkeys:
A Method for Acute Drug Challenge
Christopher C. Lay, Ronald D. Schneider, Amber J. Kirsten, Sophia A. Davis, Stefani N. Von Huben, Simon N. Katner and Michael A. Taffe
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA
EDS stage occurrence was not predictable
EDS: line S+
EDR: line S-
EDS: line SEDR: line S+
180
160
140
120
100
80
60
40
20
0
Test Administration
1
N=10
2
3
N=5
N=6
*
*
SD
SR
CD
7
0.56 mp
6
0.01 rac
5
CR
#
IDS
Stage
#
IDR
EDS
EDR
8
*
*
*
0.0178 rac
4
3
7
0
0
EDS
ED/ID Shift Ratio
*
N=4
(sem)
Errors to Criterion
10
3
1
CD
*
4
1
IDS
0.01 d-amp
N=6
(sem)
5
2
CD
saline
6
2
8
7
sqrt(Errors)
CD: shape S+
CR: shape S-
Errors
CD: shape SCR: shape S+
EDS stage is more difficult than IDS stage, effect persists
when evaluated at 6 month intervals
0.32 mp
N=7
(sem)
Vehicle
Scopolamine
8
6
4
2
0
CD
IDS
CD
EDS
ED/ID Shift Ratio
5
CD
IDS
CD
EDS
4
sqrt(Errors)
Required 8-20 sessions to complete
Introduction
Amphetamine abusers are selectively impaired on extradimensional shifts where heroin abusers are impaired on
intra-dimensional shifts
Criterion: 18/20 correct
sqrt(Errors)
SD: shape SSR: shape S+
IDS: shape S+ IDS: shape SIDR: shape S- IDR: shape S+
Shifting attentional focus or set, e.g., from one stimulus
dimension to another, depends on intact function of frontal
cortical circuits.
Owen et al., 1991, Neuropsychologia
8
60 trials per session
SD: shape S+
SR: shape S-
saline
9
Scopolamine Effect
sqrt(Errors)
9
sqrt(Errors)
Abstract
The ability to direct attention to one stimulus attribute (e.g., color) or to shift
attention to another attribute (e.g., shape) can be disrupted in a number of
neurological conditions including schizophrenia, ADHD and frontal lobe damage.
Such evidence indicates that attentional shifts may depend on dopaminergic
mechanisms within prefrontal cortex. Importantly, abusers of opiates, alcohol
and amphetamines show attentional shift deficits thus development of animal
models of attentional shift will assist in determining possible causal relationships
between attentional shift deficits and substance abuse. A simplified version of a
common procedure (i.e., the Wisconsin Card Sort Task) employed to assess
attentional shift and executive function in humans has been developed to
evaluate such capabilities in nonhuman primates (CANTAB intra-dimensional /
extra-dimensional attentional shift task; ID/ED). The prior version of the monkey
ID/ED procedure has most commonly been employed in between-subjects
designs and frequently requires multiple daily sessions to complete one run of
the test. The present study was conducted to validate the use of the ID/ED task
in repeated fashion for within-subjects designs necessary for acute drug
challenge investigations. A two-session version of the ID/ED task was designed
and trained in a group (7) of male rhesus monkeys. Monkeys were then
challenged with methylphenidate (0.32, 0.56 mg/kg, IM) and raclopride (0.01,
0.0178 mg/kg, IM) to determine to determine if the ID/ED procedure depends on
dopaminergic neurotransmission. Extradimensional shifts were facilitated by
methylphenidate and performance on a bimanual motor skill test was both
facilitated by methylphenidate and impaired by raclopride. This study therefore
validates the use of the ID/ED procedure for acute pharmacological challenge
and suggests that attentional shifts are sensitive to dopaminergic manipulations
in this assay.
Supported by DA13390 and MH62261.
Errors to Criterion
Original Version of ID/ED Task for Monkeys
*
3
2
1
0
6
5
Methylphenidate facilitated shifts of
attention to a different stimulus dimension
4
3
2
Raclopride did not affect discrimination
learning but may impair shifts of attention
1
0
saline
Weed et al., 1999, Cog Br Res
0.01
d-amp
saline
0.32
mp
0.56
mp
0.01 0.0178
rac
rac
Drug Treatment Condition
Vehicle
Scop
Scopolamine impaired discrimination
learning without affecting attentional shift.
d-Amphetamine facilitated and impaired
shifts of attention in different individuals
at this dose.
Ornstein et al., 2000; Neuropsychopharm
Revised (2-day) ID/ED Task for Monkeys
Development of a nonhuman primate model of attentional
set shifting suitable for pharmacological challenge would
further attempts to determine the time course and possible
mechanisms by which drug abuse impairs such attentional
capabilities.
Session 1
To adapt the CANTAB ID/ED Attentional Set Shifting task for use in acute drug-challenge studies.
CD (shape relevant)
Compound Discrimination
CD (shape relevant)
Compound Discrimination
Methods
Young adult male rhesus monkeys
Responding on a touch-screen to obtain food pellets
Trained to perform 2-alternative visual discriminations
Evaluated with a revised 2-day ID/ED sequence.
Drug Challenge
S+
S-
IDS (shape relevant)
Intra-Dimensional Shift
S-
S+
EDS (line relevant)
Extra-Dimensional Shift
Methylphenidate (Ritalin ; 0.32, 0.56 mg/kg i.m.)
d-Amphetamine (Adderall ; 0.01 mg/kg i.m.)
Dopamine D2 Antagonist
Muscarinic Cholinergic Antagonist
scopolamine (0.014 mg/kg i.m.)
Criterion: 12/15 correct
Requires 2 sessions to complete
15 raisins in Lexan holeboard
Latency to extract raisins
Bimanual strategy universally used
Challenge drugs may be administered
prior to either session
To investigate effects on extradimensional shifts, drugs were
administered prior to Session 2
+
S
+
S
S
No systematic alterations in the extradimensional shift
impairment (relative to IDS) were observed with repeated
testing.
130%
120%
*
110%
100%
*
90%
80%
0.01
d-amp
Veh
0.32
mp
The indirect dopamine agonist methylphenidate
facilitates extradimensional shifts of attention.
The revised procedure may be useful in further studies to
determination of the mechanisms involved in attentional
set formation and executive function. Further studies may
contribute to understanding the etiology of attentional
problems that may be selectively produced in abusers of
different drug classes.
*
Veh
S
The revised version of the CANTAB ID/ED Attentional Set
Shift Task may be successfully employed in acute drug
challenge studies.
Methylphenidate facilitated raisin retrieval
while raclopride slowed performance.
Timing of IDS and EDS stages
are predictable
Indirect Dopamine Agonists
raclopride (0.01, 0.0178 mg/kg i.m.)
240 trials per session
Bimanual Motor Skill
% Baseline (sec)
Objective
Session 2
Discussion
0.56
mp
0.01 0.0178
raclo raclo
Drug Treatment Condition