Neuropsychopharmacology (2006), 1–10& 2006 Nature Publishing Group
Time Course of the Antipsychotic Effect and the UnderlyingBehavioral Mechanisms
MingLi1,5, PaulJ Fletcher2,3 and Shitij Kapur*,1,4
Schizophrenia-PET program, Centre for Addiction and Mental Health, Toronto, ON, Canada; 2Biopsychology Section, Centre for Addiction and
Mental Health, Toronto, ON, Canada; 3Department of Psychology, University of Toronto, Toronto, ON, Canada; 4Department of Psychiatry,
University of Toronto, Toronto, ON, Canada
Antipsychotic drugs work for patients only when given repeatedly. The overall temporal pattern of symptom improvement is not clear.
Some recent data question the traditional ‘delayed-onset’ hypothesis and suggest that the onset of antipsychotic response may be
relatively early, and the improvement may grow with repeated treatment. The present study systematically examined the time course of
the antipsychotic effect and the underlying behavioral mechanisms using a conditioned avoidance response (CAR) model. Rats
repeatedly treated with either typical (haloperidol) or atypical (olanzapine, risperidone) antipsychotics, but not anxiolytics
(chlordiazepoxide), show an early-onset, progressive across-session decline in avoidance responding, which re-emerges when the
treatment is stopped. This effect is dose-dependent, transferable between antipsychotics, and cannot be attributed to simple sedation or
motor side effects. Furthermore, we found that the pattern of this drug-induced decline depends on the number of exposures to the
conditioned stimulus in the presence of the drug, and is best understood as the result of drug-induced attenuation of the reinforcing
effectiveness of the conditioned stimulus. We also found that repeated drug exposure can create a drug interoceptive state that allows
the attenuated reinforcing property of the stimulus to be maintained over time. Together, these data provide preclinical support for the
newly postulated ‘early-onset’ hypothesis, and suggest that the repeated antipsychotic CAR model may be useful for understanding the
neurochemical and behavioral mechanisms underlying the clinical effects of antipsychotics in patients with schizophrenia.
Neuropsychopharmacology advance online publication, 31 May 2006; doi:10.1038/sj.npp.1301110
Keywords: haloperidol; olanzapine; risperidone; conditioned avoidance response; time course of antipsychotic effect; drug
beginning drug treatment (Gelder et al, 2000), so priorityis given to studying neurobiological changes that emerged
Antipsychotics have now been in clinical use for over half a
after a delay (Bunney and Grace, 1978). This has led to a
century, and their clinical potencies correlate with their
focus on various late-onset phenomena such as delayed
ability to block dopamine D2 receptors (Seeman, 2000).
depolarization (Grace, 1992), delayed onset of neuroplasti-
One interesting phenomenon is that although the stable
city (Konradi and Heckers, 2001), and others (Stein and
dopamine D2 receptor blockade can be achieved within
hours after drug administration (Nordstrom et al, 1992;
Recently, this long-held idea of delayed onset has been
Tauscher et al, 2002), substantial improvement of symp-
questioned by several converging clinical observations
toms is usually seen 2–3 weeks later. This apparent lag in
(Agid et al, 2003; Kapur et al, 2005; Leucht et al, 2005).
the manifestation of symptom improvement is perplexing.
Agid et al (2003) examined 42 double-blind, comparator-
Traditionally, it has been thought that the onset of
controlled studies (47000 patients) using a meta-analysis
antipsychotic response is delayed for 2–3 weeks after
technique, and found that psychotic symptoms improvedwithin the first week of treatment and showed a progressive
*Correspondence: Dr S Kapur, Centre for Addiction and Mental
improvement over subsequent weeks, with the overall
Health, Clarke Site, 250 College Street, Toronto, ON, Canada M5R
pattern of improvement approximating an exponential
1T8, Tel: + 1 416 535 8501 x6176, Fax: + 1 416 260 4206,
curve. Other studies show that the onset occurs within the
first day, contemporaneous with the blockade of dopamine
Current address: Department of Psychology, 238 Burnett Hall,
receptors (Kapur et al, 2005), and that more improvement
University of Nebraska-Lincoln, Lincoln, NE 68588-0308, USA
occurs in the first few days than in any other later period of
Received 6 February 2006; revised 23 March 2006; accepted 25 April
equal duration (Leucht et al, 2005). The time course of the
2006Online publication: 28 April 2006 at http://www.acnp.org/citations/
antipsychotic action is thus still an unsettled central issue in
psychiatry, which warrants further investigation because of
its widespread scientific and clinical implications. The
compartments by a white PVC partition with an arch style
present study was designed to investigate this issue using
doorway (15 cm high  9 cm wide at base). A 4 cm high
a well-established preclinical animal model of antipsycho-
barrier was placed between the two compartments, so the
ticsFconditioned avoidance response (CAR) model.
rats had to jump from one compartment to the other. The
We chose the CAR model because it shows high
grid floor consisted of 40 stainless-steel rods with a
predictive validity for antipsychotic activity (Wadenberg
diameter of 0.48 cm, spaced 1.6 cm apart center to center,
and Hicks, 1999). All currently available antipsychotics
through which scrambled footshock (US, 0.8 mA) was
selectively disrupt avoidance responding without altering
delivered by a constant current shock generator (Model
unconditioned escape response and their effects in this test
ENV-410B) and scrambler (Model ENV-412). The rat
correlate positively with their clinical potencies (Arnt, 1982;
location was detected by activation of microswitches affixed
Wadenberg et al, 2001). To better model clinical condition
at the corner of the box. Illumination was provided by a
of antipsychotic treatment, which requires medications to
houselight (28 V) mounted at the top of right compartment.
be taken repeatedly for a prolonged period of time, in the
The CS was a 74 dB white noise produced by a speaker
present study, we used a repeated antipsychotic treatment
(ENV 224AMX) mounted on the ceiling of the cubicle,
regimen and tested animals throughout the entire course of
centered above the shuttle box. All the training and testing
treatment. In a series of experiments reported here, we first
procedures were controlled by Med Associates programs
demonstrated that a repeated-treatment conditioned avoid-
running on a computer. Background noise (approximately
ance response model can be used to examine the time
68 dB) was provided by a ventilation fan affixed at the top
course of the antipsychotic effect (when the antipsychotic
effect starts, what the overall pattern of this effect looks like,and when relapse occurs after drug withdrawal) (Experi-ments 1 and 2) and then used this repeated treatment model
to identify the behavioral mechanisms underlying this
A regular training session consisted of 30 trials. Every trial
pattern of antipsychotic response (Experiments 3–6). Our
started by presenting the white noise (CS) for 10 s, followed
results suggest that antipsychotics may suppress avoidance
by a continuous scrambled footshock (0.8 mA, US) on the
responding by (a) decreasing the reinforcing property of
grid floor. If a subject moved from one compartment to
stimuli and (b) providing an internal drug cue that allows
the other within the 10 s of CS presentation, it avoided
the decreased reinforcing property of stimuli to be
the shock and this shuttling response was recorded as
maintained over time. Correspondingly, we speculate that
avoidance. If the rat remained in the same compartment
antipsychotics may exert their therapeutic effects in the
for more than 10 s and made a crossing upon receiving the
clinic through a dual action: (a) selectively attenuating the
footshock, this response was recorded as escape. If the rat
reinforcing property of psychotic thoughts or perceptions
did not respond during the entire 20 s presentation of the
and (b) creating a drug interoceptive state that allows the
shock, the trial was terminated and escape failure was
attenuated reinforcement of psychotic thoughts or percep-
recorded. Intertrial intervals varied randomly between 30
tions to be maintained over the treatment period.
The injection solutions of haloperidol (5 mg/ml ampoules,
Male Sprague–Dawley rats, weighing 250–325 g upon arrival
Sabex Inc., Boucheville, Quebec, Canada) and chlordiazep-
(Charles River, Montre´al, Canada), were housed two per
oxide (Sigma-Aldrich, St Louis, MO) were obtained by
cage, in 48.3 Â 26.7 Â 20.3 cm transparent polycarbonate
mixing drugs with sterile water. Olanzapine (gift from Eli
cages (Lab Products Inc., Seaforth, DE, USA) under 12-h
Lilly & Co., Indianapolis, IN) and risperidone (Sigma-
light/dark conditions with light on at 2000 hours. Room
Aldrich, St Louis, MO) were dissolved in 2% glacial acetic
temperature was maintained at 21711C with a relative
acid in distilled water. Haloperidol, olanzapine, and
humidity of 55–60%. Food and water were available
risperidone were administered subcutaneously (s.c.), 1 h
ad libitum. Rats were allowed at least 1 week of habituation
before testing, whereas chlordiazepoxide was administered
to the animal facility before being used in experiments.
intraperitoneally, 0.5 h before testing. PET studies in human
All procedures were performed during the dark phase of
patients have suggested that a reliable antipsychotic effect of
the light–dark cycle and were approved by the animal
most antipsychotic drugs requires at least 65% of D2
care committee at the Centre for Addiction and Mental
occupancy (Farde et al, 1992; Kapur et al, 1999, 2000).
Animal research also find that D2 occupancy at around 70%elicits CAR deficits (an indication of antipsychotic effect)
(Wadenberg et al, 2000). The doses of drugs were thuschosen based upon rat brain D2 receptor occupancy data
Six identical two-way shuttle boxes custom designed and
(Kapur et al, 2003) showing that at the doses tested in this
manufactured by Med Associates (St Albans, VT) were used.
study the drugs give rise to 50–80% D2 occupancy. The dose
Each box was housed in a ventilated, sound-insulated
of chlordiazepoxide (10 mg/kg) was chosen on the basis that
isolation cubicle (96.52 cm W Â 35.56 cm D Â 55.88–63.5 cm
it is an effective dose in other aversively conditioned
H). Each box was 64 cm long, 30 cm high (from grid floor),
paradigms, such as Pavlovian fear conditioning, and passive
and 24 cm wide, and was divided into two equal-sized
avoidance responding (Klint, 1991; Joordens et al, 1998).
Time course of the antipsychotic effectM Li et al
Experiment 1: Effects of Repeated Haloperidol
drug-free re-training sessions was used to ensure no drug
Treatment (0.025 and 0.05 mg/kg) on Avoidance
accumulation. Twenty-four rats were randomly assigned to
one of the three groups, each group being trained with adifferent CS–US interval, 6 s (n ¼ 8), 12 s (n ¼ 7), and 24 s
This experiment was designed to examine when the
(n ¼ 9), for 11 sessions. Three CS–US intervals were used to
antipsychotic effect on the CAR starts, whether repeated
examine whether the effect of haloperidol was restrained by
haloperidol treatment could dose-dependently disrupt
any specific CS–US interval. By the end of the last training
avoidance responding progressively across sessions, and
session, all rats showed 470% avoidance criterion, except
whether a relapse-like avoidance responding recovery could
one rat in the 6 s group, which was dropped from the
be observed after the discontinuation of the drug treatment.
experiment. Four days after the last day of training, the drug
Twenty-one rats were trained for conditioned avoidance
testing phase started. Exactly the same procedure was
responding for a total of 11 sessions (B2 weeks period). At
employed during testing, except that 1 h before each testing
the end of the training session, 16 rats reached training
session, one of three doses of haloperidol was administered,
criterion (470% avoidance in each of the last two sessions).
0.03, 0.05, and 0.07 mg/kg, to all the subjects in such an
They were randomly assigned to two groups (n ¼ 8) and
order (a within-subject design). At least 4 days were allowed
repeatedly tested daily for 7 days. Exactly the same
to elapse between each drug session, and at least one vehicle
procedure as that used during the CAR training was
re-training session was given during that interval to
employed during testing, except that 1 h before each testing
maintain a high level of avoidance responding. Each dose
session haloperidol 0.05 mg/kg or vehicle (water) was
of haloperidol (0.03, 0.05, and 0.07 mg/kg) was tested twice
administered s.c. One day after the end of the seventh test,
in two rounds (separated by two vehicle re-training
the vehicle group was switched to haloperidol (0.025 mg/
sessions) with the same drug test sequence in each round.
kg), whereas the previous haloperidol 0.05 mg/kg group was
Because there was no statistical difference among any of the
tested drug-free and under the CS-only condition (no shock
three CS–US interval groups, to simplify the presentation,
was presented) for another seven sessions. The CS-only
all three groups were combined into one single group.
condition was used to exclude any possible relearning effectcaused by the presence of the US, so any recovery ofavoidance responding could only be attributed to the
Experiment 4: Functional Equivalence between
persistence nature of this CS-elicited behavior.
Haloperidol Treatment and ‘ReinforcementAttenuation’ on Avoidance Responding
Experiment 2: Effects of Repeated Olanzapine
This experiment examined whether reinforcement attenua-
(1.0 mg/kg), Risperidone (0.2 mg/kg), and
tion contributes to the antipsychotic-induced avoidance
responding decline by comparing the effect of haloperidol
with a behavioral technique that is known to attenuatereinforcement of the stimulus in this model (Bolles et al,
This experiment examined whether the effects observed in
1971). Forty-two rats were initially trained for conditioned
Experiment 1 with haloperidol can generalize to atypical
avoidance responding for a total of 12 sessions. Among 30
antipsychotics, but not to other psychotropic drugs such
rats that reached training criterion (470% avoidance in
as anxiolytics. Forty-two rats were trained for conditioned
each of the last two sessions), 22 were randomly assigned to
avoidance responding for a total of 11 sessions. At the end
one of three groups: haloperidol 0.05 mg/kg (n ¼ 7),
of the training session, 29 rats reached training criterion
chlordiazepoxide 10 mg/kg (n ¼ 8), and ‘reinforcement
(470% avoidance in each of the last two sessions). They
attenuation’ (n ¼ 7, injected with water). All rats were
were then randomly assigned to one of four groupsF
repeatedly tested for 5 consecutive days. The haloperidol
risperidone 0.2 mg/kg (n ¼ 8), olanzapine 1.0 mg/kg (n ¼ 6),
and chlordiazepoxide groups were tested in a typical
chlordiazepoxide 10 mg/kg (n ¼ 7), and vehicle (n ¼ 8)F
training procedure (CS–US pairing), whereas the ‘reinforce-
and tested daily for 7 days after receiving the corresponding
ment attenuation’ group was tested in the condition in
drug or vehicle treatment. Risperidone and olanzapine rats
which a brief 0.1 s shock was presented at the end of each
and half of vehicle rats received their treatments 1 h before
trial regardless of whether a rat made an avoidance response
testing, whereas the chlordiazepoxide rats and another
or not. One day after the fifth test, all rats were tested
half of vehicle rats received their treatments 0.5 h before
again under the training condition for 7 days without
testing. One day after the seventh drug test, all rats were
drug (all rats were injected with the vehicle) to assess the
tested drug-free and under the CS-only (10 s white noise)
re-emergence of avoidance responding.
condition for 2 consecutive days to assess the re-emergenceof avoidance responding.
Experiment 5: Effects of Number of CS Trials perSession on the Haloperidol-Induced Avoidance
Experiment 3: Non-Consecutive Haloperidol Treatment
Intermixed with Drug-Free Re-Trainings on AvoidanceResponding Decline across Sessions
This experiment further examined the reinforcementattenuation mechanism identified in the last two experi-
This experiment examined whether simple drug accumula-
ments. We examined whether the speed of avoidance
tion across sessions contributed to the progressive effect of
responding decline is dependent on the number of stimulus
repeated antipsychotic treatment on avoidance responding.
exposures in the presence of the drug. Forty-eight rats were
A periodic drug treatment regimen intermixed with several
initially trained for conditioned avoidance responding for
a total of 12 sessions. Of 40 rats that reached training
way ANOVAs (43 groups) or independent-samples t-tests
criterion (470% avoidance in each of the last two sessions),
(two groups) were conducted for each test time point,
32 were randomly assigned to one of four groups:
followed by post hoc LSD tests to compare the group
haloperidol-3 trials (n ¼ 8), haloperidol-10 trials (n ¼ 8),
differences if necessary. Once significant interaction
haloperidol-40 trials (n ¼ 8), and vehicle-40 trials groups.
between ‘Drug’ and ‘Session’ was found, paired-sample t-tests
One day after the last training session, all rats were first
were used to determine across-session differences within
tested under the CS-only condition (no shock) to assess
a group. A conventional two-tailed level of significance at
their baseline avoidance responding (40 trials of the CS
presentations). Then, they were tested under drug or vehiclefor 3 consecutive days, then 48 h later (to eliminate drug
accumulation), tested for another 3 consecutive days. Thethree haloperidol groups received the same haloperidol
Experiment 1: Effects of Repeated Haloperidol
treatment (0.025 mg/kg, s.c., À60 min); the only difference
was the number of CS trials per session (three, 10, or 40 CS
Haloperidol dose-dependently disrupted avoidance re-
presentations per session). The vehicle-40 trial groups were
sponding starting on the first day of treatment and this
tested after receiving vehicle treatment. At 48 h after the last
effect increased across test sessions (Figure 1a and b). For
drug test (a total of six drug tests was given to assess the
the first eight sessions (one pre-drug and seven drug test
across-session decline effect), all groups were tested after
sessions), a repeated measure ANOVA showed a significant
receiving 0.025 mg/kg haloperidol treatment in a 40 trials
(F(7, 98) ¼ 23.251, p ¼ 0.000), and a significant ‘Drug’ ‘Session’ interaction (F(7, 98) ¼ 19.862, p ¼ 0.000). Figure 1b
Experiment 6: Effects of Prior Haloperidol Treatment
also indicates that avoidance responding re-emerged when
on Avoidance Responding under Olanzapine,
the haloperidol treatment was stopped, even though there
was no shock (only the white noise) present at this stage. A repeated measure ANOVA confirmed this observation
This experiment examined whether repeated antipsychotic
treatment produces a drug internal state that allows animals
to ‘remember’ the attenuated reinforcing property of the
‘Drug’ Â ‘Session’ interaction, F
stimulus in the CAR model. Fifty-four rats were initially
trained for conditioned avoidance responding for a total
Experiment 2: Effects of Repeated Olanzapine or
of 11 sessions, of which 44 reached training criterion
Risperidone Treatment on Avoidance Responding
(470% avoidance in each of the last two sessions). Theywere then randomly assigned to one of two groups,
Rats repeatedly treated with either olanzapine (1.0 mg/kg)
haloperidol (n ¼ 30) and vehicle (n ¼ 14), and tested daily
or risperidone (0.2 mg/kg) showed a progressive, across-
after receiving either haloperidol (0.03 mg/kg) or vehicle
session decline in avoidance responding. In contrast, rats
treatment for 7 consecutive days. At the end of this first test
treated with chlordiazepoxide (10 mg/kg) or vehicle main-
phase, the haloperidol group was then randomly subdivided
tained a high level of avoidance responding throughout the
into four groups: haloperidol–vehicle (water, n ¼ 7), halo-
entire testing period (Figure 1d). An ANOVA using ‘Drug’
peridol–haloperidol (0.03 mg/kg, n ¼ 7), haloperidol–olan-
as a between-subjects factor and ‘Session’ as a within-
zapine (1.0 mg/kg, n ¼ 8), or haloperidol–chlordiazepoxide
subjects factor showed a significant main effect of ‘Drug’
(10 mg/kg, n ¼ 8). All groups were then tested daily for 5
(F(3, 25) ¼ 15.008, p ¼ 0.000), ‘Session’ (F(7, 175) ¼ 21.904,
consecutive days under the new drug treatment regimens.
p ¼ 0.000), and a significant ‘Drug’ Â ‘Session’ interaction
The vehicle group was subdivided into two groups that
(F(21, 175) ¼ 8.799, p ¼ 0.000). Post hoc two-group compar-
either continued on the vehicle treatment (vehicle–vehicle,
isons showed that the olanzapine and risperidone groups
n ¼ 8) or switched to olanzapine (vehicle–olanzapine,
were significantly different from the vehicle and chlordia-
1.0 mg/kg, n ¼ 6). Haloperidol and olanzapine rats and half
zepoxide groups (all p’so0.015), which did not differ from
of vehicle rats received their treatments 60 min before
each other (p ¼ 0.937). Similar to the haloperidol-treated
testing, whereas chlordiazepoxide rats and another half of
rats in Experiment 1, rats that were treated with olanzapine
vehicle rats received their treatments 30 min before testing.
and risperidone reinstated their avoidance responding injust two sessions when the drug treatments were stopped(Figure 1c and d). Paired samples t-tests indicated that
for both olanzapine and risperidone groups, avoidance
The percent of avoidance responding trials (number of
responding percentages on the second drug-free test day
avoidance responses/30 Â 100%) was calculated as the
were not significantly different from their pre-drug
main dependent variable. Data were expressed as mean
levels (p ¼ 0.064 and 0.081, respectively).
values7SEM, and were analyzed using a factorial repeatedmeasures analysis of variance (ANOVA) with the between-
Experiment 3: Non-Consecutive Haloperidol Treatment
subjects factor being treatment condition (‘Drug’) and the
Intermixed with Drug-Free Re-Trainings on Avoidance
within-subject factor being the test sessions (‘Session’).
Two-group comparisons were tested using post hoc LSDtests. To determine the temporal course of the drug effect
The data from the three CS groups were combined into one
and to pinpoint when significant differences appeared, one-
group because this factor was not statistically significant on
Time course of the antipsychotic effectM Li et al
Effects of repeated antipsychotic treatments on conditioned avoidance responding. Each point represents mean avoidance percent + SEM.
Repeated haloperidol (0.025 and 0.05 mg/kg, s.c., À60 min) (a and b) or olanzapine (1.0 mg/kg, s.c., À60 min) (c), or risperidone (0.2 mg/kg, s.c., À60 min) (d)treatment significantly disrupted avoidance responding across the seven daily test sessions. Throughout the sessions, the disruptive effect was enhanced. Avoidance responding re-emerged once the treatment was stopped, even when no shock was presented. Repeated chlordiazepoxide treatment had littleeffect on avoidance responding (e). *po0.05, **po0.01 for comparisons between the vehicle (or no treatment group) and antipsychotic treatment groups(haloperidol, olanzapine, or risperidone). + po0.05, + + po0.01 for comparisons between the pre-drug (baseline) and each drug test session.
either drug or vehicle test sessions, nor was its interaction
performance was maintained (ranging from the lowest 88%
with other factors significant (all p’s40.1). As can be seen
to the highest 96%). Statistically, avoidance performance
from Figure 2a, avoidance responding was dose-depen-
during these days was not significantly different from
dently decreased by haloperidol and the mean percent
that of the pre-drug day (Figure 2a, inset), except on the
avoidance was also decreased progressively across the test
post-0.05 and post-0.07 days in the first round of halo-
sessions. These observations were confirmed statistically in
peridol testing (paired sample t-tests, p ¼ 0.011 and 0.003,
that the effect of drug dosage was highly significant,
F(2, 40) ¼ 175.14, po0.001, as was the effect of repeated drug
The mean numbers of avoidance in each 10-trial block on
testing sessions, F(2, 40) ¼ 134.10, po0.001. Within each
the drug test days are shown in Figure 2b. First, it is evident
haloperidol dose, the group difference between the two
that haloperidol had a much stronger effect on the last block
rounds of drug tests was also significant (all p’so0.05).
than on the first, and this within-session deterioration of
During the intervening vehicle days, the high avoidance
avoidance responding was apparent in both rounds of the
Haloperidol attenuates the reinforcing property of the CS. (a) Avoidance responding was dose-dependently decreased by repeated haloperidol
treatment. The magnitude of disruption was always larger in the second test than in the first one. Inset: avoidance % during the drug-free sessions. *po0.05,**po0.01: first round vs second round. Inset: avoidance performance during the intervening vehicle test days. + po0.05 for comparisons between the pre-drug (baseline) and each vehicle test session. (b) Under each dose of haloperidol, a clear dose-dependent within-session decline was seen. *po0.05,**po0.01: the first block vs other blocks. + po0.05, + + po0.01: the second vs third block. (c) Both haloperidol and ‘reinforcement attenuation’ treatment,but not chlordiazepoxide, produced a similar pattern of avoidance responding decline, as well as avoidance responding re-emergence. (d) Haloperidol(0.025 mg/kg, s.c., À60 min) had differential effects on the speed of avoidance responding decline, depending on the number of the CS exposures persession. The 40-trial haloperidol group showed a faster decline than other haloperidol groups. (e) The 40-trial haloperidol group (HAL-40) still showedsignificantly lower number of avoidance responses than the 3-trial group (HAL-3) when they were tested 48 h later in a 40-trial CS session. *po0.05,**po0.01 for between-group comparisons. + po0.05, + + po0.01 for baseline comparisons. #po0.05, ##po0.01 for comparisons between thehaloperidol-40 and haloperidol-3 group. &po0.05 for comparisons between the haloperidol-10 and haloperidol-3 groups.
drug treatment. Second, at each dose level, the avoidance
interaction between drug doses and blocks, F(4, 80) ¼ 5.303,
performance at the beginning of the second test (eg first
p ¼ 0.001, an interaction between drug doses and rounds,
10-trial block in the second test) was very similar to the
F(2, 40) ¼ 6.357, p ¼ 0.004, and an interaction among drug
performance at the end of the previous test (eg last 10-trial
doses, blocks, and round, F(4, 80) ¼ 13.159, p ¼ 0.000. Thus,
block in the first test), even though there were intervening
the magnitude of haloperidol-induced avoidance decreases
non-drug sessions (Figure 2b). Statistical analysis con-
depended on the drug doses, trial blocks, and the treatment
firmed these observations. We subjected these data to a
four-way ANOVA with repeated measures on the drugdoses, blocks, and treatment rounds variables and a
Experiment 4: Functional Equivalence between
between-subjects factor on the groups variable. The
Haloperidol Treatment and ‘Reinforcement
groups factor was not significant, F(2, 20) ¼ 0.797, p ¼ 0.465.
However, all three within-subjects factors were: doses,F(2, 40) ¼ 179.55, p ¼ 0.000, blocks, F(2, 40) ¼ 58.26, p ¼ 0.000,
Figure 2c shows that both haloperidol and the ‘reinforce-
and rounds, F(1, 20) ¼ 136.07, p ¼ 0.000. There was also an
ment attenuation’ groups, but not the chlordiazepoxide
Time course of the antipsychotic effectM Li et al
group, produced a very similar pattern of avoidanceresponding decline, as well as re-emergence of respondingwhen the drug, or the attenuation condition, was stopped. For the drug (or reinforcement attenuation) test sessions, arepeated measure ANOVA showed a significant main effectof ‘Drug’ (F(2, 19) ¼ 31.476, p ¼ 0.000), ‘Session’ (F(5, 95) ¼40.976, p ¼ 0.000), and a significant ‘Drug’ Â ‘Session’interaction (F(10, 95) ¼ 11.298, p ¼ 0.000). Post hoc LSD two-group comparisons showed that the haloperidol and the‘reinforcement attenuation’ groups did not differ fromeach other (p ¼ 0.116), but were significantly differentfrom the chlordiazepoxide group (p ¼ 0.000). During thedrug-free test sessions, both haloperidol and ‘reinforcementattenuation’ groups gradually reinstated their avoidanceresponding. They did not differ significantly from eachother (p ¼ 0.099).
Experiment 5: Effects of Number of CS Trials perSession on the Haloperidol-Induced AvoidanceResponding Decline
As can be seen from Figure 2d, despite their identical drughistories, the 40-trial haloperidol group showed a fasterdecline than other haloperidol groups, and the 10-trialgroup declined faster than the 3-trial group. A repeatedmeasure ANOVA (4 Â 7) using ‘Drug’ (4 : 1 vehicle + threelevels of CS trials) as a between-subjects factor and ‘Session’as a within-subjects factor showed a significant main effectof ‘Drug’ (F(3, 28) ¼ 14.574, p ¼ 0.000), ‘Session’ (F(6, 168) ¼
Prior antipsychotic experience influences subsequent anti-
29.127, p ¼ 0.000), and a significant ‘Drug’ Â ‘Session’
psychotic experience. In the first phase, avoidance responding was
interaction (F(18, 175) ¼ 6.058, p ¼ 0.000). Post hoc two-group
progressively decreased by repeated haloperidol treatment. In the second
comparisons showed that the haloperidol-40 trial group was
phase, olanzapine (1.0 mg/kg, s.c., À60 min) disrupted avoidance respond-
significantly different from all other groups (all p’so0.003),
ing significantly more in the rats with previous haloperidol experience than
and the haloperidol-10 trial group was significantly
those without (a). In the second phase, the previous haloperidol-treated
different from the haloperidol-3 trial and vehicle groups
group still showed decreased avoidance responding even 2 days after the
(all p’so0.044), which did not differ from each other
last drug treatment (b). ‘HAL’, haloperidol; ‘OLZ’, olanzapine; ‘VEH’, vehicle;‘CDP’, chlordiazepoxide. *po0.05, **po0.01 for comparisons between
the vehicle group and antipsychotic treatment groups (haloperidol or
After 48 h, all groups were tested again in a 40-trial
olanzapine) on the basis of independent-samples t-test.
session after being injected with haloperidol 0.025 mg/kg. Once again, the 40-trial haloperidol had significantly loweravoidance responding than the 3-trial group (p ¼ 0.037,
‘Drug’ Â ‘Session’ interaction (F(20, 152) ¼ 11.744, p ¼ 0.000),
but not a significant main effect of ‘Session’ (F(4, 152) ¼ 1.163,p ¼ 0.330). Post hoc two-group comparisons showed that the
Experiment 6: Effects of Prior Haloperidol Treatment
haloperidol–olanzapine group did not differ from the
on Avoidance Responding under Olanzapine,
haloperidol–haloperidol group (p ¼ 0.933), but was signifi-
cantly different from the haloperidol–vehicle, haloperi-dolFchlordiazepoxide, and vehicle–vehicle groups (all
In the first phase, well-trained rats first received either
p’so0.002). The haloperidol–chlordiazepoxide group did
repeated haloperidol or vehicle treatment and were tested
not differ from the haloperidol–vehicle (p ¼ 0.694) or
for 7 consecutive days. The haloperidol group showed
vehicle–vehicle group (p ¼ 0.083).
an orderly decline in avoidance responding, whereas thevehicle showed no change (a significant ‘Drug’ Â ‘Session’interaction, F(1, 42) ¼ 207.996, p ¼ 0.000). The groups with
previous haloperidol experience (in the first phase)continued to show the suppressed avoidance responding
In this series of sequential experiments, we showed that
when switched to olanzapine or continued on haloperidol in
suppression in avoidance responding by repeated antipsy-
the second phase (Figure 3a). In contrast, the haloperidol-
chotic treatment exhibits an early onset and a progressive
treated group that was switched to chlordiazepoxide showed
increase. This effect is observed with both typical and
re-emergence of avoidance responding (Figure 3b) as did
atypical antipsychotics, but not with other sedatives or
the haloperidol subgroup switched to the vehicle. A
anxiolytics such as chlordiazepoxide. It is dose-dependent,
repeated measure ANOVA showed a significant main effect
and as in the clinical conditions, the animals ‘relapse’ when
of ‘Drug’ (F(5, 38) ¼ 11.419, p ¼ 0.000) and a significant
taken off the drug. The increase of the effect over time does
not reflect drug accumulation or a motoric fatigue, but
demonstrated that anxiolytic chlordiazepoxide does not
instead is most compatible with a drug-induced facilitation
possess this property, and the drug-decreased avoidance
on extinction of behaviors (eg the progressive enhanced
responding can re-emerge if the drug treatment is
decline in avoidance responding). We identified two
discontinued, providing a novel model mimicking a
mechanisms that contribute to this effect: a drug-induced
relapse-like phenomenon in the clinic. More importantly,
attenuation in the (negative) reinforcing property of the
our work highlights two behavioral mechanisms that could
conditioned stimulus; and a ‘memory-like’ mechanism that
provide a plausible link between the neurochemical effects
allows the attenuated reinforcing property of the stimulus to
of antipsychotics on the dopamine system, their observed
be carried over from one drug session to another.
behavioral effects in the animal model presented here, and
As it has traditionally been assumed that the onset of
their clinical effects on psychosis.
antipsychotic action is ‘delayed’, the preclinical studies of
It has been shown previously that the effects of
antipsychotics fall into two camps. Hundreds of studies
antipsychotics in the CAR model are dependent upon D2
have examined the acute effects of antipsychotics in a
blockade in the nucleus accumbens (Wadenberg et al,
number of paradigms ranging from amphetamine-induced
1990). One prominent function of dopaminergic transmis-
hyperlocomotion, the catalepsy and paw test to prepulse
sion in this region is to mediate the reinforcing property of
inhibition, latent inhibition and social interaction (Arnt,
stimuli in the control of behavior (Berridge and Robinson,
1982; Ellenbroek et al, 1987; Hoffman and Donovan, 1995;
1998). It has long been recognized that when a neutral
Sams-Dodd, 1999; Swerdlow et al, 2000; Weiner, 2003). In
stimulus is paired with an aversive outcome (eg shock), the
general, most of these models have high predictive validity
stimulus itself can acquire conditioned aversive quali-
for antipsychotic effect (eg conditioned avoidance response,
tiesFsuch that it now can motivate and reinforce instru-
catalepsy test, paw test, etc) (Arnt, 1982; Ellenbroek et al,
mental behavior that leads to its termination (Miller, 1948;
1987; Hoffman and Donovan, 1995). Some may possess
McAllister and McAllister, 1971). Several findings from our
certain degrees of face and neuropsychological construct
experiments suggest that the effect of antipsychotics on
validity (eg amphetamine-induced prepulse inhibition
avoidance responding is most likely owing to attenuation of
deficit and latent inhibition deficit, phencyclidine-induced
this reinforcing ability of the aversively conditioned
social interaction deficit, etc) (Johansson et al, 1995; Sams-
stimulus. First, haloperidol caused a within-session decline
Dodd, 1998; Weiner, 2003), or neurobiological construct
in avoidance responding (Figure 2b), suggesting that the CS
validity (eg neonatal hippocampal lesions, genetic models,
was gradually losing its reinforcing ability under the
etc) (Lipska, 2004). However, none of these models provides
influence of drug. A within-session decline has often been
a good modeling of the time course of the antipsychotic
used as evidence supporting the reinforcement attenuation
effect owing to the nature of the acute single injection
effect of dopamine antagonists (Fouriezos et al, 1978;
regimen, nor could they model the relapse. On the other
Dickinson et al, 2000). Second, one behavioral technique
hand, models that have used chronic treatment regimens
(Experiment 4; Figure 2c) that is known to attenuate
such as ‘depolarization block’ (Grace and Bunney, 1986),
reinforcement of the CS in this model (Bolles et al, 1971)
antipsychotic-induced Fos or FosB expressions (Hiroi and
produced a pattern of avoidance responding decline, as well
Graybiel, 1996), chronic prepulse inhibition model (Ander-
as recovery, very similar to that produced by haloperidol.
sen and Pouzet, 2001) have often examined behavioral or
Other (unpublished) data from our lab indicate that this
physiological changes after a certain period of treatment has
behavioral technique can even substitute for haloperidol in
elapsed (eg B21 days after the first drug administration),
maintaining decreased avoidance responding, indicating a
instead of during the chronic treatment period. Thus, they
functional equivalence between haloperidol and ‘reinforce-
are limited in tracking the changes that occurred along the
ment attenuation’. Finally, the haloperidol-induced avoid-
ance responding decline was not dependent on simple drug
There are, however, a few early CAR studies in the 1980s
exposure, nor on the repeated exposure to the CS, but most
that had used a repeated treatment schedule and tested
critically, on the number of exposures to the CS in the
animals throughout the treatment period. Fregnan and
presence of the drug. Together, these data indicate that the
Chieli (1980) found that the anti-avoidance effect of
progressive antipsychotic effect may reflect the ability of
haloperidol started on the first testing day and was
antipsychotics to attenuate the reinforcing ability of the
progressively enhanced with each subsequent drug admin-
CSFa position compatible with the finding in the literature
istration (across-session decline in avoidance responding).
that rats previously treated with antipsychotics still show
It reached a maximum level within 5–8 days (Fregnan and
significantly lower avoidance responses even in the absence
Chieli, 1980). Kuribara and Tadokoro (1981) and Beninger
et al (1983) confirmed this finding and extended it to two
However, a simple attenuation of reinforcement would
other classes of antipsychotics, YM-08050, YM-08051 and
not be enough to explain how avoidance responding
pimizode, respectively. Using a home-cage control group
progressively declined across sessions or how this low
injected with drugs but not tested repeatedly for avoidance
performance on drug survived intervening drug-free high-
responding, they also showed that the across-session
performance sessions. These data implicate a drug-state-
decline in avoidance responding was not because of
dependent ‘memory-like’ mechanism that allows animal to
accumulation of the drugs with repeated dosing (Kuribara
‘remember’ the attenuated reinforcement across multiple
and Tadokoro, 1981; Beninger et al, 1983). The present
drug sessions. This mechanism is likely driven by the
study not only confirmed the across-session enhancement
interoceptive state caused by the antipsychotics (Schechter
effect with typical antipsychotics, but also extended it to
and Cook, 1975; Overton, 1979). A similar mechanism was
atypical drugs such as olanzapine and risperidone. It further
implicated by Wise et al (1978) in an appetitive condition-
Time course of the antipsychotic effectM Li et al
ing paradigm where they found that pimozide dose-
identified in animals (reinforcement attenuation, and drug
dependently decreased the lever-pressing for food progres-
state acting as ‘memory’ cue) may provide a set of new
sively across four drug test sessions, despite normal
targets for drug development and evaluation.
responding on drug-free test days inserted between drugtests (Wise et al, 1978). In the context of our experiments, itcan be argued that antipsychotics may provide an internal
drug state that allows the animals to ‘recall’ (withoutimplying any cognitive or conscious recall) the diminished
Dr Ming Li was supported by a fellowship from Ontario
reinforcing property of the CS across sessions. We would
Mental Health Foundation. Dr Shitij Kapur is supported by
thus speculate that antipsychotic drugs, by blocking the
Canada Research Chair program. We thank Jun Parkes for
dopamine system, may dampen the (aberrant) reinforcing
effectiveness of stimuli that the patient is experiencing. Thismay lead to the almost immediate halt of the generation ofnew psychotic material, and allows for the gradually
progressive extinction of the psychotic symptoms. Asthe diminished reinforcement of the conditioned stimuli
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DAVID L. PEARLE, M.D. DAVID L. PEARLE, M.D. PERSONAL INFORMATION HOME ADDRESS: (202) 444-8833 / (877) 303-1461 Facsimile EDUCATION 1964 M.D., Harvard Medical School, Boston, Massachusetts TRAINING/ PROFESSIONAL POSITIONS 1968-1969 Internship in Medicine, New York Hospital Residency in Medicine, New York Hospital Commissioned Officer, Public Health Servic
Human Reproduction, Vol.24, No.12 pp. 3196 – 3204, 2009Advanced Access publication on October 3, 2009ORIGINAL ARTICLE Reproductive epidemiologyPhysical activity and fertility in women:the North-Trøndelag Health StudyS.L. Gudmundsdottir1, W.D. Flanders2, and L.B. Augestad1,31Human Movement Science Programme, Faculty of Social Sciences and Technology Management, Norwegian University of Sci