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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 Agid O, Kapur S, Arenovich T, Zipursky RB (2003). Delayed-onset is dependent upon the presence of the drug, so long as hypothesis of antipsychotic action: a hypothesis tested andrejected. Arch Gen Psychiat 60: 1228–1235.
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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

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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

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