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Effect of olanzapine on behavioural changes induced by FG 7142 and dizocilpine on active avoidance and plus maze tasks
Brain Research 830 Ž1999. 337–344
Research report
Effect of olanzapine on behavioural changes induced by FG 7142 and dizocilpine on active avoidance and plus maze tasks Ipe Ninan, Shrinivas K. Kulkarni
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Pharmacology DiÕision, UniÕersity Institute of Pharmaceutical Sciences, Panjab UniÕersity, Chandigarh 160014, India Accepted 23 March 1999
Abstract The present study examined the effect of atypical antipsychotic olanzapine on FG 7142- Ž N-methyl-b-carboline-3-carboxamide. and dizocilpine-induced cognitive impairment in active avoidance paradigm and elevated plus maze in mice. Both FG 7142 Ž5 mgrkg. and dizocilpine Ž0.1 mgrkg. increased the latency to reach shock-free zone ŽSFZ. both during training and retention session in active avoidance paradigm. This effect was reversed by olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg.. Similarly, FG 7142 Ž5 mgrkg. increased transfer latency ŽTL. on both first and second day in elevated plus maze. The lower doses of olanzapine Ž0.063 and 0.125 mgrkg. reversed the effect of FG 7142 on second day in elevated plus maze but higher doses Ž0.25 and 0.5 mgrkg. failed to modify the effect of FG 7142 both on first and second day. Dizocilpine Ž0.1 mgrkg. treatment did not affect TL on first day while on second day, it increased TL significantly. Olanzapine Ž0.063 and 0.125 mgrkg. reversed the effect of dizocilpine on elevated plus maze but the higher doses Ž0.25 and 0.5 mgrkg. failed to reverse it. Even though olanzapine Ž0.063, 0.125 and 0.25 mgrkg. failed show any effect per se in active avoidance task, the higher dose Ž0.5 mgrkg. increased the latency to reach SFZ on second day. Olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. did not show any per se effect on TL in elevated plus maze on first day while on second day, olanzapine Ž0.125, 0.25 and 0.5 mgrkg. increased TL as compared to control group. The present study demonstrated olanzapine’s reversal of dizocilpine- and FG 7142-induced behavioural changes in active avoidance paradigm and elevated plus maze. Although the precise mechanism of action is unknown, olanzapine might be acting by blocking excessive dopaminergic activity in the prefrontal cortex. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Olanzapine; FG 7142; Dizocilpine; Cognition; Active avoidance paradigm; Elevated plus maze
1. Introduction Cognitive impairment is a relatively frequent aspect of schizophrenia. Deficits are most prominent in tasks involving attention, memory and executive function. Imaging and biochemical studies show that schizophrenia is characterised by a number of morphological, hemodynamic, and neurochemical abnormalities within systems integrating the cortex, temporal lobes and various limbic structures. Neurochemical assays suggest that the neurotransmitters serotonin Ž5-HT., dopamine ŽDA. and glutamate play a significant role in the disease-associated decrement w46x. Prefrontal cortical ŽPFC. cognitive deficits are prominent
AbbreÕiations: SFZ—shock-free zone; DA—dopamine; 5-HT—5hydroxytryptamine; PFC—prefrontal cortex; TL—transfer latency ) Corresponding author. Fax: q 91-172-541142; E-m ail: [email protected]
in schizophrenia w21,27,50x, a disorder that appears to involve dysregulation of mesocortical DA systems w1,17,18x. Schizophrenia is exacerbated andror precipitated by stress w6,11x, a condition known to increase PFC DA turnover w16,31,45x. Recent research in non-human primates and rodents indicates that there is a narrow range of DA receptor stimulation for optimal PFC cognitive function and for neuronal firing patterns relevant to memory w32,51x, suggesting that there may be correspondingly restricted dose-range for DA treatment of cognitive deficits in humans. Studies in experimental animals demonstrate that either too little or too much DA receptor stimulation in the PFC impairs spatial working memory performance w2,3,9,31,32,43,49,55 x. DA receptor stimulation in the PFC impairs learning and memory process w10,19,23x. For example, the degree of cognitive impairment induced by the anxiogenic b-carboline, FG 7142 Ž N-methyl-b-carboline3-carboxamide. and non-competitive NMDA receptor antagonists correlate with increased DA turnover in the
0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 9 . 0 1 4 2 2 - 5
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rodent PFC and therefore, this cognitive impairment in rats and monkeys could be reversed by pre-treatment with DA antagonists haloperidol, SCH 23390 or clozapine w31,32, 47x. Dizocilpine ŽMK-801: 5-methyl-10,11-dihydro-5H-dibenzoŽ a,d .cyclohepten-5, 10-imine., a non-competitive NMDA receptor antagonist has been shown to impair cognitive functions in animals models w7,13,52–54x. Recent evidences suggest that atypical neuroleptics such as clozapine, olanzapine, risperidone, quetiapine and sertindole have the capacity to remediate cognitive impairment in schizophrenia whereas the classical antipsychotics like haloperidol cause dulling of cognition w4,15x. Olanzapine ŽLY 170053: 2-methyl-4-Ž4-methyl-1-piperazinyl.1OH-thienow2,3-b xw1,5xbenzodiazepine. is the most recent example of an ‘atypical’ neuroleptic. Olanzapine not only possesses few extrapyramidal side effects but also has clinical efficacy against negative symptoms in schizophrenia and treatment resistant schizophrenia w5x. Radioligand binding studies have shown olanzapine to have high affinity for a number of neuronal receptors including DA D 1 , D 2 , D4 , 5-HT2A , 5-HT2C , a 1-adrenergic, histaminic H 1 and muscarinic receptors w14,30x. Given the interest in olanzapine’s effect on cognition, the current study was designed to characterise the effects of olanzapine pre-treatment on the FG 7142- and dizocilpine-induced behaviour on active avoidance and plus maze tasks.
2.2. ActiÕe aÕoidance test Learning and memory processes were evaluated in a modified learning paradigm that has been validated in our laboratory w44x. The apparatus consisted of a plexiglass rectangular box Ž22 cm = 24 cm = 30 cm. featuring a grid floor Ž3 mm stainless steel rods set 7.5 mm apart., with a wooden platform Ž10 cm = 7 cm = 1 cm. in the centre of the grid floor. Electric shocks Ž20 V DC. were delivered to the grid floor with a stimulator. The wooden platform served as shock-free zone ŽSFZ. during training and retention testing. A pre-screening session and training trial was carried out under identical conditions. Each mouse was gently placed all its paws on the grid floor, a 20-V electric shock was given and the latency to reach SFZ within 30 s were used for training and retention tests. The training session was carried out 60 min after the pre-screening session. Each animal was placed on the electric grid floor, and the latency to reach SFZ was recorded. Retention was tested 24 h after the training session. If the animal did not move to SFZ within 30 s, latency was assigned as 30 s. FG 7142 and dizocilpine were administered 30 min before training session and olanzapine was administered 30 min before FG 7142 or dizocilpine treatment Ž1 h before training session.. 2.3. EleÕated plus maze test
2. Materials and methods 2.1. Animals Male BalbrC mice ŽCentral Animal House, Panjab University., weighing 20–30 g were used. They were housed in groups of eight in plastic cages Ž40 cm = 28 cm = 15 cm. in a room maintained at 25 " 28C and 12L:12D cycle. The mice had free access to food and water. All experiments were carried out between 09:00 and 13:00 h.
The elevated plus maze was used to evaluate spatial long-term memory, following the procedure described previously w25x. Briefly, the apparatus consisted of two open arms Ž16 cm = 5 cm. and two enclosed arms Ž16 cm = 5 cm = 12 cm.. The arms extended from a central platform Ž5 cm = 5 cm., and the maze was elevated to height of 25 cm from the floor. On the first day, each mouse was placed at the end of an open arm, facing away from the central platform 30 min after administration of FG 7142 or dizocilpine. Olanzapine was administered 30 min before FG 7142 or dizocilpine. Transfer latency ŽTL., the time
Table 1 Effect of olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. on FG 7142 Ž5 mgrkg.-induced cognitive dysfunction in active avoidance paradigm in mice. The data are expressed as medians and interquartile ranges. There were six to eight mice in each group Number
Treatment Žmgrkg.
1 2 3 4 5 6
vehicleq saline vehicleq FG 7142 Ž5. olanzapine Ž0.063. q FG 7142 Ž5. olanzapine Ž0.125. q FG 7142 Ž5. olanzapine Ž0.25. q FG 7142 Ž5. olanzapine Ž0.5. q FG 7142 Ž5.
a
Step-up latency Žs. Training session
Retention session
2.25 Ž0.3–4.2. 23.05 Ž3.9–78.7. 1.75 Ž1.1–3.3. a 2.00 Ž0.2–3.8. a 2.25 Ž0.8–6.3. a 1.8 Ž1.2–2.8. a
1.20 Ž0.5–2.9. 9.2 Ž3.9–30. 1.1 Ž0.5–3.9. a 1.55 Ž0.5–3.2. a 3.3 Ž1.2–8.6. a 1.5 Ž0.9–3.5. a
Significantly different from saline pre-treated control group ŽMann–Whitney U-test.. Olanzapine and FG 7142 were administered 60 and 30 min, respectively, before training session.
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Table 2 Effect of olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. on dizocilpine Ž0.1 mgrkg.-induced cognitive dysfunction in active avoidance paradigm in mice. The data are expressed as medians and interquartile ranges. There were six to eight mice in each group Number
Treatment Žmgrkg.
1 2 3 4 5 6
vehicle q saline vehicle q dizocilpine Ž0.1. olanzapine Ž0.063. q dizocilpine Ž0.1. olanzapine Ž0.125. q dizocilpine Ž0.1. olanzapine Ž0.25. q dizocilpine Ž0.1. olanzapine Ž0.5. q dizocilpine Ž0.1.
Step-up latency Žs. Training session
Retention session
2.25 Ž0.3–4.2. 30.00 Ž3.2–30. 2.6 Ž1.8–2.8. a 9.65 Ž0.9–28.5. a 6.65 Ž3.5–9.4. a 7.00 Ž3.3–30. a
1.20 Ž0.5–2.9. 10.3 Ž3.5–30. 2.5 Ž1.1–3.7. a 2.95 Ž1.2–6.2. a 1.7 Ž1.2–4.1. a 2.00 Ž0.8–3.8. a
a
Significantly different from saline pre-treated control group ŽMann–Whitney U-test.. Olanzapine and dizocilpine were administered 60 and 30 min, respectively, before training session.
taken by the mouse to move in to one of the enclosed arms, was recorded on the first day. If the animal did not enter an enclosed arm within 120 s, it was gently pushed in to one enclosed arm and TL was assigned as 120 s. The mouse was allowed to explore the maze for 20 s and then returned to its home cages. Retention was examined 24 h after the first day trial. Each mouse was again placed in to the maze and TL was recorded.
2.4. Locomotor actiÕity test Locomotor activity Žambulation. was measured using a computerised animal activity meter ŽOpto Varimex Mini, Columbus Instruments, OH, USA.. Briefly, after 1 h of drug treatment mice were placed individually in a transparent plastic cage Ž30 = 23 = 22 cm. and activity was recorded for 5 min after allowing the mice to adapt to the new environment for 2 min. An array of 11 infrared emitterrdetector pairs Žspaced at 2.65-cm intervals; beam wavelengths 875 nm; distance between the emitter and detector mounted on an external frame s 50 cm. measured the animal’s activity along a single axis of motion, the digital data being displayed on the front panel meter as ambulatory activity. Locomotion was expressed in terms of
total photobeam counts per 5 min per animal. There were eight mice per group. 2.5. Drugs Dizocilpine maleate ŽMerck, Sharp & Dohme, Rahway, NJ, USA., FG 7142 ŽSchering, Berlin, Germany. and olanzapine ŽEli Lilly, Indianapolis, USA. were used in the study. FG 7142 and dizocilpine were dissolved in saline. Olanzapine was dissolved in few drops of diluted HCl and then the volume was made up with saline and the pH was adequately adjusted. All drugs were administered i.p. in a constant volume of 1 mlr100 g of b.wt of mice. The selection of doses was based on previous reports from our laboratory. 2.6. Statistical analysis Results are expressed as means " S.E.M. except for the latencies to reach SFZ in case of active avoidance paradigm which are expressed as medians and interquartile ranges. The data were analysed using non-parametric Kruskal– Wallis ANOVA followed by Mann–Whitney U-test. The locomotor activity data were subjected to one-way ANOVA
Table 3 Effect of olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. on step-up latency in active avoidance paradigm in mice. The data are expressed as medians and interquartile ranges. There were six to eight mice in each group Number
1 2 3 4 5 a
Treatment Žmgrkg.
vehicleq saline olanzapine Ž0.063. q saline olanzapine Ž0.125. q saline olanzapine Ž0.25. q saline olanzapine Ž0.5. q saline
Step-up latency Žs. Training session
Retention session
2.25 Ž0.3–4.2. 2.15 Ž1.1–3.8. 2.05 Ž0.9–4. 2.85 Ž3.2–7.4. 3.1 Ž1.3–5.4.
1.20 Ž0.5–2.9. 2.36 Ž1.2–3.7. 2.50 Ž1.4–4.2. 1.65 Ž1.5–3.5. 3.5 Ž3–5.4. a
Significantly different from saline pre-treated control group ŽMann–Whitney U-test.. Olanzapine and saline were administered 60 and 30 min, respectively, before training session.
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Fig. 1. Effect of olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. on FG 7142 Ž5 mgrkg.-induced cognitive dysfunction in elevated plus maze in mice. TL, the time taken by the mouse to move in to one of the enclosed arms, was recorded on the first ŽI. and second day ŽB.. The data are expressed as means" S.E.M. There were six to eight mice in each group. Ža. Significantly different from saline pre-treated control group Ž P - 0.05, Mann–Whitney U-test.. Olanzapine and FG 7142 were administered 60 and 30 min, respectively, before trial on first day.
followed by Dunnett’s t-test. In all tests, the criterion for statistical significance was P - 0.05.
3. Results 3.1. Effect of olanzapine on FG 7142-induced delay in latency to reach SFZ in actiÕe aÕoidance paradigm As shown in Table 1, FG 7142 Ž5 mgrkg. administered 30 min after pre-training session produced significant increase in latency to reach SFZ during both training and retention session Ž P - 0.05, Mann–Whitney U-test.. Olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. pre-treatment reversed the effect of FG 7142 on latency to reach SFZ significantly during both training and retention session. However, this reversal was not dose-dependent ŽKruskal– Wallis ANOVA..
3.2. Effect of olanzapine on dizocilpine-induced behaÕiour in actiÕe aÕoidance paradigm As shown in Table 2, dizocilpine Ž0.1 mgrkg. administered 30 min after pre-training session produced significant increase in latency to reach SFZ during both training and retention session Ž P - 0.05, Mann–Whitney U-test.. Olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. reversed the effect of dizocilpine on latency to reach SFZ significantly during both training and retention session. However, this reversal was not dose-dependent ŽKruskal–Wallis ANOVA.. The behaviours observed during the training and retention sessions after pre-treatment with olanzapine are summarised in Table 3. The latencies to reach SFZ during the training session was not affected by olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. pre-treatment as compared to vehicle-pre-treated control group. During retention session,
Fig. 2. Effect of olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. on dizocilpine Ž0.1 mgrkg.-induced cognitive dysfunction in elevated plus maze in mice. TL, the time taken by the mouse to move in to one of the enclosed arms, was recorded on the first ŽI. and second day ŽB.. The data are expressed as means" S.E.M. There were six to eight mice in each group. Ža. Significantly different from saline pre-treated control group Ž P - 0.05, Mann–Whitney U-test.. Olanzapine and dizocilpine were administered 60 and 30 min, respectively, before trial on first day.
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Fig. 3. Effect of olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. on TL in elevated plus maze in mice. TL the time taken by the mouse to move in to one of the enclosed arms, was recorded on the first ŽI. and second day ŽB.. Olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. did not show any effect on first day. On second day, olanzapine Ž0.125, 0.25 and 0.5 mgrkg. increased TL as compared to saline treated control group Ž H4 s 13.7, P - 0.05. ŽKruskal–Wallis ANOVA.. The data are expressed as means " S.E.M. There were six to eight mice in each group. Olanzapine and saline were administered 60 and 30 min, respectively, before trial on first day.
olanzapine Ž0.063, 0.125 and 0.25 mgrkg. did not show significant difference in latency to reach SFZ as compared to vehicle pre-treated control group. However, the higher dose Ž0.5 mgrkg. of olanzapine exhibited an increase in latency to reach SFZ as compared to vehicle pre-treated control group Ž P - 0.05, Mann–Whitney U-test.. 3.3. Effect of olanzapine on FG 7142-induced increase in TL on eleÕated plus maze The effects of FG 7142 Ž5 mgrkg. and its combination with olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. are shown in Fig. 1. Control Žsaline. mice exhibited TL of 64 " 10 s Ž n s 8. on the first day, decreasing to 18 " 3 s on the second day, indicating that the mice remembered the presence of the enclosed arms. FG 7142 Ž5 mgrkg. treatment 30 min prior to the test on first day resulted in increase in impairing effect of FG 7142 on both acquisition and retention Ž P - 0.05, Mann–Whitney U-test.. On the first day, olanzapine Ž0.125 mgrkg. pre-treatment did not modify the TL in FG 7142-treated mice but on second day, it reversed the effect of FG 7142 Ž P - 0.05, Mann– Whitney U-test.. The higher doses of olanzapine Ž0.25 and 0.5 mgrkg. failed to modify the effect of FG 7142 on TL both on first and second day. 3.4. Effect of olanzapine on dizocilpine-induced increase in TL on eleÕated plus maze The effects of dizocilpine and its combination with olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. is shown in Fig. 2. The dizocilpine Ž0.1 mgrkg. treatment 30 min prior to the test on first day, did not modify the TL on first day. However, it resulted in a marked amnesia, since TL on the second day was significantly higher than control
Žsaline. value. Olanzapine Ž0.063 and 0.125 mgrkg. pretreatment decreased TL on second day compared to dizocilpine treated group Ž P - 0.05, Mann–Whitney U-test.. The higher doses of olanzapine Ž0.25 and 0.5 mgrkg. further increased TL on first day without affecting TL second day Ž P - 0.05, Mann–Whitney U-test.. Olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. did not show any per se effect on TL in elevated plus maze on first day. However, on second day, olanzapine Ž0.125, 0.25 and 0.5 mgrkg. increased TL as compared to saline treated control group Ž H4 s 13.7, P - 0.05. ŽFig. 3.. 3.5. Effect of olanzapine on spontaneous locomotor actiÕity In order to assess the effect of olanzapine Ž0.062, 0.125, 0.25 and 0.5 mgrkg. on spontaneous locomotor activity, we measured locomotor activity after 1 h of its administration. Olanzapine Ž0.062, 0.125, 0.25 and 0.5 mgrkg. did not show decrease in spontaneous locomotor activity Ždata not shown..
4. Discussion FG 7142, a b-carboline anxiogenic produced delay in reaching SFZ in active avoidance task on both first and second day. Similarly, FG 7142 increased TL on both first and second day in elevated plus maze. This shows that FG 7142 affects both acquisition and retention in the memory process. FG 7142 was reported to produce spatial working memory deficits in monkeys w33x. However, it is possible that the delay in reaching SFZ in active avoidance task or increase in TL in elevated plus maze on first day could be due to FG 7142-induced freezing behaviour. Hence, these
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animals would be exposed to more shock on first day thus induce more conditioned fear on second day. Dizocilpine, a non-competitive NMDA receptor blocker produced delay in reaching SFZ in active avoidance task on both first and second day while it affected only retention in elevated plus maze. This observation is consistent with the earlier observation w42x. The results of this study suggest that lower doses of olanzapine reversed the effects of FG 7142 and dizocilpine on both active avoidance and elevated plus maze tasks. Olanzapine at all the doses reversed FG 7142- and dizocilpine-induced delay in reaching SFZ in active avoidance paradigm. But only the lower dose of olanzapine reversed the effect of both FG 7142 and dizocilpine on elevated plus maze. The difference in the response of olanzapine in these animal models of learning and memory is that higher doses of olanzapine are not effective in reversing the effect of FG 7142 or dizocilpine on elevated plus maze whereas all the doses of olanzapine reversed the effect of FG 7142 and dizocilpine on active avoidance paradigm. This could be due to the difference in the quality of negative reinforcement, i.e., fear of open arm and electric shock, respectively, in elevated plus maze and active avoidance paradigm. A similar difference was observed in the effect of olanzapine per se. The higher dose Ž0.5 mgrkg. of olanzapine impaired retention in both models whereas the lower doses Ž0.062, 0.125 and 0.25 mgrkg. of olanzapine impaired retention only in elevated plus maze. The olanzapine-induced impairment of retention process could be due to the antimuscarinic activity of olanzapine. Earlier, we have reported cognitive impairment caused by clozapine in these models, which was reversed by physostigmine w34x. Studies in experimental animals demonstrated the role of DA in cognitive functions w9,49x. DA receptor stimulation in PFC impairs spatial working memory performance. The involvement of dopaminergic mechanism in the impairment of learning and memory process by FG 7142 and non-competitive NMDA receptor antagonists has been documented earlier w32,47x. Recently, Murphy et al. w33x reported reversal of FG 7142-induced spatial working memory deficit by clozapine. The degree of cognitive impairment caused by FG 7142 correlates with increased DA turnover in the rodent PFC w33x. It is more likely that olanzapine’s beneficial effects arise from its blockade of DA receptor. It was recently reported that D 1 receptor antagonist fully reversed the FG 7142 response in rats and monkeys, suggesting that olanzapine’s D 1 receptor blocking property may be involved w32x. Recently, we have shown that olanzapine and clozapine behaved like partial agonist at DA D 2 receptors but olanzapine was found to be a comparatively more potent blocker of DA D 1 receptors w35–37x. The D 2 receptor family may also contribute to the cognitive deficits observed with FG 7142 treatment. The involvement of dopaminergic system in the cognitive process is a well documented one. The non-competi-
tive NMDA receptor antagonists such as ketamine and dizocilpine are reported to increase central DA activity w24,26,38,48x. But recent evidences suggested that other neurotransmitter systems such as 5-HT and noradrenaline are also involved in dizocilpine-induced behaviours w28, 29,39x. Therefore, it is not reasonable to argue that DA receptor antagonistic activity alone is responsible for the observed effect of olanzapine on dizocilpine-induced cognitive impairment. Studies on the involvement of different DA and 5-HT receptor subtypes in dizocilpine- and FG 7142-induced responses will be of particular interest given olanzapine’s high affinity for these receptors. The available evidences indicate that novel antipsychotics can be differentiated from haloperidol, the classical antipsychotics particularly in models of cognitive side effects. Atypical antipsychotics such as clozapine, olanzapine, sertindole and quetiapine show limbic selectivity whereas classical antipsychotic haloperidol does not show such selectivity w4,20,22,40x. Recently, we have shown that at lower doses olanzapine selectively inhibited behaviours mediated by mesolimbicrmesocortical system while at higher doses it inhibited behaviours mediated by both mesolimbicrmesocortical and nigrostriatal systems w41x. The beneficial effect of lower doses of olanzapine in cognitive functions could be due to its selective action at mesolimbicrmesocortical area. The available preclinical paradigms have limitations in demonstrating the clinical superiority of atypical antipsychotic drugs compared to typical antipsychotics. The data suggestive of mesocorticolimbic anatomic specificity for the atypical drugs could be extrapolated to postulate that these drugs may have some unique clinical effect on behaviours reliably mapped to this region as well as the absence of adverse effects which derive from striatal regions that atypical drugs spare. Several studies have demonstrated that clozapine treatment significantly improved neuropsychological assessment of executive function, memory retrieval and attention in addition to improvement in psychiatric symptoms w12x. The effect of atypical antipsychotics on negative symptoms of schizophrenia have been attributed to their selective effects on mesolimbicrmesocortical area w8x. In conclusion, the present study demonstrated reversal by olanzapine of dizocilpine- and FG 7142-induced behavioural changes in active avoidance paradigm and elevated plus maze. Although the precise mechanism of action is unknown, olanzapine might be acting by blocking excessive dopaminergic activity in the PFC. Better understanding of the mechanisms underlying olanzapine’s beneficial effect in cognitive functions should be of help in designing treatment strategy for PFC cognitive disorders.
Acknowledgements The Senior Research Fellowship ŽI.N.. of the Council of Scientific and Industrial Research ŽCSIR., New Delhi, is
I. Ninan, S.K. Kulkarnir Brain Research 830 (1999) 337–344
gratefully acknowledged. The authors also thank Eli Lilly ŽIndianapolis, USA. for generously donating olanzapine used in this study.
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Research report
Effect of olanzapine on behavioural changes induced by FG 7142 and dizocilpine on active avoidance and plus maze tasks Ipe Ninan, Shrinivas K. Kulkarni
)
Pharmacology DiÕision, UniÕersity Institute of Pharmaceutical Sciences, Panjab UniÕersity, Chandigarh 160014, India Accepted 23 March 1999
Abstract The present study examined the effect of atypical antipsychotic olanzapine on FG 7142- Ž N-methyl-b-carboline-3-carboxamide. and dizocilpine-induced cognitive impairment in active avoidance paradigm and elevated plus maze in mice. Both FG 7142 Ž5 mgrkg. and dizocilpine Ž0.1 mgrkg. increased the latency to reach shock-free zone ŽSFZ. both during training and retention session in active avoidance paradigm. This effect was reversed by olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg.. Similarly, FG 7142 Ž5 mgrkg. increased transfer latency ŽTL. on both first and second day in elevated plus maze. The lower doses of olanzapine Ž0.063 and 0.125 mgrkg. reversed the effect of FG 7142 on second day in elevated plus maze but higher doses Ž0.25 and 0.5 mgrkg. failed to modify the effect of FG 7142 both on first and second day. Dizocilpine Ž0.1 mgrkg. treatment did not affect TL on first day while on second day, it increased TL significantly. Olanzapine Ž0.063 and 0.125 mgrkg. reversed the effect of dizocilpine on elevated plus maze but the higher doses Ž0.25 and 0.5 mgrkg. failed to reverse it. Even though olanzapine Ž0.063, 0.125 and 0.25 mgrkg. failed show any effect per se in active avoidance task, the higher dose Ž0.5 mgrkg. increased the latency to reach SFZ on second day. Olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. did not show any per se effect on TL in elevated plus maze on first day while on second day, olanzapine Ž0.125, 0.25 and 0.5 mgrkg. increased TL as compared to control group. The present study demonstrated olanzapine’s reversal of dizocilpine- and FG 7142-induced behavioural changes in active avoidance paradigm and elevated plus maze. Although the precise mechanism of action is unknown, olanzapine might be acting by blocking excessive dopaminergic activity in the prefrontal cortex. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Olanzapine; FG 7142; Dizocilpine; Cognition; Active avoidance paradigm; Elevated plus maze
1. Introduction Cognitive impairment is a relatively frequent aspect of schizophrenia. Deficits are most prominent in tasks involving attention, memory and executive function. Imaging and biochemical studies show that schizophrenia is characterised by a number of morphological, hemodynamic, and neurochemical abnormalities within systems integrating the cortex, temporal lobes and various limbic structures. Neurochemical assays suggest that the neurotransmitters serotonin Ž5-HT., dopamine ŽDA. and glutamate play a significant role in the disease-associated decrement w46x. Prefrontal cortical ŽPFC. cognitive deficits are prominent
AbbreÕiations: SFZ—shock-free zone; DA—dopamine; 5-HT—5hydroxytryptamine; PFC—prefrontal cortex; TL—transfer latency ) Corresponding author. Fax: q 91-172-541142; E-m ail: [email protected]
in schizophrenia w21,27,50x, a disorder that appears to involve dysregulation of mesocortical DA systems w1,17,18x. Schizophrenia is exacerbated andror precipitated by stress w6,11x, a condition known to increase PFC DA turnover w16,31,45x. Recent research in non-human primates and rodents indicates that there is a narrow range of DA receptor stimulation for optimal PFC cognitive function and for neuronal firing patterns relevant to memory w32,51x, suggesting that there may be correspondingly restricted dose-range for DA treatment of cognitive deficits in humans. Studies in experimental animals demonstrate that either too little or too much DA receptor stimulation in the PFC impairs spatial working memory performance w2,3,9,31,32,43,49,55 x. DA receptor stimulation in the PFC impairs learning and memory process w10,19,23x. For example, the degree of cognitive impairment induced by the anxiogenic b-carboline, FG 7142 Ž N-methyl-b-carboline3-carboxamide. and non-competitive NMDA receptor antagonists correlate with increased DA turnover in the
0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 9 . 0 1 4 2 2 - 5
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rodent PFC and therefore, this cognitive impairment in rats and monkeys could be reversed by pre-treatment with DA antagonists haloperidol, SCH 23390 or clozapine w31,32, 47x. Dizocilpine ŽMK-801: 5-methyl-10,11-dihydro-5H-dibenzoŽ a,d .cyclohepten-5, 10-imine., a non-competitive NMDA receptor antagonist has been shown to impair cognitive functions in animals models w7,13,52–54x. Recent evidences suggest that atypical neuroleptics such as clozapine, olanzapine, risperidone, quetiapine and sertindole have the capacity to remediate cognitive impairment in schizophrenia whereas the classical antipsychotics like haloperidol cause dulling of cognition w4,15x. Olanzapine ŽLY 170053: 2-methyl-4-Ž4-methyl-1-piperazinyl.1OH-thienow2,3-b xw1,5xbenzodiazepine. is the most recent example of an ‘atypical’ neuroleptic. Olanzapine not only possesses few extrapyramidal side effects but also has clinical efficacy against negative symptoms in schizophrenia and treatment resistant schizophrenia w5x. Radioligand binding studies have shown olanzapine to have high affinity for a number of neuronal receptors including DA D 1 , D 2 , D4 , 5-HT2A , 5-HT2C , a 1-adrenergic, histaminic H 1 and muscarinic receptors w14,30x. Given the interest in olanzapine’s effect on cognition, the current study was designed to characterise the effects of olanzapine pre-treatment on the FG 7142- and dizocilpine-induced behaviour on active avoidance and plus maze tasks.
2.2. ActiÕe aÕoidance test Learning and memory processes were evaluated in a modified learning paradigm that has been validated in our laboratory w44x. The apparatus consisted of a plexiglass rectangular box Ž22 cm = 24 cm = 30 cm. featuring a grid floor Ž3 mm stainless steel rods set 7.5 mm apart., with a wooden platform Ž10 cm = 7 cm = 1 cm. in the centre of the grid floor. Electric shocks Ž20 V DC. were delivered to the grid floor with a stimulator. The wooden platform served as shock-free zone ŽSFZ. during training and retention testing. A pre-screening session and training trial was carried out under identical conditions. Each mouse was gently placed all its paws on the grid floor, a 20-V electric shock was given and the latency to reach SFZ within 30 s were used for training and retention tests. The training session was carried out 60 min after the pre-screening session. Each animal was placed on the electric grid floor, and the latency to reach SFZ was recorded. Retention was tested 24 h after the training session. If the animal did not move to SFZ within 30 s, latency was assigned as 30 s. FG 7142 and dizocilpine were administered 30 min before training session and olanzapine was administered 30 min before FG 7142 or dizocilpine treatment Ž1 h before training session.. 2.3. EleÕated plus maze test
2. Materials and methods 2.1. Animals Male BalbrC mice ŽCentral Animal House, Panjab University., weighing 20–30 g were used. They were housed in groups of eight in plastic cages Ž40 cm = 28 cm = 15 cm. in a room maintained at 25 " 28C and 12L:12D cycle. The mice had free access to food and water. All experiments were carried out between 09:00 and 13:00 h.
The elevated plus maze was used to evaluate spatial long-term memory, following the procedure described previously w25x. Briefly, the apparatus consisted of two open arms Ž16 cm = 5 cm. and two enclosed arms Ž16 cm = 5 cm = 12 cm.. The arms extended from a central platform Ž5 cm = 5 cm., and the maze was elevated to height of 25 cm from the floor. On the first day, each mouse was placed at the end of an open arm, facing away from the central platform 30 min after administration of FG 7142 or dizocilpine. Olanzapine was administered 30 min before FG 7142 or dizocilpine. Transfer latency ŽTL., the time
Table 1 Effect of olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. on FG 7142 Ž5 mgrkg.-induced cognitive dysfunction in active avoidance paradigm in mice. The data are expressed as medians and interquartile ranges. There were six to eight mice in each group Number
Treatment Žmgrkg.
1 2 3 4 5 6
vehicleq saline vehicleq FG 7142 Ž5. olanzapine Ž0.063. q FG 7142 Ž5. olanzapine Ž0.125. q FG 7142 Ž5. olanzapine Ž0.25. q FG 7142 Ž5. olanzapine Ž0.5. q FG 7142 Ž5.
a
Step-up latency Žs. Training session
Retention session
2.25 Ž0.3–4.2. 23.05 Ž3.9–78.7. 1.75 Ž1.1–3.3. a 2.00 Ž0.2–3.8. a 2.25 Ž0.8–6.3. a 1.8 Ž1.2–2.8. a
1.20 Ž0.5–2.9. 9.2 Ž3.9–30. 1.1 Ž0.5–3.9. a 1.55 Ž0.5–3.2. a 3.3 Ž1.2–8.6. a 1.5 Ž0.9–3.5. a
Significantly different from saline pre-treated control group ŽMann–Whitney U-test.. Olanzapine and FG 7142 were administered 60 and 30 min, respectively, before training session.
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Table 2 Effect of olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. on dizocilpine Ž0.1 mgrkg.-induced cognitive dysfunction in active avoidance paradigm in mice. The data are expressed as medians and interquartile ranges. There were six to eight mice in each group Number
Treatment Žmgrkg.
1 2 3 4 5 6
vehicle q saline vehicle q dizocilpine Ž0.1. olanzapine Ž0.063. q dizocilpine Ž0.1. olanzapine Ž0.125. q dizocilpine Ž0.1. olanzapine Ž0.25. q dizocilpine Ž0.1. olanzapine Ž0.5. q dizocilpine Ž0.1.
Step-up latency Žs. Training session
Retention session
2.25 Ž0.3–4.2. 30.00 Ž3.2–30. 2.6 Ž1.8–2.8. a 9.65 Ž0.9–28.5. a 6.65 Ž3.5–9.4. a 7.00 Ž3.3–30. a
1.20 Ž0.5–2.9. 10.3 Ž3.5–30. 2.5 Ž1.1–3.7. a 2.95 Ž1.2–6.2. a 1.7 Ž1.2–4.1. a 2.00 Ž0.8–3.8. a
a
Significantly different from saline pre-treated control group ŽMann–Whitney U-test.. Olanzapine and dizocilpine were administered 60 and 30 min, respectively, before training session.
taken by the mouse to move in to one of the enclosed arms, was recorded on the first day. If the animal did not enter an enclosed arm within 120 s, it was gently pushed in to one enclosed arm and TL was assigned as 120 s. The mouse was allowed to explore the maze for 20 s and then returned to its home cages. Retention was examined 24 h after the first day trial. Each mouse was again placed in to the maze and TL was recorded.
2.4. Locomotor actiÕity test Locomotor activity Žambulation. was measured using a computerised animal activity meter ŽOpto Varimex Mini, Columbus Instruments, OH, USA.. Briefly, after 1 h of drug treatment mice were placed individually in a transparent plastic cage Ž30 = 23 = 22 cm. and activity was recorded for 5 min after allowing the mice to adapt to the new environment for 2 min. An array of 11 infrared emitterrdetector pairs Žspaced at 2.65-cm intervals; beam wavelengths 875 nm; distance between the emitter and detector mounted on an external frame s 50 cm. measured the animal’s activity along a single axis of motion, the digital data being displayed on the front panel meter as ambulatory activity. Locomotion was expressed in terms of
total photobeam counts per 5 min per animal. There were eight mice per group. 2.5. Drugs Dizocilpine maleate ŽMerck, Sharp & Dohme, Rahway, NJ, USA., FG 7142 ŽSchering, Berlin, Germany. and olanzapine ŽEli Lilly, Indianapolis, USA. were used in the study. FG 7142 and dizocilpine were dissolved in saline. Olanzapine was dissolved in few drops of diluted HCl and then the volume was made up with saline and the pH was adequately adjusted. All drugs were administered i.p. in a constant volume of 1 mlr100 g of b.wt of mice. The selection of doses was based on previous reports from our laboratory. 2.6. Statistical analysis Results are expressed as means " S.E.M. except for the latencies to reach SFZ in case of active avoidance paradigm which are expressed as medians and interquartile ranges. The data were analysed using non-parametric Kruskal– Wallis ANOVA followed by Mann–Whitney U-test. The locomotor activity data were subjected to one-way ANOVA
Table 3 Effect of olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. on step-up latency in active avoidance paradigm in mice. The data are expressed as medians and interquartile ranges. There were six to eight mice in each group Number
1 2 3 4 5 a
Treatment Žmgrkg.
vehicleq saline olanzapine Ž0.063. q saline olanzapine Ž0.125. q saline olanzapine Ž0.25. q saline olanzapine Ž0.5. q saline
Step-up latency Žs. Training session
Retention session
2.25 Ž0.3–4.2. 2.15 Ž1.1–3.8. 2.05 Ž0.9–4. 2.85 Ž3.2–7.4. 3.1 Ž1.3–5.4.
1.20 Ž0.5–2.9. 2.36 Ž1.2–3.7. 2.50 Ž1.4–4.2. 1.65 Ž1.5–3.5. 3.5 Ž3–5.4. a
Significantly different from saline pre-treated control group ŽMann–Whitney U-test.. Olanzapine and saline were administered 60 and 30 min, respectively, before training session.
340
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Fig. 1. Effect of olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. on FG 7142 Ž5 mgrkg.-induced cognitive dysfunction in elevated plus maze in mice. TL, the time taken by the mouse to move in to one of the enclosed arms, was recorded on the first ŽI. and second day ŽB.. The data are expressed as means" S.E.M. There were six to eight mice in each group. Ža. Significantly different from saline pre-treated control group Ž P - 0.05, Mann–Whitney U-test.. Olanzapine and FG 7142 were administered 60 and 30 min, respectively, before trial on first day.
followed by Dunnett’s t-test. In all tests, the criterion for statistical significance was P - 0.05.
3. Results 3.1. Effect of olanzapine on FG 7142-induced delay in latency to reach SFZ in actiÕe aÕoidance paradigm As shown in Table 1, FG 7142 Ž5 mgrkg. administered 30 min after pre-training session produced significant increase in latency to reach SFZ during both training and retention session Ž P - 0.05, Mann–Whitney U-test.. Olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. pre-treatment reversed the effect of FG 7142 on latency to reach SFZ significantly during both training and retention session. However, this reversal was not dose-dependent ŽKruskal– Wallis ANOVA..
3.2. Effect of olanzapine on dizocilpine-induced behaÕiour in actiÕe aÕoidance paradigm As shown in Table 2, dizocilpine Ž0.1 mgrkg. administered 30 min after pre-training session produced significant increase in latency to reach SFZ during both training and retention session Ž P - 0.05, Mann–Whitney U-test.. Olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. reversed the effect of dizocilpine on latency to reach SFZ significantly during both training and retention session. However, this reversal was not dose-dependent ŽKruskal–Wallis ANOVA.. The behaviours observed during the training and retention sessions after pre-treatment with olanzapine are summarised in Table 3. The latencies to reach SFZ during the training session was not affected by olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. pre-treatment as compared to vehicle-pre-treated control group. During retention session,
Fig. 2. Effect of olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. on dizocilpine Ž0.1 mgrkg.-induced cognitive dysfunction in elevated plus maze in mice. TL, the time taken by the mouse to move in to one of the enclosed arms, was recorded on the first ŽI. and second day ŽB.. The data are expressed as means" S.E.M. There were six to eight mice in each group. Ža. Significantly different from saline pre-treated control group Ž P - 0.05, Mann–Whitney U-test.. Olanzapine and dizocilpine were administered 60 and 30 min, respectively, before trial on first day.
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Fig. 3. Effect of olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. on TL in elevated plus maze in mice. TL the time taken by the mouse to move in to one of the enclosed arms, was recorded on the first ŽI. and second day ŽB.. Olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. did not show any effect on first day. On second day, olanzapine Ž0.125, 0.25 and 0.5 mgrkg. increased TL as compared to saline treated control group Ž H4 s 13.7, P - 0.05. ŽKruskal–Wallis ANOVA.. The data are expressed as means " S.E.M. There were six to eight mice in each group. Olanzapine and saline were administered 60 and 30 min, respectively, before trial on first day.
olanzapine Ž0.063, 0.125 and 0.25 mgrkg. did not show significant difference in latency to reach SFZ as compared to vehicle pre-treated control group. However, the higher dose Ž0.5 mgrkg. of olanzapine exhibited an increase in latency to reach SFZ as compared to vehicle pre-treated control group Ž P - 0.05, Mann–Whitney U-test.. 3.3. Effect of olanzapine on FG 7142-induced increase in TL on eleÕated plus maze The effects of FG 7142 Ž5 mgrkg. and its combination with olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. are shown in Fig. 1. Control Žsaline. mice exhibited TL of 64 " 10 s Ž n s 8. on the first day, decreasing to 18 " 3 s on the second day, indicating that the mice remembered the presence of the enclosed arms. FG 7142 Ž5 mgrkg. treatment 30 min prior to the test on first day resulted in increase in impairing effect of FG 7142 on both acquisition and retention Ž P - 0.05, Mann–Whitney U-test.. On the first day, olanzapine Ž0.125 mgrkg. pre-treatment did not modify the TL in FG 7142-treated mice but on second day, it reversed the effect of FG 7142 Ž P - 0.05, Mann– Whitney U-test.. The higher doses of olanzapine Ž0.25 and 0.5 mgrkg. failed to modify the effect of FG 7142 on TL both on first and second day. 3.4. Effect of olanzapine on dizocilpine-induced increase in TL on eleÕated plus maze The effects of dizocilpine and its combination with olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. is shown in Fig. 2. The dizocilpine Ž0.1 mgrkg. treatment 30 min prior to the test on first day, did not modify the TL on first day. However, it resulted in a marked amnesia, since TL on the second day was significantly higher than control
Žsaline. value. Olanzapine Ž0.063 and 0.125 mgrkg. pretreatment decreased TL on second day compared to dizocilpine treated group Ž P - 0.05, Mann–Whitney U-test.. The higher doses of olanzapine Ž0.25 and 0.5 mgrkg. further increased TL on first day without affecting TL second day Ž P - 0.05, Mann–Whitney U-test.. Olanzapine Ž0.063, 0.125, 0.25 and 0.5 mgrkg. did not show any per se effect on TL in elevated plus maze on first day. However, on second day, olanzapine Ž0.125, 0.25 and 0.5 mgrkg. increased TL as compared to saline treated control group Ž H4 s 13.7, P - 0.05. ŽFig. 3.. 3.5. Effect of olanzapine on spontaneous locomotor actiÕity In order to assess the effect of olanzapine Ž0.062, 0.125, 0.25 and 0.5 mgrkg. on spontaneous locomotor activity, we measured locomotor activity after 1 h of its administration. Olanzapine Ž0.062, 0.125, 0.25 and 0.5 mgrkg. did not show decrease in spontaneous locomotor activity Ždata not shown..
4. Discussion FG 7142, a b-carboline anxiogenic produced delay in reaching SFZ in active avoidance task on both first and second day. Similarly, FG 7142 increased TL on both first and second day in elevated plus maze. This shows that FG 7142 affects both acquisition and retention in the memory process. FG 7142 was reported to produce spatial working memory deficits in monkeys w33x. However, it is possible that the delay in reaching SFZ in active avoidance task or increase in TL in elevated plus maze on first day could be due to FG 7142-induced freezing behaviour. Hence, these
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animals would be exposed to more shock on first day thus induce more conditioned fear on second day. Dizocilpine, a non-competitive NMDA receptor blocker produced delay in reaching SFZ in active avoidance task on both first and second day while it affected only retention in elevated plus maze. This observation is consistent with the earlier observation w42x. The results of this study suggest that lower doses of olanzapine reversed the effects of FG 7142 and dizocilpine on both active avoidance and elevated plus maze tasks. Olanzapine at all the doses reversed FG 7142- and dizocilpine-induced delay in reaching SFZ in active avoidance paradigm. But only the lower dose of olanzapine reversed the effect of both FG 7142 and dizocilpine on elevated plus maze. The difference in the response of olanzapine in these animal models of learning and memory is that higher doses of olanzapine are not effective in reversing the effect of FG 7142 or dizocilpine on elevated plus maze whereas all the doses of olanzapine reversed the effect of FG 7142 and dizocilpine on active avoidance paradigm. This could be due to the difference in the quality of negative reinforcement, i.e., fear of open arm and electric shock, respectively, in elevated plus maze and active avoidance paradigm. A similar difference was observed in the effect of olanzapine per se. The higher dose Ž0.5 mgrkg. of olanzapine impaired retention in both models whereas the lower doses Ž0.062, 0.125 and 0.25 mgrkg. of olanzapine impaired retention only in elevated plus maze. The olanzapine-induced impairment of retention process could be due to the antimuscarinic activity of olanzapine. Earlier, we have reported cognitive impairment caused by clozapine in these models, which was reversed by physostigmine w34x. Studies in experimental animals demonstrated the role of DA in cognitive functions w9,49x. DA receptor stimulation in PFC impairs spatial working memory performance. The involvement of dopaminergic mechanism in the impairment of learning and memory process by FG 7142 and non-competitive NMDA receptor antagonists has been documented earlier w32,47x. Recently, Murphy et al. w33x reported reversal of FG 7142-induced spatial working memory deficit by clozapine. The degree of cognitive impairment caused by FG 7142 correlates with increased DA turnover in the rodent PFC w33x. It is more likely that olanzapine’s beneficial effects arise from its blockade of DA receptor. It was recently reported that D 1 receptor antagonist fully reversed the FG 7142 response in rats and monkeys, suggesting that olanzapine’s D 1 receptor blocking property may be involved w32x. Recently, we have shown that olanzapine and clozapine behaved like partial agonist at DA D 2 receptors but olanzapine was found to be a comparatively more potent blocker of DA D 1 receptors w35–37x. The D 2 receptor family may also contribute to the cognitive deficits observed with FG 7142 treatment. The involvement of dopaminergic system in the cognitive process is a well documented one. The non-competi-
tive NMDA receptor antagonists such as ketamine and dizocilpine are reported to increase central DA activity w24,26,38,48x. But recent evidences suggested that other neurotransmitter systems such as 5-HT and noradrenaline are also involved in dizocilpine-induced behaviours w28, 29,39x. Therefore, it is not reasonable to argue that DA receptor antagonistic activity alone is responsible for the observed effect of olanzapine on dizocilpine-induced cognitive impairment. Studies on the involvement of different DA and 5-HT receptor subtypes in dizocilpine- and FG 7142-induced responses will be of particular interest given olanzapine’s high affinity for these receptors. The available evidences indicate that novel antipsychotics can be differentiated from haloperidol, the classical antipsychotics particularly in models of cognitive side effects. Atypical antipsychotics such as clozapine, olanzapine, sertindole and quetiapine show limbic selectivity whereas classical antipsychotic haloperidol does not show such selectivity w4,20,22,40x. Recently, we have shown that at lower doses olanzapine selectively inhibited behaviours mediated by mesolimbicrmesocortical system while at higher doses it inhibited behaviours mediated by both mesolimbicrmesocortical and nigrostriatal systems w41x. The beneficial effect of lower doses of olanzapine in cognitive functions could be due to its selective action at mesolimbicrmesocortical area. The available preclinical paradigms have limitations in demonstrating the clinical superiority of atypical antipsychotic drugs compared to typical antipsychotics. The data suggestive of mesocorticolimbic anatomic specificity for the atypical drugs could be extrapolated to postulate that these drugs may have some unique clinical effect on behaviours reliably mapped to this region as well as the absence of adverse effects which derive from striatal regions that atypical drugs spare. Several studies have demonstrated that clozapine treatment significantly improved neuropsychological assessment of executive function, memory retrieval and attention in addition to improvement in psychiatric symptoms w12x. The effect of atypical antipsychotics on negative symptoms of schizophrenia have been attributed to their selective effects on mesolimbicrmesocortical area w8x. In conclusion, the present study demonstrated reversal by olanzapine of dizocilpine- and FG 7142-induced behavioural changes in active avoidance paradigm and elevated plus maze. Although the precise mechanism of action is unknown, olanzapine might be acting by blocking excessive dopaminergic activity in the PFC. Better understanding of the mechanisms underlying olanzapine’s beneficial effect in cognitive functions should be of help in designing treatment strategy for PFC cognitive disorders.
Acknowledgements The Senior Research Fellowship ŽI.N.. of the Council of Scientific and Industrial Research ŽCSIR., New Delhi, is
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gratefully acknowledged. The authors also thank Eli Lilly ŽIndianapolis, USA. for generously donating olanzapine used in this study.
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