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Characterization of clozapine-induced changes in synaptic plasticity in the hippocampal–mPFC pathway of anesthetized rats
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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s
Research Report
Characterization of clozapine-induced changes in synaptic plasticity in the hippocampal–mPFC pathway of anesthetized rats Machiko Matsumotoa,b,⁎, Hiroki Shikanaib , Hiroko Togashia , Takeshi Izumib , Takeya Kittac , Riki Hiratab , Taku Yamaguchib , Mitsuhiro Yoshiokab a Department of Pharmacological Sciences, School of Pharmaceutical Science, Health Sciences University of Hokkaido, Ishikari-Tobetsu, 060-0293 Japan b Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638 Japan c Department of Urology, Hokkaido University Graduate School of Medicine, Japan
A R T I C LE I N FO
AB S T R A C T
Article history:
Synaptic plasticity expressed as long-term potentiation (LTP) in the hippocampal–medial
Accepted 5 December 2007
prefrontal cortex (mPFC) pathway is considered to be involved in cognitive function and
Available online 14 December 2007
learning and memory processes, but its synaptic mechanism remains unknown. The present study characterized LTP in the mPFC using the atypical antipsychotic clozapine, with a focus on
Keywords:
dopaminergic modulation. The magnitude of LTP was facilitated by pretreatment with
Synaptic plasticity
clozapine (20 mg/kg, i.p.), but not by the typical antipsychotic haloperidol (1 mg/kg, i.p.).
Clozapine
Clozapine-induced LTP augmentation was blocked by the dopamine D1 receptor antagonist
Medial prefrontal cortex
SCH-23390 (10 μg/rat, i.c.v.), but not by the D2 receptor antagonist remoxipride (10 μg/rat, i.c.v.)
Dopamine D1 receptors
or the 5-HT1A receptor antagonist WAY-100635 (20 μg/rat, i.c.v.). SCH-23390 (10 μg/rat, i.c.v.) by itself did not affect LTP induction. The D1 receptor agonist SKF-38393 (10 μg/kg, i.c.v.) facilitated LTP, mimicking the clozapine-induced response. Furthermore, in vivo microdialysis showed that transient increases in mPFC dopamine levels induced by tetanic stimulation sustained facilitation following clozapine administration (20 mg/kg, i.p.). These results demonstrate the importance of the D1 receptor as a mediator of clozapine-induced LTP augmentation through enhanced dopaminergic activity. Augmentation of synaptic plasticity in the hippocampalmPFC pathway via D1 receptors appears to be responsible for the therapeutic effects of clozapine. © 2007 Elsevier B.V. All rights reserved.
1.
Introduction
Medial prefrontal cortex (mPFC) neurons are essential for normal cognitive performance related to working memory and attention (Williams and Goldman-Rakic, 1995; Pratt and
Mizumori, 2001), and its dysfunction is a core symptom of schizophrenia. Numerous animal studies have provided evidence that working memory requires optimum levels of dopamine neurotransmission in the mPFC and that D1 receptors are involved in the sustained activity of PFC neurons.
⁎ Corresponding author. Department of Pharmacological Sciences, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido Pharmacological Science, Ishikari-Tobetsu, 061-0293, Japan. Fax: +81 133 23 1379. E-mail address: [email protected] (M. Matsumoto). 0006-8993/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2007.12.010
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Chudasama and Robbins (2004) reported that bilateral intraprefrontal cortical infusion of a D1 receptor agonist improved attentional accuracy in an attention–memory task, but it either disrupts or facilitates memory depending on the dose. Based on these findings, they suggested that cortical dopaminergic neurons differentially regulate attention and working memory performance. It is considered that dopamine function and working memory decline with age. Castner and GoldmanRakic (2004) showed that intermittent treatment with a D1 receptor agonist sustained cognitive function in aged, but not young, monkeys. They proposed that this phenomenon was due to fundamental alterations in the D1 receptor-mediated signal transduction pathway that comprises functional circuitry underlying working memory. Murphy and colleagues (1996), in contrast, found that elevations of cortical dopamine turnover caused by stress or anxiogenic agents are associated
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with impaired cognitive function. These findings led to the hypothesis that either reduced or excessive dopamine neuronal activity in the PFC, presumably via D1 receptors, can lead to impairments in working memory. In turn, D1 receptors associated with sustained activity of mPFC neurons are essential for normal cognitive performance, a theory supported by numerous reports showing that cortical application of D1 receptor antagonists impaired working memory performance (Williams and Goldman-Rakic, 1995; Seamans et al., 1998; Granon et al., 2000; Castner and Goldman-Rakic, 2004). Anatomically, the mPFC receives direct glutamatergic projections from the hippocampal CA1/subicular region that can express synaptic plasticity such as long-term potentiation (LTP) (Jay et al., 1995; Burette et al., 1997; Takita et al., 1999). Dopamine terminals in this region are in close proximity to glutamatergic afferents emanating from the hippocampal formation (Carr and Sesack, 1996). A dopaminergic mechanism may contribute to LTP formation in the mPFC, and changes in synaptic plasticity in the mPFC, therefore, may be associated with functions associated with the mPFC, such as cognition and leaning and memory processes. In general, atypical antipsychotics are more effective than typical antipsychotics in treating cognitive dysfunction in patients with schizophrenia (Bhana et al., 2001; Javitt, 2001). The atypical antipsychotic clozapine improves many cognitive and behavioral deficits in schizophrenia patients (Breier, 1999) and in animal models of schizophrenia (Hauber, 1993; Malhotra et al., 1997). Here, we characterized synaptic plasticity in the rat hippocampal–mPFC pathway using clozapine, with a focus on dopaminergic modulation. For this purpose, electrophysiological and neurochemical experiments were performed under anesthesia.
2.
Results
2.1.
Effects of clozapine on LTP induction in the mPFC
Prior to the electrophysiological experiment, we examined dynamic changes in extracellular dopamine levels in the mPFC
Fig. 1 – Effects of clozapine on LTP induction (A) and extracellular dopamine levels induced by tetanic stimulation (tetanus) (B) in the mPFC. (A) Specimen recordings and time course of the population spike amplitude (PSA) after clozapine (20 mg/kg, i.p.) administration. The dotted arrow in the top two panels shows the amplitude of the evoked potential. Time course response is presented as the percentage of PSA obtained immediately before clozapine or saline administration. Each value represents mean ± SEM. The numbers of rats tested are shown in parenthesis. (B) Time course of tetanic stimulation-induced dopamine levels in the mPFC measured by in vivo microdialysis following administration of clozapine (20 mg/kg, i.p.) (Clozapine + Tetanus). Values are expressed as a percentage of basal levels obtained before tetanic stimulation. Each value represents mean ± SEM. The numbers of rats tested are shown in parentheses. *p < 0.05 vs. tetanic stimulation group following administration of saline (Saline + Tetanus).
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induced increases in dopamine levels showed long-lasting and significant augmentation following clozapine administration (20 mg/kg, i.p.) (Fig. 1B).
2.3. Involvement of dopamine receptors in clozapine-induced LTP augmentation
Fig. 2 – Effects of dopamine and serotonin antagonists on clozapine-induced LTP augmentation in the mPFC. Area-under-the-curve (AUC) values of the population spike amplitude (PSA) after clozapine (20 mg/kg, i.p.) administration in the presence or absence of dopamine and serotonin antagonists. The D1 receptor antagonist SCH-23390 (SCH.) (10 μg/rat, i.c.v.), the D2 receptor antagonist remoxipride (Remo.) (10 μg/rat, i.c.v.), or the 5-HT1A receptor antagonist WAY-100635 (WAY) (20 μg/rat, i.c.v.) was administered 10 min before clozapine administration. Saline: saline-administered control. AUC was calculated 60 min after tetanic stimulation. Each value represents mean ± SEM. The numbers of rats tested are shown in parentheses. *p < 0.05.
Clozapine (20 mg/kg, i.p.)-induced LTP augmentation was significantly inhibited by the D1 receptor antagonist SCH23390 (10 μg/rat, i.c.v.). SCH-23390 by itself did not affect LTP induction (AUC: SCH-23390, 7.56 ± 0.14, n = 4; control: 7.73 ± 0.34, n = 7). The D2 receptor antagonist remoxipride (10 μg/rat, i.c.v.) did not influence clozapine-induced LTP augmentation (Fig. 2). Based on previous reports showing that clozapine indirectly activates 5-HT1A receptors (Chung et al., 2004; DiazMataix et al., 2005), we examined the possible involvement of 5-HT1A receptors in clozapine-induced LTP augmentation. As shown in Fig. 2, the 5-HT1A receptor antagonist WAY-100635 (20 μg/rat, i.c.v.) did not affect clozapine-induced facilitation. It seems unlikely that 5-HT1A receptors contribute to clozapineinduced LTP augmentation, at least under the present experimental conditions.
2.4. Effects of the D1 receptor agonist SKF-38393 on LTP induction in the mPFC To confirm the involvement of D1 receptors in the clozapineinduced response, the effect of the D1 receptor agonist SKF38393 on LTP induction was examined. SKF-38393 (10 μg/rat, i.c.v.) induced significant facilitation of the magnitude of LTP compared to controls (AUC: SKF-38393, 10.34 ± 0.97, n = 6;
following clozapine or haloperidol administration using in vivo microdialysis. Clozapine (20 mg/kg, i.p.) caused increases in extracellular dopamine levels, whereas haloperidol (1 mg/ kg, i.p.) did not affect dopamine levels. The AUC (% d min × 103) value calculated 60 min after drug treatment showed significant increases in dopamine levels in clozapine-treated rats (8.27 ± 0.69, n = 5) compared to saline-treated controls (5.85 ± 0.13, n = 5) ( p < 0.05). Haloperidol (AUC: 6.57 ± 0.57, n = 6) did not significantly affect dopamine levels compared to controls. Tetanic stimulation produced a sustained elevation of synaptic response in the mPFC, i.e., LTP was induced. Pretreatment with clozapine (20 mg/kg, i.p.) facilitated the magnitude of LTP without affecting basal synaptic transmission (Fig. 1A). AUC values in the clozapine-treated group were significantly elevated compared to saline-treated controls (AUC: clozapine, 9.59 ± 0.80, n = 6; control, 7.73 ± 0.34, n = 7) ( p < 0.05) (Fig. 2). In contrast, no facilitation of LTP was found with the typical antipsychotic drug haloperidol (1 mg/kg, i.p.) (AUC: 7.63 ± 1.12, n = 5) compared to controls.
2.2. Effects of clozapine on LTP-induced changes in dopamine release in the mPFC In vivo microdialysis combined with electrophysiology was performed to elucidate the effects of clozapine on LTP-induced changes in dopamine release in the mPFC. Extracellular levels of dopamine were significantly but transiently increased by tetanic stimulation compared to nontetanic-stimulated controls ( p < 0.05) but returned to basal levels. Tetanic stimulation-
Fig. 3 – Effects of D1 receptor agonist SKF-38393 on LTP induction in the mPFC. Specimen recordings and time course of the population spike amplitude (PSA) after administration of the D1 receptor agonist SKF-38393 (SKF) (10 μg/rat, i.c.v.). The dotted arrow in the top panel shows the amplitude of the evoked potential. The time course is presented as the percentage of PSA obtained immediately before SKF-38393 or saline administration. Each value represents mean ± SEM. The numbers of rats tested are shown in parentheses.
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control, 7.73 ± 0.34, n = 7) ( p < 0.05), thus mimicking the clozapine (20 mg/kg, i.p.)-induced response (Fig. 3).
3.
Discussion
The present study demonstrated that the magnitude of LTP in the mPFC of anesthetized rats was enhanced by clozapine. Clozapine-induced LTP facilitation was blocked by the selective D1 receptor antagonist SCH-23390 but not by the D2 receptor antagonist remoxipride. These results suggest that clozapineinduced augmentation of LTP is mediated via D1, but not D2, receptors. This notion was supported by the finding that haloperidol, which possesses D2 receptor antagonistic action, did not induce LTP augmentation. Furthermore, the D1 receptor agonist SKF-38393 produced a sustained facilitation of LTP similar to the clozapine-induced response. These data demonstrate that the dopaminergic system mediated via D1 receptors is required for clozapine to elicit its facilitating action on LTP. In this study, a significant but transient increase in dopamine release in the mPFC was caused during tetanic stimulation of the CA1/subicular region, and this response was facilitated by pretreatment with clozapine. In general, atypical antipsychotics, in contrast to typical antipsychotics, preferentially increase dopamine release in the mPFC (Westerink et al., 1998; Watanabe and Hagino, 1999). We also observed significant increases in dopamine release in the mPFC following administration of clozapine but not haloperidol. Therefore, increased basal dopamine levels induced by clozapine might lead to facilitation of the transient increase in dopamine levels induced by tetanic stimulation. Dopamine has been shown to facilitate the N-methyl-D-aspartate (NMDA)-mediated excitatory response (Seamans et al., 2001; Wang and O'Donnell, 2001). In addition, dopamine can act preferentially at D1 receptors to augment NMDA receptor-mediated neurotransmission in mPFC pyramidal cells (Zheng et al., 1999; Gurden et al., 2000), suggesting that D1 receptors and NMDA receptors cooperate in LTP induction mechanisms. It is possible, therefore, that enhanced dopamine in the mPFC activates postsynaptic D1 receptors, thereby exerting a facilitating action on the NMDA contribution to LTP. Assuming that LTP has a role in the output of cellular information from the mPFC, the present results lead us to hypothesize that D1 receptor-mediated LTP augmentation is a cellular process associated with cognitive function. This hypothesis is strengthened by a report showing impairment in a delayed spatial memory task by ventral hippocampal inactivation combined with PFC infusion of a D1 receptor antagonist (Seamans et al., 1998). Baldwin and colleagues (2002) showed that normal acquisition of appetitive operant conditioning in the rat requires D1 receptors and NMDA receptors in the PFC, supporting the involvement of LTP-like processes in the mPFC in learning and memory (Herry and Garcia, 2002; Otani, 2002). The ability of clozapine to facilitate dopaminergic transmission induced by tetanic stimulation may contribute to its atypical profile. The involvement of dopaminergic and/or glutamatergic hypofunction in the PFC has been suggested in the pathogenesis of both negative symptomatology and cognitive deficits observed in schizophrenia (Lynch, 1992; van der
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Heijden et al., 2004; Goff and Coyle, 2001). Clozapine-induced increases in dopamine release mediated via D1 receptors in the mPFC therefore may contribute to improving such disturbances in schizophrenia. In summary, this is the first in vivo study demonstrating the importance of the D1 receptor as a mediator of clozapineinduced facilitation of LTP in the mPFC. The changes in synaptic plasticity, i.e., augmentation of LTP in the hippocampal–mPFC pathway, may be responsible for the atypical profile of clozapine through stimulation of D1 receptors.
4.
Experimental procedures
4.1.
Animals
Male Wistar–ST rats (10–14 weeks old; Shizuoka Laboratory Animal Center, Hamamatsu, Japan) were used. Animals were housed in a room with a 12-h light/dark cycle at 21 ± 2 °C and were given free access to food and water. All handling of animals was performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of the Hokkaido University Graduate School of Medicine.
4.2.
Electrophysiological experiments
Rats were anesthetized with urethane (1 g/kg, i.p.) and fixed in a stereotaxic frame so that the bregma and the lambda were in the same horizontal plane. A bipolar stimulating electrode with a tip separation of 500 μm was placed in the CA1/subicular region of the ventral hippocampus (6.0 mm posterior, 5.6 mm lateral to bregma, 4.5–5.5 mm ventral from the cortical surface), and a stainless steel recording electrode (100 μm diameter) was lowered into the mPFC (3.3 mm anterior, 0.8 mm lateral to the bregma, 3.3 mm ventral from the cortical surface) according to the atlas of Paxinos and Watson (1986). The potential evoked by a test stimulation (frequency 0.1 Hz, pulse duration 250 μs, stimulus interval 30 s) was monitored with an oscilloscope (AD-5141, Nihon Kohden Co. Ltd., Tokyo, Japan). The input/ output characterization of each individual rat was determined by varying the stimulus intensity in a stepwise fashion from 50 to 600 μA. The intensity of the test stimulation was adjusted for each rat to elicit a population spike amplitude (PSA) of approximately 60% maximum amplitude. The integrated PSA obtained from seven successive stimuli was recorded every 5 min with a data analysis system (Concurrent, MASSCOMP, Tokyo, Japan). LTP was induced by two series of 10 high-frequency stimulations (i.e., tetanic stimulation, 250 Hz, 250 μs duration, 50 trains) at the same intensity as the test stimulus.
4.3.
In vivo microdialysis combined with electrophysiology
Rats were examined for dynamic changes in extracellular dopamine levels in the mPFC induced by tetanic stimulation using in vivo microdialysis combined with electrophysiology under anesthesia. First, a recording electrode and a stimulating electrode were respectively inserted into the mPFC and the CA1/subicular region of the ventral hippocampus as described in Section 2.2 above. The intensity of the test stimulation of
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each rat was adjusted, and then the recording electrode was gently removed from the mPFC. Immediately thereafter, a concentric 1 mm dialysis probe was directly inserted into the mPFC in place of the recording electrode. The probe was stereotaxically fixed with a pipette holder and perfused with artificial cerebrospinal fluid (aCSF) (KCl 2.7, NaCl 140, CaCl2 1.2, MgCl2 1.0, NaH2PO4 0.3, Na2HPO4 1.7 mM) at a flow rate of 1 μl/min. To obtain a stable baseline measurement, aCSF was perfused for 60 min, and sampling began with simultaneous test stimulation of the hippocampal CA1/subicular region. Successive samples were collected at 20-min intervals; 60 min later, tetanic stimulation was performed as described above. Extracellular dopamine levels were determined using high-performance liquid chromatography with an electrochemical detector (ECD 300, Eicom Co. Ltd., Kyoto, Japan). Briefly, a working electrode was maintained at 450 mV, and the mobile phase consisted of 2.1 mM sodium 1-decansulfonate, 0.1 mM EDTA-2Na/0.1 M phosphate buffer, pH 6.0, and 1% (v/v) methanol. Some rats were used for a preliminary in vivo microdialysis study to determine appropriate drug dosages. Under anesthesia, a 3-mm concentric guide cannula was stereotaxically implanted into the mPFC (3.3 mm anterior, 0.8 mm lateral to the bregma, 3.3 mm ventral from the cortical surface). Three days after surgery, a probe was inserted into the mPFC through the guide cannula, and the in vivo microdialysis experiment was carried out in awake rats as described previously (Matsumoto et al., 2005).
4.4.
Drug administration
Clozapine and haloperidol were systemically (i.p.) administered 20 min before tetanic stimulation. The D1 receptor agonist SKF-38393 was administered intracerebroventricularly (i.c.v.) 20 min before tetanic stimulation. The D1 receptor antagonist SCH-23390, the D2 receptor antagonist remoxipride, and the serotonin1A (5-HT1A) receptor antagonist WAY100635 were administered i.c.v. 10 min before clozapine administration. Saline or aCSF were administered i.p. or i.c.v., respectively, as controls. The drug dose and injection route were chosen based on previous reports (Broderick and Piercey, 1998; Gessa et al., 2000; Jaskiw et al., 2001) and based on our preliminary experiments. Clozapine was donated by Novartis Co. Ltd. (Tokyo, Japan). Haloperidol, SKF-38393, SCH-23390, remoxipride, and WAY-100635 were purchased from SigmaRBI Research Biochemicals (Boston, MA, USA). All solutions were prepared immediately prior to use.
4.5.
Statistical analysis
Experimental values are given as mean ± SEM. Values are expressed as a percentage of baseline before drug treatment. Area-under-the-curve (AUC) (% min × 103) was calculated 60 min after tetanic stimulation to evaluate the ensemble effect of PSA. Statistical analysis of AUC data was performed using one-factor analysis of variance (ANOVA) followed by Dunnett's post hoc test to calculate differences from the salinetreated group (control) or Fisher's test for multiple comparisons. Values of p less than 5% were considered statistically significant.
REFERENCES
Baldwin, A.E., Sadeghian, K., Kelley, A.E., 2002. Appetitive instrumental learning requires coincident activation of NMDA and dopamine D1 receptors within the medial prefrontal cortex. J. Neurosci. 22, 1063–1071. Bhana, N., Foster, R.H., Olney, R., Plosker, G.L., 2001. Olanzapine: an updated review of its use in the management of schizophrenia. Drugs 61, 111–161. Breier, A., 1999. Cognitive deficit in schizophrenia and its neurochemical basis. Br. J. Psychiatr., Suppl. 37, 16–18. Broderick, P.A., Piercey, M.F., 1998. Clozapine, haloperidol, and the D4 antagonist PNU-101387G: in vivo effects on mesocortical, mesolimbic, and nigrostriatal dopamine and serotonin release. J. Neural Transm. 105, 749–767. Burette, F., Jay, T.M., Laroche, S., 1997. Reversal of LTP in the hippocampal afferent fiber system to the prefrontal cortex in vivo with low-frequency patterns of stimulation that do not produce LTD. J. Neurophysiol. 78, 1155–1160. Carr, D.B., Sesack, S.R., 1996. Hippocampal afferents to the rat prefrontal cortex: synaptic targets and relation to dopamine terminals. J. Comp. Neurol. 369, 1–15. Castner, S.A., Goldman-Rakic, P.S., 2004. Enhancement of working memory in aged monkeys by a sensitizing regimen of dopamine D1 receptor stimulation. J. Neurosci. 24, 1446–1450. Chudasama, Y., Robbins, T.W., 2004. Dopaminergic modulation of visual attention and working memory in the rodent prefrontal cortex. Neuropsychopharmacology 29, 1628–1636. Chung, Y.C., Li, Z., Dai, J., Meltzer, H.Y., Ichikawa, J., 2004. Clozapine increases both acetylcholine and dopamine release in rat ventral hippocampus: role of 5-HT1A receptor agonism. Brain Res. 1023, 54–63. Diaz-Mataix, L., Scorza, M.C., Bortolozzi, A., Toth, M., Celada, P., Artigas, F., 2005. Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: role in atypical antipsychotic action. J. Neurosci. 25, 10831–10843. Gessa, G.L., Devoto, P., Diana, M., Flore, G., Melis, M., Pistis, M., 2000. Dissociation of haloperidol, clozapine, and olanzapine effects on electrical activity of mesocortical dopamine neurons and dopamine release in the prefrontal cortex. Neuropsychopharmacology 22, 642–649. Goff, D.C., Coyle, J.T., 2001. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am. J. Psychiatry 158, 1367–1377. Granon, S., Passetti, F., Thomas, K.L., Dalley, J.W., Everitt, B.J., Robbins, T.W., 2000. Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex. J. Neurosci. 20, 1208–1215. Gurden, H., Takita, M., Jay, T.M., 2000. Essential role of D1 but not D2 receptors in the NMDA receptor-dependent long-term potentiation at hippocampal–prefrontal cortex synapses in vivo. J. Neurosci. 20, RC106. Hauber, W., 1993. Clozapine improves dizocilpine-induced delayed alteration impairment in rats. J. Neural Transm. Gen. Sect. 94, 223–233. Herry, C., Garcia, R., 2002. Prefrontal cortex long-term potentiation, but not long-term depression, is associated with the maintenance of extinction of learned fear in mice. J. Neurosci. 22, 577–583. Jaskiw, G.E., Collins, K.A., Pehek, E.A., Yamamoto, B.K., 2001. Tyrosine augments acute clozapine- but not haloperidol-induced dopamine release in the medial prefrontal cortex of the rat: an in vivo microdialysis study. Neuropsychopharmacology 25, 149–156. Jay, T.M., Burette, F., Laroche, S., 1995. NMDA receptor-dependent long-term potentiation in hippocampal afferent fibre system to the prefrontal cortex in the rat. Eur. J. Neurosci. 7, 247–250.
BR A IN RE S E A RCH 1 1 95 ( 20 0 8 ) 5 0 –5 5
Javitt, D.C., 2001. Management of negative symptoms of schizophrenia. Curr. Psychiatry Rep. 3, 413–417. Lynch, M.R., 1992. Schizophrenia and the D1 receptor: focus on negative symptoms. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 16, 797–832. Malhotra, A.K., Adler, C.M., Kennison, S.D., Elman, I., Pickar, D., Breier, A., 1997. Clozapine blunts N-methyl-D-aspartate antagonist-induced psychosis: a study with ketamine. Biol. Psychiatry 42, 664–668. Matsumoto, M., Togashi, H., Kaku, A., Kanno, M., Tahara, K., Yoshioka, M., 2005. Cortical GABAergic regulation of dopaminergic responses to psychological stress in the rat dorsolateral striatum. Synapse 56, 117–121. Murphy, B.L., Arnsten, A.F.T., Goldman-Rakic, P.S., Roth, R.H., 1996. Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. Proc. Natl. Acad. Sci. U. S. A. 93, 1325–1329. Otani, S., 2002. Memory trace in prefrontal cortex: theory for the cognitive switch. Biol. Rev. Camb. Philos. Soc. 77, 563–577. Paxinos, G., Watson, C., 1986. The Rat Brain in Stereotaxic Coordinates, 2nd ed. Academic Press, New York. Pratt, W.E., Mizumori, S.J., 2001. Neurons in rat medial prefrontal cortex show anticipatory rate changes to predictable differential rewards in a spatial memory task. Behav. Brain Res. 123, 165–183. Seamans, J.K., Floresco, S.B., Phillips, A.G., 1998. D1 receptor modulation of hippocampal–prefrontal cortical circuits integrating spatial memory with executive functions in the rat. J. Neurosci. 18, 1613–1621.
55
Seamans, J.K., Durstewitz, D., Christie, B.R., Stevens, C.F., Sejnowski, T.J., 2001. Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons. Proc. Natl. Acad. Sci. U. S. A. 98, 301–306. Takita, M., Izaki, Y., Jay, T.M., Kaneko, H., Suzuki, S.S., 1999. Induction of stable long-term depression in vivo in the hippocampal–prefrontal cortex pathway. Eur. J. Neurosci. 11, 4145–4148. van der Heijden, F.M., Tuinier, S., Fekkes, D., Sijben, A.E., Kahn, R.S., Verhoeven, W.M., 2004. Atypical antipsychotics and the relevance of glutamate and serotonin. Eur. Neuropsychopharmacol. 14, 259–265. Wang, J., O'Donnell, P., 2001. D1 dopamine receptors potentiate NMDA-mediated excitability increase in layer V prefrontal cortical pyramidal neurons. Cereb. Cortex 11, 452–462. Watanabe, M., Hagino, Y., 1999. The atypical antipsychotic sertindole enhances efflux of dopamine and its metabolites in the rat cortex and striatum. Eur. J. Pharmacol. 367, 19–23. Westerink, B.H., de Boer, P., de Vries, J.B., Kruse, C.G., Long, S.K., 1998. Antipsychotic drugs induce similar effects on the release of dopamine and noradrenaline in the medial prefrontal cortex of the rat brain. Eur. J. Pharmacol. 361, 27–33. Williams, G.V., Goldman-Rakic, P.S., 1995. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376, 572–575. Zheng, P., Zhang, X.X., Bunney, B.S., Shi, W.X., 1999. Opposite modulation of cortical N-methyl-D-aspartate receptor-mediated responses by low and high concentrations of dopamine. Neuroscience 91, 527–535.
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s
Research Report
Characterization of clozapine-induced changes in synaptic plasticity in the hippocampal–mPFC pathway of anesthetized rats Machiko Matsumotoa,b,⁎, Hiroki Shikanaib , Hiroko Togashia , Takeshi Izumib , Takeya Kittac , Riki Hiratab , Taku Yamaguchib , Mitsuhiro Yoshiokab a Department of Pharmacological Sciences, School of Pharmaceutical Science, Health Sciences University of Hokkaido, Ishikari-Tobetsu, 060-0293 Japan b Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638 Japan c Department of Urology, Hokkaido University Graduate School of Medicine, Japan
A R T I C LE I N FO
AB S T R A C T
Article history:
Synaptic plasticity expressed as long-term potentiation (LTP) in the hippocampal–medial
Accepted 5 December 2007
prefrontal cortex (mPFC) pathway is considered to be involved in cognitive function and
Available online 14 December 2007
learning and memory processes, but its synaptic mechanism remains unknown. The present study characterized LTP in the mPFC using the atypical antipsychotic clozapine, with a focus on
Keywords:
dopaminergic modulation. The magnitude of LTP was facilitated by pretreatment with
Synaptic plasticity
clozapine (20 mg/kg, i.p.), but not by the typical antipsychotic haloperidol (1 mg/kg, i.p.).
Clozapine
Clozapine-induced LTP augmentation was blocked by the dopamine D1 receptor antagonist
Medial prefrontal cortex
SCH-23390 (10 μg/rat, i.c.v.), but not by the D2 receptor antagonist remoxipride (10 μg/rat, i.c.v.)
Dopamine D1 receptors
or the 5-HT1A receptor antagonist WAY-100635 (20 μg/rat, i.c.v.). SCH-23390 (10 μg/rat, i.c.v.) by itself did not affect LTP induction. The D1 receptor agonist SKF-38393 (10 μg/kg, i.c.v.) facilitated LTP, mimicking the clozapine-induced response. Furthermore, in vivo microdialysis showed that transient increases in mPFC dopamine levels induced by tetanic stimulation sustained facilitation following clozapine administration (20 mg/kg, i.p.). These results demonstrate the importance of the D1 receptor as a mediator of clozapine-induced LTP augmentation through enhanced dopaminergic activity. Augmentation of synaptic plasticity in the hippocampalmPFC pathway via D1 receptors appears to be responsible for the therapeutic effects of clozapine. © 2007 Elsevier B.V. All rights reserved.
1.
Introduction
Medial prefrontal cortex (mPFC) neurons are essential for normal cognitive performance related to working memory and attention (Williams and Goldman-Rakic, 1995; Pratt and
Mizumori, 2001), and its dysfunction is a core symptom of schizophrenia. Numerous animal studies have provided evidence that working memory requires optimum levels of dopamine neurotransmission in the mPFC and that D1 receptors are involved in the sustained activity of PFC neurons.
⁎ Corresponding author. Department of Pharmacological Sciences, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido Pharmacological Science, Ishikari-Tobetsu, 061-0293, Japan. Fax: +81 133 23 1379. E-mail address: [email protected] (M. Matsumoto). 0006-8993/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2007.12.010
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Chudasama and Robbins (2004) reported that bilateral intraprefrontal cortical infusion of a D1 receptor agonist improved attentional accuracy in an attention–memory task, but it either disrupts or facilitates memory depending on the dose. Based on these findings, they suggested that cortical dopaminergic neurons differentially regulate attention and working memory performance. It is considered that dopamine function and working memory decline with age. Castner and GoldmanRakic (2004) showed that intermittent treatment with a D1 receptor agonist sustained cognitive function in aged, but not young, monkeys. They proposed that this phenomenon was due to fundamental alterations in the D1 receptor-mediated signal transduction pathway that comprises functional circuitry underlying working memory. Murphy and colleagues (1996), in contrast, found that elevations of cortical dopamine turnover caused by stress or anxiogenic agents are associated
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with impaired cognitive function. These findings led to the hypothesis that either reduced or excessive dopamine neuronal activity in the PFC, presumably via D1 receptors, can lead to impairments in working memory. In turn, D1 receptors associated with sustained activity of mPFC neurons are essential for normal cognitive performance, a theory supported by numerous reports showing that cortical application of D1 receptor antagonists impaired working memory performance (Williams and Goldman-Rakic, 1995; Seamans et al., 1998; Granon et al., 2000; Castner and Goldman-Rakic, 2004). Anatomically, the mPFC receives direct glutamatergic projections from the hippocampal CA1/subicular region that can express synaptic plasticity such as long-term potentiation (LTP) (Jay et al., 1995; Burette et al., 1997; Takita et al., 1999). Dopamine terminals in this region are in close proximity to glutamatergic afferents emanating from the hippocampal formation (Carr and Sesack, 1996). A dopaminergic mechanism may contribute to LTP formation in the mPFC, and changes in synaptic plasticity in the mPFC, therefore, may be associated with functions associated with the mPFC, such as cognition and leaning and memory processes. In general, atypical antipsychotics are more effective than typical antipsychotics in treating cognitive dysfunction in patients with schizophrenia (Bhana et al., 2001; Javitt, 2001). The atypical antipsychotic clozapine improves many cognitive and behavioral deficits in schizophrenia patients (Breier, 1999) and in animal models of schizophrenia (Hauber, 1993; Malhotra et al., 1997). Here, we characterized synaptic plasticity in the rat hippocampal–mPFC pathway using clozapine, with a focus on dopaminergic modulation. For this purpose, electrophysiological and neurochemical experiments were performed under anesthesia.
2.
Results
2.1.
Effects of clozapine on LTP induction in the mPFC
Prior to the electrophysiological experiment, we examined dynamic changes in extracellular dopamine levels in the mPFC
Fig. 1 – Effects of clozapine on LTP induction (A) and extracellular dopamine levels induced by tetanic stimulation (tetanus) (B) in the mPFC. (A) Specimen recordings and time course of the population spike amplitude (PSA) after clozapine (20 mg/kg, i.p.) administration. The dotted arrow in the top two panels shows the amplitude of the evoked potential. Time course response is presented as the percentage of PSA obtained immediately before clozapine or saline administration. Each value represents mean ± SEM. The numbers of rats tested are shown in parenthesis. (B) Time course of tetanic stimulation-induced dopamine levels in the mPFC measured by in vivo microdialysis following administration of clozapine (20 mg/kg, i.p.) (Clozapine + Tetanus). Values are expressed as a percentage of basal levels obtained before tetanic stimulation. Each value represents mean ± SEM. The numbers of rats tested are shown in parentheses. *p < 0.05 vs. tetanic stimulation group following administration of saline (Saline + Tetanus).
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induced increases in dopamine levels showed long-lasting and significant augmentation following clozapine administration (20 mg/kg, i.p.) (Fig. 1B).
2.3. Involvement of dopamine receptors in clozapine-induced LTP augmentation
Fig. 2 – Effects of dopamine and serotonin antagonists on clozapine-induced LTP augmentation in the mPFC. Area-under-the-curve (AUC) values of the population spike amplitude (PSA) after clozapine (20 mg/kg, i.p.) administration in the presence or absence of dopamine and serotonin antagonists. The D1 receptor antagonist SCH-23390 (SCH.) (10 μg/rat, i.c.v.), the D2 receptor antagonist remoxipride (Remo.) (10 μg/rat, i.c.v.), or the 5-HT1A receptor antagonist WAY-100635 (WAY) (20 μg/rat, i.c.v.) was administered 10 min before clozapine administration. Saline: saline-administered control. AUC was calculated 60 min after tetanic stimulation. Each value represents mean ± SEM. The numbers of rats tested are shown in parentheses. *p < 0.05.
Clozapine (20 mg/kg, i.p.)-induced LTP augmentation was significantly inhibited by the D1 receptor antagonist SCH23390 (10 μg/rat, i.c.v.). SCH-23390 by itself did not affect LTP induction (AUC: SCH-23390, 7.56 ± 0.14, n = 4; control: 7.73 ± 0.34, n = 7). The D2 receptor antagonist remoxipride (10 μg/rat, i.c.v.) did not influence clozapine-induced LTP augmentation (Fig. 2). Based on previous reports showing that clozapine indirectly activates 5-HT1A receptors (Chung et al., 2004; DiazMataix et al., 2005), we examined the possible involvement of 5-HT1A receptors in clozapine-induced LTP augmentation. As shown in Fig. 2, the 5-HT1A receptor antagonist WAY-100635 (20 μg/rat, i.c.v.) did not affect clozapine-induced facilitation. It seems unlikely that 5-HT1A receptors contribute to clozapineinduced LTP augmentation, at least under the present experimental conditions.
2.4. Effects of the D1 receptor agonist SKF-38393 on LTP induction in the mPFC To confirm the involvement of D1 receptors in the clozapineinduced response, the effect of the D1 receptor agonist SKF38393 on LTP induction was examined. SKF-38393 (10 μg/rat, i.c.v.) induced significant facilitation of the magnitude of LTP compared to controls (AUC: SKF-38393, 10.34 ± 0.97, n = 6;
following clozapine or haloperidol administration using in vivo microdialysis. Clozapine (20 mg/kg, i.p.) caused increases in extracellular dopamine levels, whereas haloperidol (1 mg/ kg, i.p.) did not affect dopamine levels. The AUC (% d min × 103) value calculated 60 min after drug treatment showed significant increases in dopamine levels in clozapine-treated rats (8.27 ± 0.69, n = 5) compared to saline-treated controls (5.85 ± 0.13, n = 5) ( p < 0.05). Haloperidol (AUC: 6.57 ± 0.57, n = 6) did not significantly affect dopamine levels compared to controls. Tetanic stimulation produced a sustained elevation of synaptic response in the mPFC, i.e., LTP was induced. Pretreatment with clozapine (20 mg/kg, i.p.) facilitated the magnitude of LTP without affecting basal synaptic transmission (Fig. 1A). AUC values in the clozapine-treated group were significantly elevated compared to saline-treated controls (AUC: clozapine, 9.59 ± 0.80, n = 6; control, 7.73 ± 0.34, n = 7) ( p < 0.05) (Fig. 2). In contrast, no facilitation of LTP was found with the typical antipsychotic drug haloperidol (1 mg/kg, i.p.) (AUC: 7.63 ± 1.12, n = 5) compared to controls.
2.2. Effects of clozapine on LTP-induced changes in dopamine release in the mPFC In vivo microdialysis combined with electrophysiology was performed to elucidate the effects of clozapine on LTP-induced changes in dopamine release in the mPFC. Extracellular levels of dopamine were significantly but transiently increased by tetanic stimulation compared to nontetanic-stimulated controls ( p < 0.05) but returned to basal levels. Tetanic stimulation-
Fig. 3 – Effects of D1 receptor agonist SKF-38393 on LTP induction in the mPFC. Specimen recordings and time course of the population spike amplitude (PSA) after administration of the D1 receptor agonist SKF-38393 (SKF) (10 μg/rat, i.c.v.). The dotted arrow in the top panel shows the amplitude of the evoked potential. The time course is presented as the percentage of PSA obtained immediately before SKF-38393 or saline administration. Each value represents mean ± SEM. The numbers of rats tested are shown in parentheses.
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control, 7.73 ± 0.34, n = 7) ( p < 0.05), thus mimicking the clozapine (20 mg/kg, i.p.)-induced response (Fig. 3).
3.
Discussion
The present study demonstrated that the magnitude of LTP in the mPFC of anesthetized rats was enhanced by clozapine. Clozapine-induced LTP facilitation was blocked by the selective D1 receptor antagonist SCH-23390 but not by the D2 receptor antagonist remoxipride. These results suggest that clozapineinduced augmentation of LTP is mediated via D1, but not D2, receptors. This notion was supported by the finding that haloperidol, which possesses D2 receptor antagonistic action, did not induce LTP augmentation. Furthermore, the D1 receptor agonist SKF-38393 produced a sustained facilitation of LTP similar to the clozapine-induced response. These data demonstrate that the dopaminergic system mediated via D1 receptors is required for clozapine to elicit its facilitating action on LTP. In this study, a significant but transient increase in dopamine release in the mPFC was caused during tetanic stimulation of the CA1/subicular region, and this response was facilitated by pretreatment with clozapine. In general, atypical antipsychotics, in contrast to typical antipsychotics, preferentially increase dopamine release in the mPFC (Westerink et al., 1998; Watanabe and Hagino, 1999). We also observed significant increases in dopamine release in the mPFC following administration of clozapine but not haloperidol. Therefore, increased basal dopamine levels induced by clozapine might lead to facilitation of the transient increase in dopamine levels induced by tetanic stimulation. Dopamine has been shown to facilitate the N-methyl-D-aspartate (NMDA)-mediated excitatory response (Seamans et al., 2001; Wang and O'Donnell, 2001). In addition, dopamine can act preferentially at D1 receptors to augment NMDA receptor-mediated neurotransmission in mPFC pyramidal cells (Zheng et al., 1999; Gurden et al., 2000), suggesting that D1 receptors and NMDA receptors cooperate in LTP induction mechanisms. It is possible, therefore, that enhanced dopamine in the mPFC activates postsynaptic D1 receptors, thereby exerting a facilitating action on the NMDA contribution to LTP. Assuming that LTP has a role in the output of cellular information from the mPFC, the present results lead us to hypothesize that D1 receptor-mediated LTP augmentation is a cellular process associated with cognitive function. This hypothesis is strengthened by a report showing impairment in a delayed spatial memory task by ventral hippocampal inactivation combined with PFC infusion of a D1 receptor antagonist (Seamans et al., 1998). Baldwin and colleagues (2002) showed that normal acquisition of appetitive operant conditioning in the rat requires D1 receptors and NMDA receptors in the PFC, supporting the involvement of LTP-like processes in the mPFC in learning and memory (Herry and Garcia, 2002; Otani, 2002). The ability of clozapine to facilitate dopaminergic transmission induced by tetanic stimulation may contribute to its atypical profile. The involvement of dopaminergic and/or glutamatergic hypofunction in the PFC has been suggested in the pathogenesis of both negative symptomatology and cognitive deficits observed in schizophrenia (Lynch, 1992; van der
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Heijden et al., 2004; Goff and Coyle, 2001). Clozapine-induced increases in dopamine release mediated via D1 receptors in the mPFC therefore may contribute to improving such disturbances in schizophrenia. In summary, this is the first in vivo study demonstrating the importance of the D1 receptor as a mediator of clozapineinduced facilitation of LTP in the mPFC. The changes in synaptic plasticity, i.e., augmentation of LTP in the hippocampal–mPFC pathway, may be responsible for the atypical profile of clozapine through stimulation of D1 receptors.
4.
Experimental procedures
4.1.
Animals
Male Wistar–ST rats (10–14 weeks old; Shizuoka Laboratory Animal Center, Hamamatsu, Japan) were used. Animals were housed in a room with a 12-h light/dark cycle at 21 ± 2 °C and were given free access to food and water. All handling of animals was performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of the Hokkaido University Graduate School of Medicine.
4.2.
Electrophysiological experiments
Rats were anesthetized with urethane (1 g/kg, i.p.) and fixed in a stereotaxic frame so that the bregma and the lambda were in the same horizontal plane. A bipolar stimulating electrode with a tip separation of 500 μm was placed in the CA1/subicular region of the ventral hippocampus (6.0 mm posterior, 5.6 mm lateral to bregma, 4.5–5.5 mm ventral from the cortical surface), and a stainless steel recording electrode (100 μm diameter) was lowered into the mPFC (3.3 mm anterior, 0.8 mm lateral to the bregma, 3.3 mm ventral from the cortical surface) according to the atlas of Paxinos and Watson (1986). The potential evoked by a test stimulation (frequency 0.1 Hz, pulse duration 250 μs, stimulus interval 30 s) was monitored with an oscilloscope (AD-5141, Nihon Kohden Co. Ltd., Tokyo, Japan). The input/ output characterization of each individual rat was determined by varying the stimulus intensity in a stepwise fashion from 50 to 600 μA. The intensity of the test stimulation was adjusted for each rat to elicit a population spike amplitude (PSA) of approximately 60% maximum amplitude. The integrated PSA obtained from seven successive stimuli was recorded every 5 min with a data analysis system (Concurrent, MASSCOMP, Tokyo, Japan). LTP was induced by two series of 10 high-frequency stimulations (i.e., tetanic stimulation, 250 Hz, 250 μs duration, 50 trains) at the same intensity as the test stimulus.
4.3.
In vivo microdialysis combined with electrophysiology
Rats were examined for dynamic changes in extracellular dopamine levels in the mPFC induced by tetanic stimulation using in vivo microdialysis combined with electrophysiology under anesthesia. First, a recording electrode and a stimulating electrode were respectively inserted into the mPFC and the CA1/subicular region of the ventral hippocampus as described in Section 2.2 above. The intensity of the test stimulation of
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each rat was adjusted, and then the recording electrode was gently removed from the mPFC. Immediately thereafter, a concentric 1 mm dialysis probe was directly inserted into the mPFC in place of the recording electrode. The probe was stereotaxically fixed with a pipette holder and perfused with artificial cerebrospinal fluid (aCSF) (KCl 2.7, NaCl 140, CaCl2 1.2, MgCl2 1.0, NaH2PO4 0.3, Na2HPO4 1.7 mM) at a flow rate of 1 μl/min. To obtain a stable baseline measurement, aCSF was perfused for 60 min, and sampling began with simultaneous test stimulation of the hippocampal CA1/subicular region. Successive samples were collected at 20-min intervals; 60 min later, tetanic stimulation was performed as described above. Extracellular dopamine levels were determined using high-performance liquid chromatography with an electrochemical detector (ECD 300, Eicom Co. Ltd., Kyoto, Japan). Briefly, a working electrode was maintained at 450 mV, and the mobile phase consisted of 2.1 mM sodium 1-decansulfonate, 0.1 mM EDTA-2Na/0.1 M phosphate buffer, pH 6.0, and 1% (v/v) methanol. Some rats were used for a preliminary in vivo microdialysis study to determine appropriate drug dosages. Under anesthesia, a 3-mm concentric guide cannula was stereotaxically implanted into the mPFC (3.3 mm anterior, 0.8 mm lateral to the bregma, 3.3 mm ventral from the cortical surface). Three days after surgery, a probe was inserted into the mPFC through the guide cannula, and the in vivo microdialysis experiment was carried out in awake rats as described previously (Matsumoto et al., 2005).
4.4.
Drug administration
Clozapine and haloperidol were systemically (i.p.) administered 20 min before tetanic stimulation. The D1 receptor agonist SKF-38393 was administered intracerebroventricularly (i.c.v.) 20 min before tetanic stimulation. The D1 receptor antagonist SCH-23390, the D2 receptor antagonist remoxipride, and the serotonin1A (5-HT1A) receptor antagonist WAY100635 were administered i.c.v. 10 min before clozapine administration. Saline or aCSF were administered i.p. or i.c.v., respectively, as controls. The drug dose and injection route were chosen based on previous reports (Broderick and Piercey, 1998; Gessa et al., 2000; Jaskiw et al., 2001) and based on our preliminary experiments. Clozapine was donated by Novartis Co. Ltd. (Tokyo, Japan). Haloperidol, SKF-38393, SCH-23390, remoxipride, and WAY-100635 were purchased from SigmaRBI Research Biochemicals (Boston, MA, USA). All solutions were prepared immediately prior to use.
4.5.
Statistical analysis
Experimental values are given as mean ± SEM. Values are expressed as a percentage of baseline before drug treatment. Area-under-the-curve (AUC) (% min × 103) was calculated 60 min after tetanic stimulation to evaluate the ensemble effect of PSA. Statistical analysis of AUC data was performed using one-factor analysis of variance (ANOVA) followed by Dunnett's post hoc test to calculate differences from the salinetreated group (control) or Fisher's test for multiple comparisons. Values of p less than 5% were considered statistically significant.
REFERENCES
Baldwin, A.E., Sadeghian, K., Kelley, A.E., 2002. Appetitive instrumental learning requires coincident activation of NMDA and dopamine D1 receptors within the medial prefrontal cortex. J. Neurosci. 22, 1063–1071. Bhana, N., Foster, R.H., Olney, R., Plosker, G.L., 2001. Olanzapine: an updated review of its use in the management of schizophrenia. Drugs 61, 111–161. Breier, A., 1999. Cognitive deficit in schizophrenia and its neurochemical basis. Br. J. Psychiatr., Suppl. 37, 16–18. Broderick, P.A., Piercey, M.F., 1998. Clozapine, haloperidol, and the D4 antagonist PNU-101387G: in vivo effects on mesocortical, mesolimbic, and nigrostriatal dopamine and serotonin release. J. Neural Transm. 105, 749–767. Burette, F., Jay, T.M., Laroche, S., 1997. Reversal of LTP in the hippocampal afferent fiber system to the prefrontal cortex in vivo with low-frequency patterns of stimulation that do not produce LTD. J. Neurophysiol. 78, 1155–1160. Carr, D.B., Sesack, S.R., 1996. Hippocampal afferents to the rat prefrontal cortex: synaptic targets and relation to dopamine terminals. J. Comp. Neurol. 369, 1–15. Castner, S.A., Goldman-Rakic, P.S., 2004. Enhancement of working memory in aged monkeys by a sensitizing regimen of dopamine D1 receptor stimulation. J. Neurosci. 24, 1446–1450. Chudasama, Y., Robbins, T.W., 2004. Dopaminergic modulation of visual attention and working memory in the rodent prefrontal cortex. Neuropsychopharmacology 29, 1628–1636. Chung, Y.C., Li, Z., Dai, J., Meltzer, H.Y., Ichikawa, J., 2004. Clozapine increases both acetylcholine and dopamine release in rat ventral hippocampus: role of 5-HT1A receptor agonism. Brain Res. 1023, 54–63. Diaz-Mataix, L., Scorza, M.C., Bortolozzi, A., Toth, M., Celada, P., Artigas, F., 2005. Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: role in atypical antipsychotic action. J. Neurosci. 25, 10831–10843. Gessa, G.L., Devoto, P., Diana, M., Flore, G., Melis, M., Pistis, M., 2000. Dissociation of haloperidol, clozapine, and olanzapine effects on electrical activity of mesocortical dopamine neurons and dopamine release in the prefrontal cortex. Neuropsychopharmacology 22, 642–649. Goff, D.C., Coyle, J.T., 2001. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am. J. Psychiatry 158, 1367–1377. Granon, S., Passetti, F., Thomas, K.L., Dalley, J.W., Everitt, B.J., Robbins, T.W., 2000. Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex. J. Neurosci. 20, 1208–1215. Gurden, H., Takita, M., Jay, T.M., 2000. Essential role of D1 but not D2 receptors in the NMDA receptor-dependent long-term potentiation at hippocampal–prefrontal cortex synapses in vivo. J. Neurosci. 20, RC106. Hauber, W., 1993. Clozapine improves dizocilpine-induced delayed alteration impairment in rats. J. Neural Transm. Gen. Sect. 94, 223–233. Herry, C., Garcia, R., 2002. Prefrontal cortex long-term potentiation, but not long-term depression, is associated with the maintenance of extinction of learned fear in mice. J. Neurosci. 22, 577–583. Jaskiw, G.E., Collins, K.A., Pehek, E.A., Yamamoto, B.K., 2001. Tyrosine augments acute clozapine- but not haloperidol-induced dopamine release in the medial prefrontal cortex of the rat: an in vivo microdialysis study. Neuropsychopharmacology 25, 149–156. Jay, T.M., Burette, F., Laroche, S., 1995. NMDA receptor-dependent long-term potentiation in hippocampal afferent fibre system to the prefrontal cortex in the rat. Eur. J. Neurosci. 7, 247–250.
BR A IN RE S E A RCH 1 1 95 ( 20 0 8 ) 5 0 –5 5
Javitt, D.C., 2001. Management of negative symptoms of schizophrenia. Curr. Psychiatry Rep. 3, 413–417. Lynch, M.R., 1992. Schizophrenia and the D1 receptor: focus on negative symptoms. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 16, 797–832. Malhotra, A.K., Adler, C.M., Kennison, S.D., Elman, I., Pickar, D., Breier, A., 1997. Clozapine blunts N-methyl-D-aspartate antagonist-induced psychosis: a study with ketamine. Biol. Psychiatry 42, 664–668. Matsumoto, M., Togashi, H., Kaku, A., Kanno, M., Tahara, K., Yoshioka, M., 2005. Cortical GABAergic regulation of dopaminergic responses to psychological stress in the rat dorsolateral striatum. Synapse 56, 117–121. Murphy, B.L., Arnsten, A.F.T., Goldman-Rakic, P.S., Roth, R.H., 1996. Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. Proc. Natl. Acad. Sci. U. S. A. 93, 1325–1329. Otani, S., 2002. Memory trace in prefrontal cortex: theory for the cognitive switch. Biol. Rev. Camb. Philos. Soc. 77, 563–577. Paxinos, G., Watson, C., 1986. The Rat Brain in Stereotaxic Coordinates, 2nd ed. Academic Press, New York. Pratt, W.E., Mizumori, S.J., 2001. Neurons in rat medial prefrontal cortex show anticipatory rate changes to predictable differential rewards in a spatial memory task. Behav. Brain Res. 123, 165–183. Seamans, J.K., Floresco, S.B., Phillips, A.G., 1998. D1 receptor modulation of hippocampal–prefrontal cortical circuits integrating spatial memory with executive functions in the rat. J. Neurosci. 18, 1613–1621.
55
Seamans, J.K., Durstewitz, D., Christie, B.R., Stevens, C.F., Sejnowski, T.J., 2001. Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons. Proc. Natl. Acad. Sci. U. S. A. 98, 301–306. Takita, M., Izaki, Y., Jay, T.M., Kaneko, H., Suzuki, S.S., 1999. Induction of stable long-term depression in vivo in the hippocampal–prefrontal cortex pathway. Eur. J. Neurosci. 11, 4145–4148. van der Heijden, F.M., Tuinier, S., Fekkes, D., Sijben, A.E., Kahn, R.S., Verhoeven, W.M., 2004. Atypical antipsychotics and the relevance of glutamate and serotonin. Eur. Neuropsychopharmacol. 14, 259–265. Wang, J., O'Donnell, P., 2001. D1 dopamine receptors potentiate NMDA-mediated excitability increase in layer V prefrontal cortical pyramidal neurons. Cereb. Cortex 11, 452–462. Watanabe, M., Hagino, Y., 1999. The atypical antipsychotic sertindole enhances efflux of dopamine and its metabolites in the rat cortex and striatum. Eur. J. Pharmacol. 367, 19–23. Westerink, B.H., de Boer, P., de Vries, J.B., Kruse, C.G., Long, S.K., 1998. Antipsychotic drugs induce similar effects on the release of dopamine and noradrenaline in the medial prefrontal cortex of the rat brain. Eur. J. Pharmacol. 361, 27–33. Williams, G.V., Goldman-Rakic, P.S., 1995. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376, 572–575. Zheng, P., Zhang, X.X., Bunney, B.S., Shi, W.X., 1999. Opposite modulation of cortical N-methyl-D-aspartate receptor-mediated responses by low and high concentrations of dopamine. Neuroscience 91, 527–535.