The effect of serotonin1A receptor agonism on antipsychotic drug-induced dopamine release in rat striatum and nucleus accumbens

Brain Research 858 Ž2000. 252–263 www.elsevier.comrlocaterbres

Research report

The effect of serotonin 1A receptor agonism on antipsychotic drug-induced dopamine release in rat striatum and nucleus accumbens Junji Ichikawa ) , Herbert Y. Meltzer The First Floor Laboratory, Psychopharmacology DiÕision, Departments of Psychiatry and Pharmacology, Vanderbilt UniÕersity School of Medicine, 1601 23rd AÕenue South, Suite 306, The Psychiatric Hospital at Vanderbilt, NashÕille, TN 37212, USA Accepted 9 November 1999

Abstract Serotonin Ž5-HT.1A receptor agonism may be of interest in regard to both the antipsychotic action and extrapyramidal symptoms ŽEPS. of antipsychotic drugs ŽAPD. based, in part, on the effect of 5-HT1A receptor stimulation on the release of dopamine ŽDA. in the nucleus accumbens ŽNAC. and striatum ŽSTR., respectively. We investigated the effect of RŽq.-8-hydroxy-2-Ždi-n-propylamino.-tetralin Ž R Žq.-8-OH-DPAT. and n-w2-w4-Ž2-methoxyphenyl.-1-piperazinylxethylx-n-Ž2-pyridinyl.cyclohexanecarboxamide trihydrochloride ŽWAY100635., a selective 5-HT1A receptor agonist and antagonist, respectively, on basal and APD-induced DA release. In both STR and NAC, RŽq.-8-OH-DPAT Ž0.2 mgrkg. decreased basal DA release; RŽq.-8-OH-DPAT Ž0.05 mgrkg. inhibited DA release produced by the 5-HT2ArD 2 receptor antagonists clozapine Ž20 mgrkg., low dose risperidone Ž0.01 and 0.03 mgrkg. and amperozide Ž10 mgrkg., but not that produced by high dose risperidone Ž0.1 and 1.0 mgrkg. or haloperidol Ž0.01–1.0 mgrkg., potent D 2 receptor antagonists. This RŽq.-8-OH-DPAT-induced inhibition of the effects of clozapine, risperidone and amperozide was antagonized by WAY100635 Ž0.05 mgrkg.. WAY100635 Ž0.1–0.5 mgrkg. alone increased DA release in the STR but not NAC. The selective 5-HT2A receptor antagonist M100907 Ž1 mgrkg. did not alter the effect of RŽq.-8-OH-DPAT or WAY100635 alone on basal DA release in either region. These results suggest that 5-HT1A receptor stimulation inhibits basal and some APD-induced DA release in the STR and NAC, and that this effect is unlikely to be mediated by an interaction with 5-HT2A receptors. The significance of these results for EPS and antipsychotic action is discussed. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Typical and atypical antipsychotic drug; Dopamine release; 5-HT1A receptor; 5-HT2A receptor; Nucleus accumbens and striatum; In vivo microdialysis; Rat

1. Introduction The role of serotonin Ž5-HT.1A receptor agonism w14x in the action of antipsychotic drugs ŽAPD. has attracted limited attention compared to 5-HT2A receptor antagonism w39x, which is a feature common to all recently approved APD in the United States. However, several APD such as clozapine w46x, nemonapride w3x, ziprasidone w54x and S16924 w42–44x which are 5-HT2A rdopamine ŽDA. D 2 receptor antagonists, also have significant 5-HT1A receptor agonist properties. 5-HT2A receptor antagonists and 5-HT1A receptor agonists may have synergistic effects w68x. For

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example, acute administration of ritanserin or ketanserin, 5-HT2A receptor antagonists, increased the 5-HT1A behavioral syndrome w4x. On the other hand, the head twitch response in rats to DOI, a 5-HT2Ar2C receptor agonist, given into the medial prefrontal cortex ŽmPFC. was attenuated by Ž".-8-hydroxy-2-Ždi-n-propylamino.-tetralin Ž8OH-DPAT., a 5-HT1A receptor agonist, and potentiated by the 5-HT1A receptor antagonist n-w2-w4-Ž2-methoxyphenyl.-1 - piperazinylxethylx- n - Ž2 - pyridinyl.cyclohexanecarboxamide trihydrochloride ŽWAY100635. w64x. There is also evidence for an interaction of 5-HT1A receptors with D 2 receptors, e.g., the selective 5-HT1A receptor agonist Ž".-8-OH-DPAT, and the D 2 receptor antagonist raclopride, synergistically suppressed conditioned avoidance, a model for antipsychotic activity w62x. We reported that the active enantiomer RŽq.-8-OH-DPAT potentiated DA release in the mPFC and nucleus accumbens ŽNAC. pro-

0006-8993r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 9 . 0 2 3 4 6 - X

J. Ichikawa, H.Y. Meltzerr Brain Research 858 (2000) 252–263 Table 1 DA and 5-HT binding affinity and uptake inhibition of APD The p K i values for D 2 and 5-HT2A receptors are from Meltzer et al. w41x and for 5-HT1A receptors are from Schotte et al. w53x, respectively. The K i values ŽmM. for w3 HxDA and w3 Hx5-HT uptake are from Leysen et al. w34x and a Pettersson w50x, respectively. Receptor affinity: p K i

Uptake: K i ŽmM.

D2

5-HT1A

DA

5-HT

Amperozide

6.3

5.9

8.0

Clozapine Risperidone Haloperidol

7.0 8.9 9.0

6.7 6.6 5.5

8.3 10.1 7.7

0.33, 1.05a )10 5.01 1.48

0.13, 0.32 a 5.45 0.58 0.84

Drug

5-HT2A

duced by SŽy.-sulpiride, a D 2 receptor antagonist w26x. These results suggest that 5-HT2A and D 2 antagonism, and

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5-HT1A receptor agonism may have synergistic effects in the mPFC and NAC. However, this may not be the case in the striatum ŽSTR. because 5-HT1A receptor agonists have been reported to reduce the effects of the two D 2 receptor antagonists, raclopride- and haloperidol-induced catalepsy in rodents w63x and primates w8,10x, models for extrapyramidal symptoms ŽEPS. w21x that are related to DA receptor blockade. Thus, 5-HT1A receptor agonism would be expected to contribute to antipsychotic activity by potentiating the effects of 5-HT2A rD 2 receptor antagonists in the NAC and to reduce EPS due to effects in the STR. We have recently reported that the atypical APD, clozapine, olanzapine and amperozide preferentially increased DA release in the mPFC compared to NAC whereas the typical APD haloperidol and SŽy.-sulpiride showed the opposite preference w32x. Similarly, 5-HT1A receptor agonists have been reported to preferentially increase DA

Fig. 1. Effects of the selective 5-HT1A receptor agonist RŽq.-8-OH-DPAT and its selective antagonist WAY100635 on DA release in the NAC and STR. ŽA. RŽq.-8-OH-DPAT significantly decreased DA release in both regions at 0.2 Žopen triangles. Ž F Ž1,10. s 10.2, p - 0.01; F Ž1,10. s 9.3, p - 0.01, respectively. but not 0.05 Žopen circles. and 0.1 Žclosed circles. mgrkg, compared to vehicle controls Žopen squares, VEH.. ŽB. WAY100635 significantly increased DA release in the STR at 0.1 Žclosed circles. Ž F Ž1,10. s 15.9, p - 0.01., 0.2 Žopen triangles. Ž F Ž1,11. s 16.2, p - 0.01. and 0.5 Žclosed triangles. Ž F Ž1,9. s 17.9, p - 0.01. but not 0.05 Žopen circles. mgrkg while having no effects on DA release in the NAC, compared to vehicle controls Žopen squares, VEH.. Each data point represents the group mean " S.E.M. of the dialysate DA levels in 30-min samples, expressed as a percentage of each pre-drug baseline DA values Ž n s 4–6.. The arrows indicate drug injection times.

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release in the mPFC w31,52,61x. This preference or selective facilitation of DA release in the mPFC may contribute to some of the unique therapeutic advantages of atypical APD. We have reported that amperozide, a 5-HT2A receptor antagonist and RŽq.-8-OH-DPAT, both inhibits amphetamine-induced DA release in the NAC w23,24x. The anxiolytic drug, buspirone, a 5-HT1A receptor partial agonist, also inhibited amphetamine-induced hyperlocomotion in rodents w19x, a model for psychotic symptoms w55x. Attenuation of stimulated DA release in the NAC by 5-HT2A receptor antagonism andror 5-HT1A receptor agonism as well as facilitation of DA release in the mPFC by 5-HT1A receptor agonism w26x would be beneficial in the treatment of schizophrenia w13,40x. Sumiyoshi et al. w59x

have recently reported that tandospirone, a 5-HT1A receptor agonist, improved some elements of memory functions in haloperidol-treated patients with schizophrenia. We have extended these earlier findings in the present study which tested the hypothesis that RŽq.-8-OH-DPAT attenuates APD-induced DA release in the NAC and STR, due to an interaction with 5-HT2A rD 2 receptor antagonism. 2. Materials and methods 2.1. Animals Male Sprague–Dawley albino rats ŽZivic-Miller, PA. weighing 250–350 g were housed two per cage and main-

Fig. 2. Effects of WAY100635 on the ability of RŽq.-8-OH-DPAT to decrease DA release in the NAC and STR. ŽA. WAY100635 Ž0.05 mgrkg. completely reversed the decrease in DA release in the NAC and STR produced by RŽq.-8-OH-DPAT Ž0.2 mgrkg., compared to RŽq.-8-OH-DPAT Ž0.2 mgrkg. alone Ž F Ž1,9. s 7.7, p s 0.02; F Ž1,8. s 5.8, p s 0.04, respectively. and vehicle controls Žopen squares, VEH–VEH. Ž F Ž1,9. s 0.3, p s 0.61; F Ž1,10. s 0.4, p s 0.54, respectively.. Each data point represents the group mean" S.E.M. of the dialysate DA levels in 30-min samples, expressed as a percentage of each pre-drug baseline DA values Ž n s 4–6.. The arrows indicate drug injection times. ŽB. Effects of RŽq.-8-OH-DPAT on DA release are shown in the %net-AUC in the NAC Žopen circles. and STR Žclosed circles. ŽNACrSTR. at dose Žmgrkg. of 0.05 Ž33 " 37r6 " 26., 0.1 Ž22 " 36r2 " 25. and 0.2 Žy135" 42ry 142 " 52., respectively, compared to vehicle controls Ždose 0. Ž13 " 21r8 " 21.. RŽq.-8-OH-DPAT Ž8-OH-DPAT, 0.2 mgrkg.-induced decrease in DA release in the NAC and STR was completely reversed by WAY100635 ŽWAY, 0.05 mgrkg. Žopen triangles, NAC and closed triangles, STR.. ŽC. The %net-AUC Žarea under the curve. clearly illustrates that WAY100635 selectively increased DA release in the STR at dose Žmgrkg. of 0.1, 0.2 and 0.5 but not 0.05, respectively, compared to vehicle controls Ždose 0.. Each data point represents the group mean " S.E.M. of the %net-AUC of six samples of the dialysate DA levels during 180 min following drug injections. Asterisks ŽU . indicate significant differences from vehicle controls Ždose 0. Ž p - 0.05..

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tained in a controlled 12–12 h light–dark cycle and under constant temperature at 228C, with free access to food and water. 2.2. Surgery and microdialysis Rats were anesthetized with a combination Ži.p.. of xylazine Ž6 mgrkg, Rompun w , Miles, KA. and ketamine hydrochloride Ž70 mgrkg, Ketaset w , Fort Dodge Lab., IA. and mounted in a stereotaxic frame ŽStoetling, Wood Dale, IL.. Two stainless 21-gauge guide cannula with a dummy probe were placed and fixed by cranioplastic cement ŽPlastic One, Roanoke, VA. onto the cortex dorsal both to the STR and NAC. Stereotaxic coordinates of each probe

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when implanted is A: q0.5, L: y4.0, V: y5.5 for the STR and A: q2.0, L: q1.5–1.7, V: y7.5 mm for the NAC, respectively, relative to bregma; incision bar level: y3.0 mm, according to the atlas of Paxinos and Watson w49x. Because of the probe size used in this study, it is likely that the dialyzed area included the shell and core of the NAC. However, dialysis probes were always implanted above or on the medial side of the anterior limb of the anterior commissure, a location which may indicate preference for the shell of the NAC. Concentric-shaped dialysis probes were constructed according to the method of Kuroki et al. w32x. In brief, a silica-glass capillary tube Ž150 mm o.d., 75 mm i.d., Polymicro Technologies, Phoenix, AZ. was inserted through the inner bore of a 25-G stainless tube. The

Fig. 3. Effects of the selective 5-HT2A receptor antagonist M100907 Ž1 mgrkg. on RŽq.-8-OH-DPAT Ž8-OH-DPAT. and WAY100635 ŽWAY.-induced changes in DA release in the NAC and STR. ŽA. M100907 Ž1 mgrkg. significantly increased DA release in the STR Ž F Ž1,9. s 18.1, p - 0.01. but not NAC Žopen triangles, M100907–VEH., compared to vehicle controls Žopen squares, VEH–VEH.. M100907 Ž1 mgrkg. had no effect on RŽq.-8-OH-DPAT Ž0.2 mgrkg.-induced decrease in DA release in the NAC. However, the effect of a combination of M100907 Ž1 mgrkg. and RŽq.-8-OH-DPAT Ž0.2 mgrkg. on DA release in the STR Žclosed circles, M100907–8-OH-DPAT. was significantly different from that of M100907 alone Ž F Ž1,10. s 8.2, p s 0.02., but not from RŽq.-8-OH-DPAT Ž0.2 mgrkg. alone Ž F Ž1,11. s 3.0, p s 0.11. Žopen circles, VEH–8-OH-DPAT. or vehicle controls Ž F Ž1,13. s 0.2, p s 0.65. Žopen squares, VEH–VEH.. ŽB. M100907 did not alter the effect of WAY100635 Ž0.1 mgrkg. on DA release in the NAC and STR. Each data point represents the group mean " S.E.M. of the dialysate DA levels in 30-min samples, expressed as a percentage of each pre-drug baseline DA values Ž n s 4–8.. The arrows indicate drug injection times ŽI and II..

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J. Ichikawa, H.Y. Meltzerr Brain Research 858 (2000) 252–263

stainless tube was inserted into a 28-G teflon tubing and then the teflon tubing was inserted into the inner bore of a 18-G stainless-tube. The hollow fiber dialysis membrane Žpolyacrylonitrilersodium methalylsulfonate polymer, 310 mm o.d., 220 mm i.d., molecular weight cutoff 40,000, AN69 HF, Hospal. was fitted over the glass capillary and into the end of the 25-G stainless tube and was glued with epoxy ŽDevkon 5-min epoxy w , Danverse, MA.. The exposed non-glued surface for dialyzing is 2 mm. Three to five days following cannulation, the dialysis probes were implanted into the STR and NAC under slight anesthesia with methoxyflurane ŽMetofane w , PitmanMoore, IL.. Rats were then housed individually overnight

in a dialysis cage. After the overnight perfusion Ž0.2 mlrmin. of the probe, the flow rate was increased to 0.8 mlrmin and then dialysate samples Ž24 ml. were collected every 30 min. The perfusion medium was Dulbecco’s phosphate buffered saline solution ŽSigma, St. Louis, MO. including Ca2q Ž138 mM NaCl, 8.1 mM Na 2 HPO4 , 2.7 mM KCl, 1.5 mM KH 2 PO4 , 0.5 mM MgCl, 1.2 mM CaCl 2 , pH s 7.4.. After obtaining stable baseline values in the dialysates, each drug or vehicle was administered to the rats. The location of the dialysis probes were verified at the end of each experiment by brain dissection. The procedures applied in these experiments were approved by the Institutional Animal Care and Use Committee of Case

Fig. 4. Effects of RŽq.-8-OH-DPAT Ž8-OH-DPAT, 0.05 mgrkg. on amperozide ŽAPZ, 10 mgrkg.- and clozapine ŽCLOZ, 20 mgrkg.-induced DA release in the NAC and STR. ŽA. Amperozide significantly increased DA release in the NAC Ž F Ž1,10. s 18.1, p - 0.01. and STR Ž F Ž1,10. s 11.6, p - 0.01. Žopen circles, VEH–APZ. compared to vehicle controls Žopen squares, VEH–VEH.. RŽq.-8-OH-DPAT Žclosed circles, 8-OH-DPAT–APZ. inhibited amperozide-induced DA release in the NAC Ž F Ž1,11. s 58.8, p - 0.01. and STR Ž F Ž1,10. s 30.4, p - 0.01. compared to amperozide alone and further decreased DA release in the NAC Ž F Ž1,11. s 8.1, p s 0.02. but not STR compared to vehicle controls. WAY100635 ŽWAY, 0.05 mgrkg., given 5 min prior to RŽq.-8-OH-DPAT, completely reversed this inhibition in both regions Žclosed triangles, WAYq 8-OH-DPAT–APZ.. ŽB. Clozapine significantly increased DA release in the NAC Ž F Ž1,11. s 8.1, p s 0.02. and STR Ž F Ž1,11. s 8.1, p s 0.02. Žopen circles, VEH–CLOZ. compared to vehicle controls Žopen squares, VEH–VEH.. RŽq.-8-OH-DPAT Žclosed circles, 8-OH-DPAT–CLOZ. inhibited clozapine-induced DA release in the NAC Ž F Ž1,13. s 15.5, p - 0.01. and STR Ž F Ž1,14. s 13.5, p - 0.01. compared to clozapine alone and had no difference from vehicle controls in either region. WAY100635 ŽWAY, 0.05 mgrkg., given 5 min prior to RŽq.-8-OH-DPAT, completely reversed this inhibition in both regions Žclosed triangles, WAY q 8-OH-DPAT–CLOZ.. Each data point represents the group mean" S.E.M. of the dialysate DA levels in 30-min samples, expressed as a percentage of each pre-drug baseline DA values Ž n s 6–8.. The arrows indicate drug injection times ŽI and II..

J. Ichikawa, H.Y. Meltzerr Brain Research 858 (2000) 252–263

Western Reserve University in Cleveland, OH, where we completed present studies. 2.3. Biochemical assay Dialysate samples were directly applied onto a HPLC with a 20-ml sample loop and analyzed for DA with an integrator ŽHP 3396A, Hewlett-Packard.. DA was separated on a stainless steel, reversed phase column ŽBDS Hypersil 3-mm C18, 2.0 = 100 mm, Keystone Scientific, Bellefonte, PA. at 358C maintained by column heater and temperature controller ŽLC-22C, BAS.. The mobile phase consisted of 32 mM citric acid anhydrous and sodium

257

acetate 54.3 mM containing EDTA–Na 2 Ž50 mgrl. and sodium octyl sulfate Ž180 mgrl, Kodak. adjusted to pH 4.2 with concentrated phosphoric acid, and 5% Žvrv. methanol and was pumped at the flow rate of 0.2 mlrmin by LC-10AD ŽShimadzu, Kyoto, Japan.. DA was detected by a dual glassy carbon working electrode ŽMF-1000, BAS. set at q0.55 V ŽLC-4C, BAS. vs. AgrAgCl reference electrode. Reagents used were analytical or HPLC grade. 2.4. Drugs RŽq.-8-OH-DPAT hydrobromide ŽRBI, Natick, MA., WAY100635 ŽSandoz, Basel, Switzerland. and amper-

Fig. 5. Effects of RŽq.-8-OH-DPAT Ž8-OH-DPAT, 0.05 mgrkg. on risperidone ŽRISP.-induced DA release in the NAC and STR. ŽA. Risperidone Ž0.01 mgrkg. significantly increased DA release in the NAC Ž F Ž1,11. s 11.5, p - 0.01. and STR Ž F Ž1,12. s 30.7, p - 0.01. Žopen circles, VEH–RISP. compared to vehicle controls Žopen squares, VEH–VEH.. RŽq.-8-OH-DPAT Žclosed circles, 8-OH-DPAT–RISP. significantly inhibited risperidone-induced DA release in the NAC Ž F Ž1,9. s 5.6, p s 0.04. and STR Ž F Ž1,11. s 11.1, p - 0.01. compared to risperidone alone and had no difference from vehicle controls in either region. WAY100635 ŽWAY, 0.05 mgrkg., given 5 min prior to RŽq.-8-OH-DPAT, completely reversed this inhibition in both regions Žclosed triangles, WAY q 8-OH-DPAT–RISP.. Each data point represents the group mean " S.E.M. of the dialysate DA levels in 30-min samples, expressed as a percentage of each pre-drug baseline DA values Ž n s 6–8.. The arrows indicate drug injection times ŽI and II.. ŽB. The %net-AUC Žarea under the curve. of DA release during 180 min Žsix samples. following risperidone Žopen circles, VEH–RISP. showed that risperidone Ž0.01, 0.03, 0.1 and 1 mgrkg. dose-dependently increased DA release in the NAC and STR, compared to vehicle controls Ždose 0. in the NAC and STR Ž p - 0.01.. RŽq.-8-OH-DPAT inhibited risperidone-induced DA release in the NAC and STR ŽNACrSTR. at dose of 0.01 Ž F Ž1,9. s 9.9, p s 0.01rF Ž1,11. s 11.1, p - 0.01. and 0.03 mgrkg Ž F Ž1,8. s 45.2, p - 0.01rF Ž1,9. s 18.7, p - 0.01. but not 0.1 and 1 mgrkg, respectively. Each data point represents the group mean " S.E.M. of the %net-AUC of six samples of the dialysate DA levels during 180 min following drug injections Ž n s 6–8.. Asterisks ŽU . indicate significant differences from correspondent dose effect of risperidone alone ŽVEH–RISP. Ž p - 0.05..

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ozide hydrochloride ŽPharmacia Leo Therapeutics, Malmo, ¨ Sweden. were dissolved in deionized water, respectively. Clozapine hydrochloride ŽSandoz., risperidone ŽRBI., haloperidol ŽMcNeil. and M100907 ŽMarion Merrell Dow, OH. were dissolved in 0.1 M tartaric acid solution, respectively. Vehicle or drugs were administered subcutaneously. The pH of each drug solution and vehicle may vary from 5 to 7. Receptor affinities and uptake inhibition of tested APD are summarized in Table 1. 2.5. Data analysis Only results derived from healthy rats with correctly positioned dialysis probes were included in the data analy-

sis. Mean pre-drug baseline levels Žtime y60, time y30 and time 0. were designated as 100%. The net-AUC Žarea under the curve. was calculated from the absolute net increase for a 180-min period Žsix samples. after subtracting each pre-drug baseline value. The %net-AUC is the net-AUC value expressed as a percentage of each baseline AUC value. Repeated measure ANOVA followed by Fisher’s protected least significant difference post-hoc pairwise comparison procedure and One-way ANOVA were used to determine group differences ŽStatView w 4.5 for the Macintosh.. A probability Ž p . of less than 0.05 was considered significant in this study. All results are given as mean " S.E.M.

Fig. 6. Effects of RŽq.-8-OH-DPAT Ž8-OH-DPAT, 0.05 mgrkg. and WAY100635 ŽWAY, 0.05 mgrkg. on haloperidol ŽHAL.-induced DA release in the NAC and STR. ŽA. Haloperidol Ž0.01 mgrkg. significantly increased DA release in the NAC Ž F Ž1,11. s 24.6, p - 0.01. and STR Ž F Ž1,15. s 19.6, p - 0.01. Žopen circles, VEH–HAL., compared to vehicle controls Žopen squares, VEH–VEH.. RŽq.-8-OH-DPAT Žclosed circles, 8-OH-DPAT–HAL. or WAY100635 Žopen triangles, WAY–HAL. did not significantly affected haloperidol-induced DA release in either NAC or STR. Each data point represents the group mean " S.E.M. of the dialysate DA levels in 30-min samples, expressed as a percentage of each pre-drug baseline DA values Ž n s 5–9.. The arrows indicate drug injection times ŽI and II.. ŽB. The %net-AUC Žarea under the curve. of DA release during 180 min Žsix samples. following haloperidol Žopen circles, VEH–HAL. showed that haloperidol Ž0.01, 0.03, 0.1 and 1 mgrkg. produced a significant and bell-shaped increase in DA release in the NAC and STR, compared to vehicle controls Ždose 0. in the NAC and STR Ž p - 0.01.. Significant increases in DA release produced by haloperidol at all doses tested were not affected by RŽq.-8-OH-DPAT Ž0.05 mgrkg. in the NAC and STR Žclosed circles, 8-OH-DPAT–HAL.. WAY100635 Ž0.05 mgrkg. had also no effect on haloperidol Ž0.01 and 0.03 mgrkg.-induced DA release in either region Žopen triangles, WAY–HAL.. Each data point represents the group mean " S.E.M. of the %net-AUC of six samples of the dialysate DA levels during 180 min following drug injections Ž n s 5–9..

J. Ichikawa, H.Y. Meltzerr Brain Research 858 (2000) 252–263

3. Results Statistical analysis data were shown in each figure legend. 3.1. Effect of R(q)-8-OH-DPAT and WAY100635 alone High dose RŽq.-8-OH-DPAT Ž0.2 mgrkg., a selective 5-HT1A receptor agonist, decreased DA release in the NAC and STR ŽFigs. 1A and 2B., an effect that was completely antagonized by WAY100635 Ž0.05 mgrkg., a selective 5-HT1A receptor antagonist w16x ŽFig. 2.. WAY100635 Ž0.1–0.5 mgrkg. alone increased DA release in the STR but not NAC ŽFigs. 1B and 2C.. 3.2. Effect of M100907 on R(q)-8-OH-DPAT and WAY100635 The selective 5-HT2A receptor antagonist M100907 increased DA release in the STR but not the NAC ŽFig. 3A.. This increase was attenuated by RŽq.-8-OH-DPAT. M100907 had no influence on the inhibitory or stimulatory effects of RŽq.-8-OH-DPAT or WAY100635, respectively, on DA release in the NAC and STR ŽFig. 3.. 3.3. Effect of R(q)-8-OH-DPAT on APD The increases in DA release in the NAC and STR produced by amperozide and clozapine were inhibited by RŽq.-8-OH-DPAT ŽFig. 4., an effect that was antagonized by WAY100635 in both regions. The ability of risperidone Ž0.01 and 0.03 but not 0.1 and 1 mgrkg. to increase DA release was inhibited by RŽq.-8-OH-DPAT in the NAC and STR ŽFig. 5.. This inhibition was also antagonized by WAY100635 in both regions. On the other hand, the ability of haloperidol to increase DA release in the NAC and STR was not affected by RŽq.-8-OH-DPAT or WAY100635 ŽFig. 6..

4. Discussion The present results demonstrate that the 5-HT1A receptor antagonist WAY100635 completely antagonized the decrease in DA release in the NAC and STR produced by the 5-HT1A receptor agonist RŽq.-8-OH-DPAT, suggesting 5-HT1A receptor stimulation decreases DA release in both regions. This is consistent with the findings that systemic administration of Ž".-8-OH-DPAT Ž0.225 mgrkg. w52x decreased striatal DA release, and that administration of RŽq.-8-OH-DPAT by reverse microdialysis decreased DA release in the NAC and STR w47x. However, reverse microdialysis of Ž".-8-OH-DPAT has also been reported to increase striatal DA release w5,6,17x. Racemic Ž".-8-OH-DPAT is a 5-HT1A receptor partial agonist w7,11x; as such, it would be expected to antagonize post-

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synaptic 5-HT1A receptors at some doses and like WAY100635, increase striatal DA release Žpresent data.. This increase may be relevant to the ability of WAY100635 to induce mild behavioral activation in rats w28x. Another 5-HT1A receptor antagonist SŽy.-UH301 has been reported to decrease DA release in the NAC and STR following systemic administration Ž2.5 mgrkg. and reverse microdialysis Ž1 mM., respectively w47x. This is likely due, in part, to its D 2 receptor agonist effect w2x, which would also be expected to inhibit DA release. The ability of RŽq.-8-OH-DPAT to decrease DA release in the NAC and STR is likely due to stimulation of 5-HT1A receptors in these regions, as was demonstrated by reverse microdialysis w47x and discussed in our previous reports w24,26x. Reduction of DA synthesis in the NAC w1x and STR w29x produced by Ž".-8-OH-DPAT may partly contribute to the decrease in DA release in the NAC and STR, respectively. Conversely, 5-HT1A receptor blockade by WAY100635 would be expected to increase DA synthesis, leading to increased striatal DA release Žpresent data.. However, the difference between the effect of WAY100635 on DA release in the NAC and STR is unexplained at present. Thus, 5-HT1A receptors may regulate DA release in the STR and NAC via different mechanisms. It should be noted that postmortem studies demonstrated regionally specific increases in the density of 5-HT1A receptors in patients with schizophrenia w18,20,58x. This increase could be a response to enhanced 5-HT2A receptor stimulation in schizophrenia, whose function is to neutralize that enhancement by increased 5-HT1A receptor stimulation. If this is the case, 5-HT1A receptor agonists could be clinically useful in schizophrenia by further antagonizing 5HT2A receptor stimulation through this interaction. There is now clinical evidence to support this w59x. This may also contribute to the efficacy of clozapine, ziprasidone, quetiapine and nemonapride which also have 5-HT1A receptor agonist properties Žsee Introduction.. The DA release in the STR and NAC produced by haloperidol and high dose risperidone was not affected by 5-HT1A receptor stimulation or blockade. This is in agreement with a previous report that Ž".-8-OH-DPAT Ž0.1 mgrkg. did not affect haloperidol Ž1 mgrkg.-induced striatal DA release, despite reducing catalepsy w36x. This would suggest a dissociation between the anticataleptic effect of 5-HT1A receptor agonists w63x and striatal DA release. On the other hand, the mixed 5-HT2Ar2C receptor antagonist ritanserin and SR46349B, a 5-HT2A receptor antagonist, have been reported to attenuate haloperidol Ž0.01 but not 0.1 or 1 mgrkg.-induced striatal DA release w56x, suggesting the 5-HT2A receptor involvement in the ability of low dose haloperidol to increase striatal DA release. Interestingly, haloperidol produced a bell-shaped increase in DA release in the STR and NAC, in accord with some reports w15,66,67x. The ability of haloperidol to increase DA release may be attenuated at high dose via the mechanismŽs. other than D 2 receptor blockade. Sumiyoshi

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et al. w59x have recently reported preliminary data that a concomitant use of the 5-HT1A receptor agonist tandospirone and haloperidol improved memory functions in schizophrenia and had no significant effects on negative or positive symptoms. This would be consistent with the inability of RŽq.-8-OH-DPAT on haloperidol-induced DA release in the NAC Žpresent results.. The ability of RŽq.-8-OH-DPAT to reverse low, but not high dose risperidone-induced DA release, in both the STR and NAC, is of particular clinical interest since lower efficacy to treat psychosis as well as more EPS has been reported at higher doses of risperidone w9,35x. The ability of low dose risperidone and haloperidol to increase DA release may not be entirely related to the level of D 2 receptor occupancy because 0.01 mgrkg of haloperidol and risperidone, but not clozapine Ž1 mgrkg, unpublished data., increased DA release in the STR and NAC, despite producing similar low striatal D 2 receptor occupancy Žapproximately 5–10%. to that of clozapine Ž0.63 mgrkg. w53x. RŽq.-8-OH-DPAT had no effect on the DA release in the STR and NAC produced by high dose risperidone which produces higher postsynaptic D 2 receptor occupancy w39x and perhaps higher D 2 autoreceptor occupancy as well. Taken together, the ability of RŽq.-8-OH-DPAT Ž0.05 mgrkg. to inhibit APD-induced DA release is unlikely to be mediated by the effect of 5-HT1A receptor stimulation on D 2 receptor blockade by APD, at least, in the NAC and STR. Amperozide Ž5 mgrkg., clozapine Ž5–30 mgrkg. and risperidone Ž0.25–3 mgrkg. preferentially occupies 5HT2A receptors whereas haloperidol preferentially occupies D 2 receptors in rodents w39,57x. The difference in the occupancy of 5-HT2A and D 2 receptors produced by risperidone becomes smaller as the dose is increased w39x, suggesting greater occupancy of 5-HT2A compared to D 2 receptors at lower doses. Thus, preferential blockade of 5-HT2A compared to D 2 receptors may contribute to the ability of RŽq.-8-OH-DPAT to inhibit amperozide, clozapine and low dose risperidone-induced DA release. These findings underline the importance of low occupancy of D 2 receptors with risperidone, and are consistent with the clinical data that risperidone is more effective and better tolerated at low than high doses w37x. 5-HT2A receptor antagonists and 5-HT1A receptor agonists have synergistic effects Žsee Introduction. and high dose RŽq.-8-OH-DPAT Ž0.2 mgrkg. can decrease DA release in the NAC and STR Žpresent results.. We have recently reported that the selective 5-HT2A receptor antagonist M100907 potentiated the ability of RŽq.-8-OH-DPAT to increase DA release in the mPFC w27x. Therefore, it is possible that a combination of 5-HT2A receptor blockade and low dose RŽq.-8-OHDPAT Ž0.05 mgrkg., which by itself has no effect on DA release, decreases DA release in the NAC and STR. However, M100907 had no effect on the ability of RŽq.-8OH-DPAT and WAY100635 to increase or decrease DA release in the NAC and STR Žpresent results.. The possi-

bility remains that the ability of RŽq.-8-OH-DPAT Ž0.2 mgrkg. to decrease DA release in the NAC is already maximum and would not be further affected by additional 5-HT2A receptor blockade. It is also notable that RŽq.-8OH-DPAT Ž0.2 mgrkg. attenuated the ability of M100907 to increase striatal DA release, although this inhibition may reflect a direct effect of RŽq.-8-OH-DPAT to decrease DA release rather than an inhibition of the effect of M100907 per se. Further studies are needed to resolve these conflicting results. Stimulation of 5-HT1A receptors is also reported to decrease acetylcholine release in the NAC w51x and increase norepinephrine release in the hypothalamus w60x and hippocampus w22x. RŽq.-8-OH-DPAT could inhibit clozapine-induced DA release by decreasing clozapine-induced acetylcholine release in the STR and NAC w48x because exogeneous acetylcholine has been reported to increase DA release in these regions w12x. The ability of clozapine and amperozide to increase 5-HT release in the NAC w25x and to inhibit the uptake of DA and 5-HT ŽTable 1. should also be considered. The increase in 5-HT release produced by amperozide and clozapine could contribute to their effects on DA release since endogenous 5-HT may increase DA release w38x. Consequently, a decrease in 5-HT release by RŽq.-8-OH-DPAT in the NAC w61x and STR w30x could attenuate the ability of amperozide and clozapine to increase DA release. The possible involvement of either of these neurotransmitters or the combination, in the mechanismŽs. underlying the effect of RŽq.-8-OH-DPAT on DA release in the STR and NAC produced by amperozide, clozapine, and low dose risperidone needs to be examined in future studies. The results reported here suggest that 5-HT1A receptor agonist activity may be useful to decrease psychosis by diminishing APD-induced DA release in the NAC in patients treated with clozapine or low dose risperidone but not with high dose risperidone or typical APD. These results suggest that 5-HT1A receptor partial agonists, e.g., buspirone, gepirone or ipsapirone w13x or the full agonist flesinoxan w33,45,65x and tandospirone w59x may be useful auxiliary agents for partial responders to clozapine or other atypical APD. Putative APD such as S16924 w42–44x are being developed which are 5-HT1A receptor agonists and D 2 antagonists, albeit with activity at other receptors as well. These agents may provide as useful or even more effective than 5-HT2A rD 2 receptor antagonist-based atypical APD in at least some patients. However, it may be preferable to achieve 5-HT1A receptor stimulation in schizophrenia by supplemental 5-HT1A receptor agonist treatment rather than via incorporation within a molecule that is also a D 2 , 5-HT2A rD 2 ,or D4 receptor antagonist, in order to achieve the appropriate balance between the various pharmacological effects in the majority of patients. Preliminary data demonstrated that concomitant use of the 5-HT1A receptor agonist tandospirone with haloperidol improved some elements of memory functions in

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schizophrenic patients, and did not reduce psychotic symptoms w59x. Lack of the effect of tandospirone added to haloperidol on psychotic symptoms may be consistent with the ability of RŽq.-8-OH-DPAT not to attenuate haloperidol-induced DA release in the NAC Žpresent data.. The clinical significance of 5-HT1A receptor agonist activity on the striatal and accumbal DA release requires clinical testing at this point to determine whether this principle provides the same or a different range of action as 5HT2A rD 2 receptor antagonist.

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Acknowledgements w17x

We are greatful to Mr. Michael T. Kitchen for an excellent laboratory assistance.

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