5-HT2 receptor regulation of acetylcholine release induced by dopaminergic stimulation in rat striatal slices

Brain Research 757 Ž1997. 17–23

Research report

5-HT2 receptor regulation of acetylcholine release induced by dopaminergic stimulation in rat striatal slices M.J. Ramırez, ´ E. Cenarruzabeitia, B. Lasheras, J. Del Rio

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Department of Pharmacology, School of Medicine, UniÕersity of NaÕarra, 31080 Pamplona, Spain Accepted 26 November 1996

Abstract The role of 5-hydroxytryptamine Ž5-HT. receptor subtypes in acetylcholine ŽACh. release induced by dopamine or neurokinin receptor stimulation was studied in rat striatal slices. The dopamine D1 receptor agonist SKF 38393 potentiated in a tetrodotoxin-sensitive manner the Kq-evoked w 3 HxACh release while SCH 23390, a dopamine D1 receptor antagonist, had no effect. w 3 HxACh release was decreased by the dopamine D 2 receptor agonist LY 171555 Žquinpirole. and slightly potentiated by the dopamine D 2 receptor antagonist haloperidol. The selective neurokinin NK 1 receptor agonist wSar 9, metŽO 2 .11 xSP also potentiated Kq-evoked release of w 3 HxACh. GR 82334, a NK 1 receptor antagonist, blocked not only the effect of wSar 9, metŽO 2 .11 xSP but also the release of ACh induced by the D1 receptor agonist SKF 38393. Among the 5-HT agents studied, only the 5-HT2A receptor antagonists ketanserin and ritanserin were able to reduce the ACh release induced by dopamine D1 receptor stimulation. Mesulergine, a more selective 5-HT2C antagonist, showed an intrinsic releasing effect but did not affect Kq-evoked ACh release induced by SKF 38393. Methysergide and methiothepin, mixed 5-HT1r2 antagonists, as well as ondansetron, a 5-HT3 receptor antagonist, showed an intrinsic effect on ACh release, their effects being additive to that of SKF 38393. 5-HT2 receptor agonists were ineffective. However, the 5-HT2 agonist DOI was able to prevent the antagonism by ketanserin of the increased w 3 HxACh efflux elicited by SKF 38393, suggesting a permissive role of 5-HT2A receptors. None of the above indicated 5-HT agents was able to reduce the ACh release induced by the selective NK 1 agonist. The results suggest that 5-HT2 receptors, probably of the 5-HT2A subtype, modulate the release of ACh observed in slices from the rat striatum after stimulation of dopamine D1 receptors. It seems that this serotonergic control is exerted on the interposed collaterals of substance P-containing neurons which promote ACh efflux through activation of NK 1 receptors located on cholinergic interneurons. Keywords: Acetylcholine release; Dopamine receptor; Neurokinin; 5-HT2 receptor; Striatum

1. Introduction Cholinergic neurons in the striatum only represent a small population w23x but are able to modulate the excitability in this brain region due to their widespread axonal fields and high sensitivity to small depolarizing potentials w44x. The use of cholinergic antagonists in the treatment of Parkinson’s disease and the extrapyramidal side effects associated to antipsychotic therapy suggests that cholinergic neurons play a role in basal ganglia physiology and pathophysiology, although the precise mechanisms involved are still elusive w1x.

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On the basis of in vitro and in vivo acetylcholine ŽACh. release studies, it was proposed that dopamine controls cholinergic transmission in a facilitatory manner through D 1 receptors, and in an inhibitory manner through D 2 receptors w8,13,15,32x. Dopamine may facilitate ACh release not only by direct stimulation of D 1 receptors located on cholinergic neurons w25x but also by an indirect intrastriatal mechanism through interposed substance P ŽSP. neurons receiving dopaminergic input, and synapsing via collaterals with ACh neurons that are reportedly the only striatal neurons expressing neurokinin NK 1 receptors for SP w21x. Dopamine, by acting on D 1 receptors would stimulate the firing of SP neurons, and the released SP would activate ACh neurons. Previous in vitro and in vivo studies showed that neurokinins ŽSP, neurokinin A and neurokinin B. were able to promote ACh release, although

0006-8993r97r$17.00 Copyright q 1997 Elsevier Science B.V. All rights reserved. PII S 0 0 0 6 - 8 9 9 3 Ž 9 6 . 0 1 4 3 4 - 5

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M.J. Ramırez ´ et al.r Brain Research 757 (1997) 17–23

the receptor involved in this effect has been controversial w4,5,35,39x. There is a great deal of evidence suggesting that 5-hydroxytryptamine Ž5-HT. controls the cholinergic system within the striatum w12,22x and anatomical studies have shown that 5-HT-containing neurons from the mesencephalic raphe nuclei innervate the striatum w33,41x. There are also many behavioural, electrophysiological and neurochemical data on the modulation of the dopaminergic system by 5-HT w7,36,46x. Accordingly, 5-HT could also control ACh released by dopamine receptor stimulation. The present study was designed to examine the role of 5-HT receptor subtypes in ACh release from rat striatal slices. Previous studies in peripheral tissues showed the existence of a 5-HT control on ACh release induced by neurokinin NK 3 receptor stimulation w37x. In the present work we have investigated the possibility of a modulatory influence of 5-HT on ACh release induced by neurokinin and dopamine receptor stimulation in rat striatum. The results suggest that 5-HT2 receptors may control ACh release evoked by dopamine D 1 receptor but not by neurokinin receptor stimulation.

2. Materials and methods 2.1. Preparation of brain slices Corpora striata from male Wistar rats Ž200–250 g. were dissected and cut sagitally into 500 mm slices which were washed with gassed Ž95% O 2r5% CO 2 . Krebs-Ringer bicarbonate buffer ŽKRB. of the following composition in mmolrl: NaCl 113; KCl 4.75; CaCl 2 2.52; MgSO4 1.19; NaH 2 PO4 1.18; NaHCO 3 25; Glucose 10; pH s 7.4. After washing, the KRB was replaced by one containing 40 mM KCl Žosmolarity was maintained by reducing the NaCl concentration. and the slices were shaken at 378C for 20 min. The slices were then incubated for 40 min at 378C with w 3 Hxcholine Ž3 mlrml, 81 Cirmmol.. 2.2. Superfusion protocol Four to six striatal slices were added to each chamber of a Brandel Superfusion 1000 apparatus. Slices were superfused at 0.45 mlrmin with KRB containing 1 mM hemicholinium-3, and after a 30 min equilibration period, 3-min samples of superfusate were collected. The superfusate samples were collected for a total of 60 min. w 3 HxACh release was stimulated from the outflow of tritium from the tissue into the superfusate, since tritium overflow has been shown to reflect the behaviour of actual w 3 HxACh released w6x.

a KRB solution containing 20 mM KCl. The total tritium overflow in response to 20 mM KCl during a 6 min stimulation was usually between 200 and 300% of the baseline release. All test drugs were added 15 min before S2. S1 and S2 were calculated as Kq-stimulated tritium increase beyond basal efflux. The results were expressed as S2rS1 ratio. In order to discard the possible influence of drugs on the basal Žspontaneous. tritium efflux, the theoretical value for the basal efflux prior to S2 stimulation was calculated in control experiments. The basal efflux before S2 was corrected from this theoretical value obtained in control experiments. 2.4. Data analysis The significance of the difference between two groups was assessed using Student’s t-test. The significance between several groups was assessed by ANOVA followed by Tukey test. 2.5. Drugs and chemicals The following drugs were used: methyl-w 3 Hxcholine ŽNEN Du Pont.; hemicholinium-3 bromide, tetrodotoxin Ž Sigm a . ; ondansetron Ž G laxo . ; m -C PP Ž 1- Ž 3chlorophenyl.piperazine dihydrochloride., cyproheptadine hydrochloride, DOI Ž1-Ž2,5-dimethoxy-4-iodophenyl.-2amino-propane., mesulergine chloride, methiothepin mesylate, 8-OH-DPAT Ž8-hydroxy-2-Ždi-n-propylamino. tetraline., ritanserin, wSar9, MetŽO 2 .11xSP, GR 82334 ŽpGluAla-Asp-Pro-Asn-Lys-Phe-Tyr-ProŽspiro-g-lactam.LeuTrp-NH 2 ., senktide, haloperidol, LY 171555 Žquinpirole., SCH 23390 ŽRŽq . 7-chloro-8-hydroxy-3-methyl-1phenyl-2, 3, 4, 5-tetrahydro-1H-3-benzazepine hydrochloride., SKF 38393 Ž1-phenyl-2, 3, 4, 5-tetrahydro-Ž1H.-3benzazepine-7, 8-diol hydrochloride. ŽRBI.; WAY 100135 Ž N-tert-butyl-3-Ž4-Ž2-methoxyphenyl.-piperazin-1-yl.-2phenylpropanamide. ŽWyeth.. Inorganic salts and other reagents were from Merck. Methysergide maleate and ketanserin were kindly provided by Sandoz and Janssen, respectively. Peptides were made up in a stock 0.1 mM concentration in 0.1 N acetic acid, aliquots were stored frozen and diluted before use. Ketanserin was dissolved in 50 mM ascorbic acid. All other drugs were dissolved in distilled water.

3. Results 3.1. Effect of drugs acting on dopamine receptors on K q-eÕoked ACh release

2.3. K q-eÕoked release of [ 3 H]ACh At 12 min ŽS1. and 45 min ŽS2., the slices were depolarized by changing the superfusion fluid for 6 min to

The dopamine D1 receptor agonist SKF 38393 Ž1 nM– 10 mM. potentiated the Kq-evoked ACh release in a concentration-dependent manner Žylog EC 50 s 6.71 "

M.J. Ramırez ´ et al.r Brain Research 757 (1997) 17–23

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0.19.. SCH 23390, a dopamine D 1 receptor antagonist, at a concentration Ž1 mM. higher than the EC 50 of the agonist, had no effect on Kq-evoked ACh release ŽS2rS1 values for control and SCH 23390 were 1.02 " 0.1 and 1.04 " 0.05, respectively; n s 6.. The dopamine D 2 receptor agonist LY 171555 Žquinpirole., 0.1–10 mM, decreased the tritium efflux Ž30% inhibition compared to S2rS1 control values, for all the concentrations tested., while the dopamine D 2 receptor antagonist haloperidol, 1 mM, slightly potentiated w 3 HxACh release ŽS2rS1 values for control and haloperidol were 1.01 " 0.08 and 1.24 " 0.07, respectively; n s 6.. There was a partial blockade by TTX Ž1 mM. of the increase in Kq-evoked w 3 HxACh efflux induced by SKF 38393 in the striatum. S2rS1 control value in absence and presence of TTX was 0.87 " 0.12 and 0.70 " 0.15, respectively. The S2rS1 value for SKF 38393, 0.1 mM, was reduced from 1.42 " 0.18 to 0.91 " 0.15 in the presence of TTX. 3.2. Effect of neurokinin analogs on K q-eÕoked ACh release The selective NK 1 receptor agonist wSar 9 , metŽO 2 .11 xSP Ž0.01–0.5 mM. potentiated Kq-evoked release of w 3 HxACh, the maximal effect being observed at a 0.1 mM concentration. In contrast, the selective NK 3 receptor agonist senktide did not affect the Kq-evoked tritium efflux except at the highest concentration tested Ž0.5 mM.. All of these results are depicted in Fig. 1. 3.3. Effect of a neurokinin antagonist on K q-eÕoked ACh release The NK 1 receptor antagonist GR 82334 fully blocked the releasing effects of wSar 9 , metŽO 2 .11 xSP Ž0.01–0.5 mM.. The tritium efflux induced by the dopamine D1

Fig. 2. Effect of the NK 1 receptor antagonist GR 82334 on the enhancement by wSar 9 , metŽO 2 .11 xSP Ža. and SKF 38393 Žb. of Kq-evoked ACh release from rat striatal slices. Open symbols: agonist alone; solid symbols: agonistqGR 82334. Values are means Ž"S.E.M. of 6–9 experiments. ) P - 0.05 significantly different from ACh release induced by the agonists alone.

receptor agonist SKF 38393 was partially blocked by the NK 1 receptor antagonist GR 82334 ŽFig. 2.. 3.4. Effect of 5-HT receptor agonists and antagonists on ACh release induced by SKF 38393

Fig. 1. Effect of the neurokinin receptor agonists wSar 9 , metŽO 2 .11 xSP ŽI. and senktide Žv . on Kq-evoked ACh release from rat striatal slices. Values are means Ž"S.E.M. mean. of 6–9 experiments.

Different agonists and antagonists at 5-HT receptor subtypes were tested at a fixed 1 mM concentration for their ability to modify the w 3 HxACh efflux induced by SKF 38393, 0.1 mM, roughly the EC 50 . The 5-HT2A receptor antagonists ketanserin and ritanserin did not show any intrinsic effect on w 3 HxACh release, but markedly reduced the concentration-related increase in tritium efflux induced by SKF 38393. Both 5-HT2 receptor antagonists produced a displacement to the right of the concentration-response curve to SKF 38393 ŽFig. 3.. The 5-HT2Ar2C receptor agonist DOI Ž0.1–10 mM. as well as m-CPP, a more selective 5-HT2C receptor agonist, 1 mM each, failed to alter the tritium overflow induced by SKF 38393 Žnot shown.. However, DOI Ž1 mM. was able to counteract the antagonistic effect of

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Fig. 3. Effect of ketanserin and ritanserin, 1 mM, on the enhancement by SKF 38393 of Kq-evoked ACh release from rat striatal slices. I, SKF 38393, e, SKF 38393qketanserin, B, SKF 38393qritanserin. Values are means Ž"S.E.M.. of 6–9 experiments. ) P - 0.05 significantly different from ACh release induced by SKF 38393 alone.

ketanserin on the increased tritium efflux elicited by SKF 38393 ŽFig. 4.. Mesulergine, a 5-HT2C receptor antagonist, showed an intrinsic effect on w 3 HxACh release, but had no effect on ACh release induced by SKF 38393. Methysergide and methiothepin Ž5-HT1r2 receptor antagonists. and ondansetron Ž5-HT3 receptor antagonist. also showed an intrinsic effect on w 3 HxACh release. The effect of these antagonists and of SKF 38393 were additive. 8-OH-DPAT and WAY 100135 Ž5-HT1A receptor agonist and antagonist, respectively. had no effect on ACh release induced by SKF 38393. All of these results are depicted in Fig. 5.

Fig. 4. Effect of DOI on the blockade by ketanserin ŽKet. of the enhancement by SKF 38393 of Kq-evoked ACh release. The concentrations used were 0.1 mM for SKF 38393 and 1 mM for ketanserin and DOI. Hatched bars: serotonergic agent alone, solid bars: serotonergic agentqSKF 38393. Values are means Ž"S.E.M.. of 6–9. ) P - 0.05 significantly different from control; †P - 0.05 significantly different from SKF 38393.

Fig. 5. Effect of different serotonergic agents on the enhancement by SKF 38393 of Kq-evoked ACh release. The concentrations used were 0.1 mM for SKF 38393 and 1 mM for all other drugs. Hatched bars: serotonergic agent alone, solid bars: serotonergic agentqSKF 38393. Values are means Ž"S.E.M.. of 6–9 experiments. C, control; SKF, SKF 38393; DPAT, 8-OH-DPAT; WAY, WAY 100135; Mes, Mesulergine; Meth, Methysergide; Meti, Methiothepin; Ond, Ondansetron. ) P - 0.05 significantly different from control; †P - 0.05 significantly different from SKF 38393.

3.5. Effect of 5-HT receptor antagonists on ACh release induced by [Sar 9 , met(O2 )11]SP Antagonists at different 5-HT receptor subtypes were tested for their ability to modify the tritium efflux induced by the NK 1 receptor agonist wSar 9 , metŽO 2 .11 xSP, 50 nM. The antagonists were tested at a fixed 1 mM concentration. Ketanserin, as well as WAY 100135 and mesulergine, had no effect on the Kq-evoked ACh release induced by

Fig. 6. Effect of different serotonergic agents on the enhancement by wSar 9 , metŽO 2 .11 xSP of Kq-evoked ACh release. The concentrations used were 0.1 mM for wSar 9 , metŽO 2 .11 xSP and 1 mM for all other drugs. Hatched bars: serotonergic agent alone, solid bars: serotonergic agentq wSar 9 , metŽO 2 . 11 xSP. Values are means Ž"S.E.M.. of 6–9 experiments. C, control; ŽSar..SP, wSar 9 , metŽO 2 .11 xSP; Meth, Methysergide; WAY, WAY 100135; Ket, Ketanserin; Ond, Ondansetron. ) P - 0.05 significantly different from control; †P - 0.05 significantly different from wSar 9 , metŽO 2 .11 xSP.

M.J. Ramırez ´ et al.r Brain Research 757 (1997) 17–23

wSar 9 , metŽO 2 .11 xSP. Like above, methysergide and ondansetron released w 3 HxACh by themselves and their effects were additive with that of wSar 9 , metŽO 2 .11 xSP ŽFig. 6..

4. Discussion The results of the present study provide evidence for the regulation by 5-HT2 receptors, probably of the 5-HT2A subtype, of w 3 HxACh release induced by dopamine D 1 receptor stimulation in slices from rat striatum. The selective stimulation of neurokinin NK 1 receptors also enhances the Kq-evoked ACh release, but there appears to exist no modulation of this neuronal pathway by 5-HT. It is generally accepted that activation of dopamine D 1 and D 2 receptors stimulates and inhibits respectively ACh release in the striatum w19,1,40,27x. Opposite effects have been described for the antagonists at these two dopamine receptor subtypes w8,13,14x. In keeping with these previous reports, we found that selective stimulation of dopamine D 1 receptors promoted a concentration-dependent ACh release and the reverse was found after D 2 receptor activation. Dopamine may enhance ACh release not only by a direct stimulation of dopamine D 1 receptors located on cholinergic neurons w25x, but also by an indirect mechanism through interposed SP neurons receiving direct dopaminergic input. The ACh releasing effect of SKF 38393 was TTX-sensitive, suggesting that this effect was dependent on excitatory input from sites distal to the terminal. It has been reported that a proportion of D1 receptors is located on SP striatonigral neurons w20x and that activation of striatal D1 receptors triggers the release of endogenous SP w39x. Furthermore, microdialysis studies have shown that antagonists at striatal NK 1 receptors reduce dopamine D 1 receptor-stimulated striatal ACh release w2x. Electron microscope studies w11x and immunocytochemical analysis w10x have revealed synaptic contacts between SP-containing neurons and cholinergic neurons. The selective localization of NK 1 receptors on cholinergic interneurons in the rat striatum has also been described and striatal neurons containing cholineacetyltransferase mRNA selectively express NK 1 receptor mRNA w21x. In accordance with a previous study w35x we found a potentiation of Kq-evoked acetylcholine release by the selective NK 1 receptor agonist wSar 9 , metŽO 2 .11 xSP w16x in a concentration-dependent manner, while the NK 3 receptor agonist senktide w45x was ineffective except at the highest concentration tested, which possibly produces also a non-selective activation of the NK 1 receptor subtype. As it was to be expected, GR 82334, a selective NK 1 receptor antagonist w24x, fully blocked the effect of the NK 1 agonist wSar 9 , metŽO 2 .11 xSP on ACh release. GR 82334 was also able to significantly antagonize the release of ACh elicited by D 1 receptor stimulation suggesting, in keeping with previous studies w2x, that SP is involved in the augmented w 3 HxACh

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efflux produced by SKF 38393. Accordingly, in vivo microdialysis studies have shown that ACh release in the rat striatum is specifically mediated by NK 1 receptors w39x. NK 2 receptor agonists were not studied since these receptors have not been found in the rat striatum w31,35x. 5-HT not only modulates dopaminergic neurotransmission in the striatum Žsee Section 1.., but may also affect ACh release in this brain region w12,22x. Among all of the 5-HT agents tested, only the 5-HT2A receptor antagonists ketanserin and ritanserin were able to reduce ACh release induced by stimulation of dopamine D 1 receptors. Ketanserin, a more selective 5-HT2A receptor antagonist, was able to inhibit ACh release more potently than ritanserin, a drug with higher affinity at 5-HT2C receptors. As ketanserin and ritanserin lack any affinity for dopamine D 1 , SP or cholinergic receptors w29x, it could be supposed that this is a 5-HT2A receptor-mediated effect. Interestingly, both the 5-HT2A antagonists and the NK 1 antagonist were able to block tritium efflux induced by SKF 38393 to approximately the same extent. The close analogy between the concentration-response curves Žsee Figs. 2 and 3. appears to suggest that the antagonism at 5-HT2A receptors prevents SP release. Other potent 5-HT2A receptor antagonists such as spiperone or risperidone were not included in the present study since they are also potent blockers of dopamine D 2 receptors w28,30x. The effect of mesulergine, a more selective 5-HT2C receptor antagonist, as well as those of methysergide and methiothepin, 5-HT1r2 receptor antagonists with high affinity for 5-HT2 receptors, on SKF 38393-induced w 3 HxACh release could not be precisely assessed as these antagonists showed a significant intrinsic effect on tritium efflux. It has been previously suggested that 5-HT exerts predominantly an inhibitory influence on cholinergic interneurons in the rat striatum w26,42x. Other studies have shown that the inhibition of the w 3 HxACh efflux by 5-HT is blocked by methysergide and methiothepin w9x. The specific 5-HT receptor involved in this inhibitory action is still unclear, but the possible involvement of the 5-HT2C receptor subtype cannot be ruled out. The present results seem to point to the possible coexistence in the rat striatum of both 5-HT2 receptor subtypes, 2A and 2C, with facilitatory or inhibitory effects on ACh release. To try to further clarify which 5-HT2 receptor subtype was involved in the control of SKF 38393-induced tritium efflux, the effect of the 5- HT2Ar2C receptor agonist DOI and of the 5-HT2C agonist mCPP was studied. The lack of effect of both 5-HT2 agonists, at concentrations devoid of any intrinsic effect, on SKF 38393-evoked ACh efflux suggests that there is a permissive role of 5-HT2A receptors which favours ACh release induced by dopamine D 1 receptor stimulation. The ability of DOI to counteract the blockade by ketanserin of ACh efflux induced by D 1 receptor stimulation supports this hypothesis. D 1 receptor activation should not result by itself in stimulation of 5-HT2 receptors in the striatum since D 1 agonists do not promote 5-HT

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release in this brain region w17x. 5-HT1A receptors did not influence w 3 HxACh release induced by the D 1 receptor agonist SKF 38393; neither a 5-HT1A receptor agonist Ž8-OH-DPAT. nor an antagonist ŽWAY 100135. were able to modify the tritium efflux. The 5-HT3 receptor antagonist ondansetron also showed an intrinsic ACh releasing effect which was additive to that of SKF 38393. In the rat striatum, it seems that 5-HT3 receptors are also able to exert a tonic inhibitory control on ACh release w38x. 5-HT2 receptors are supposed not to be located on 5-HT neurons, as the lesion of the serotonergic system by 5-7-dihydroxytryptamine does not reduce the number of 5-HT2 receptors in the rat brain w18x. Immunocytochemical studies have shown that most of the 5-HT2 receptors are not either located on the cholinergic cells of the striatum w34x. Since ACh efflux evoked by NK 1 receptor stimulation was not affected by ketanserin, it is possible to hypothesize that 5-HT2 receptors located on neurokinin-containing neurons regulate the firing of these neurons. Pharmacological and lesion studies have established that neurokinin mRNA biosynthesis in the striatum is positively regulated by the serotonergic innervation arising from the raphe w43x and it has been reported that serotonergic cells can affect striatal units directly via the raphe-striatal pathway or indirectly via the substantia nigra w43,3x. It seems likely that the 5-HT2A control is exerted on the firing of SP-containing neurons which are probably involved in the release of ACh that follows D 1 receptor stimulation. The results of the present study showing that 5-HT2A receptor antagonists are able to prevent the effect of dopaminergic stimulation on cholinergic neurons in the striatum could be of interest at the time of analyzing new approaches to the treatment of Parkinson’s disease. A reduced cholinergic tone could also account for the lower extrapyramidal side effects reported for antipsychotics with mixed D 2r5-HT2 antagonist properties.

Acknowledgements This work was supported in part by CICYT ŽSAF-941381.. The generous gift of drugs by pharmaceutical companies is gratefully acknowledged.

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