RECEPTOR DIFFERENTIATION and MECHANISMS of SIGNAL TRANSDUCTION in the CIRCULATORY SYSTEM of SEPIA OFFICINALIS R Schipp, T Lehr

RECEPTOR DIFFERENTIATION AND MECHANISMS OF SIGNAL TRANSDUCTION IN THE CIRCULATORY SYSTEM OF SEPIA OFFICINALIS R Schipp, T Lehr

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R Schipp, T Lehr. RECEPTOR DIFFERENTIATION AND MECHANISMS OF SIGNAL TRANS- DUCTION IN THE CIRCULATORY SYSTEM OF SEPIA OFFICINALIS. Vie et Milieu / Life & Environment, Observatoire Océanologique - Laboratoire Arago, 2006, pp.157-165. hal-03228738

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HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. VIE ET MILIEU – LIFE & ENVIRONMENT, 2006, 56 (2) : 157-165 The cuttlefish Sepia officinalis (N. Koueta, J.P. Andrade, S. v. Boletzky, eds)

RECEPTOR DIFFERENTIATION AND MECHANISMS OF SIGNAL TRANSDUCTION IN THE CIRCULATORY SYSTEM OF SEPIA OFFICINALIS

R. SCHIPP*, T. LEHR Institut für Allgemeine und Spezielle Zoologie, Justus-Liebig-Universität Giessen, Stephanstrasse 24, 35390 Giessen, Germany * corresponding author: [email protected]

SEPIA OFFICINALIS ABSTRACT. – Considering most recent pharmacological as well as histo- and bio- RECEPTORS chemical findings, receptor differentiations and mechanisms of signal transduction SIGNAL TRANSDUCTION in central organs of the circulatory system of Sepia officinalis are demonstrated. In CIRCULATORY SYSTEM this easily available species the systemic and branchial heart, the cephalic aorta and vein as well as the branchial vein are well accessible to experimental studies; these studies suggest: 1. The neurotransmitters: acetylcholine (ACh), noradrenaline (NA), adrenaline (A), dopamine (DA), 5-hydroxytryptamine (5-HT), FMRFamide and nitric oxide (NO) are involved in the neuroregulation showing very different action profiles in the organs mentioned. 2. As in vertebrates there is a general but differing excitatory-inhibitory antagonism between monoamines and ACh. 3. The ACh-receptor seems to be of a nicotinic type, mediating inhibitory actions in the heart organs and arteries but a peristalsis activation in the cephalic vein. 4. Cate- cholamines act by an α1-like receptor coupled with the PI-cycle, that is ascertained for the cephalic aorta, the systemic and branchial heart; for the auricle and branchial vein additionally a β-like cAMP coupled receptor seems probable. 5. 5- HT is an essential neurotransmitter in all the organs studied; in the densely- innervated, autonomously contractile auricle, the central motor of the blood circulation, four different receptors seem to be established: a 5HT1– and 5-HT4-like receptor, cAMP coupled and a 5-HT2-like receptor, PI-response-coupled as well as a 5- HT3-like receptor that is probably an ion channel. 6. NO is demonstrated for the cephalic aorta and the rhythmically contractile bulbus of the branchial heart, mediating inhibitory and dilatatory actions by the cGMP mechanism.

INTRODUCTION and biochemical investigations, especially results of physio-pharmacological bioassays applying neurotransmitters and their mimetics as well as antago- The highly evolved central nervous system, nists and inhibitors of enzymes to characterise the sense organs and behaviour of the coleoid cephalo- receptors; an undertaking that is faced with the fun- pods are supported by the efficient and sophisti- damental problem that the immense potential of cated performance of the nearly closed circulatory pharmacological tools available has been primarily system (Wells & Smith 1987, Schipp 1987a). For designed for the receptor classification of verte- experimental studies of this system Sepia brates. But for lack of other, invertebrate neurosci- officinalis is a well suited model, because the ence had to use these, and the results more and more animals are available in great number, readily yielded the insight that in cephalopods the standardised in age and size, easily cultured and neuroreceptors are as complex as those of verte- their central circulatory system clears up like an brates and that there are remarkable similarities, open book after some quick surgical cuts per- which is surprising given the fact that both groups formed on the anaesthetized animal (Fig. 1A). – have evolved separately for some hundred millions Our contribution intends to give an overview and of years. outlook on the most recent studies concerning the neurotransmitters, the receptor differentiation and putative mechanisms of signal transduction of Thesystemicheart some central organs of this system. The results concern: the systemic heart and its auricles, the ThesystemicheartofS. officinalis consists of branchial heart complex, the cephalic aorta, the ce- the ventricle – which is innervated by the nervus phalic vein and the branchial vein. This account is cardiacus – and two auricles with a remarkably considering histochemical, immunohistochemical dense nerve supply by fibres of the ganglion cardi- 158 R. SCHIPP, T. LEHR acum (Alexandrowicz 1960) (Fig. 1B). The auri- well as by transmitters released by the neurohemal cles show a myogenic automatism, in contrast to organ (NSV-system) in the cephalic vein (Martin & the ventricle, which is under control of the pace- Voigt 1987, Schipp 1987b, Marschinke & Schipp maker function of them. In vivo the beating rhythm 1993). of both auricles is neuronally synchronized by cen- Many earlier histochemical and pharmacologi- ters within the visceral ganglion (Schipp et al. cal studies suggest that, besides catecholamines, 1997, Versen et al. 1997, Versen & Schipp 1997) as serotonin (5-HT) and acetylcholine (ACh), numerous further putative neurotransmitters (particularly peptides) are involved in the neurocontrol of the systemic heart of coleoids, and it seems probable that they have also corresponding receptors situated in the sarcolemma of the cardiomyocytes (Kling & Jakobs 1987, Jakobs 1991, Messenger 1996) (Table I). More recent pharmacological and biochemical findings gave first evidence concerning a further subclassification and the pathways of signal transduction of the putative catecholaminergic and serotoninergic receptors, especially for the auricle; these will be referred to here. Phar- macological bioassays of Versen et al. (1999) using different agonists together with blocking drugs and enzyme inhibitors suggest that there are two catecholaminergic receptors established in the auricle myocytes: an α-like adrenoreceptor mediating mainly positive chronotropic effects, which accord- ing to biochemical findings seem to be generated by the G-protein coupled PI-cycle (phosphatidylinositol response) (Berridge 1987) (Fig. 2A, B) and a β-like receptor, mediating positive inotropic effects by activating the cAMP second messenger pathway that is also G-protein coupled and that could be blocked by the adenylate cyclase inhibitors MDL-12,330A and SQ-22,536. Pharmacological findings of Pflänzel (1994) concerning the cholinergic neuroregulation of the auricle of S. officinalis revealed a nicotinergic receptor, because arecoline, carbachol and nicotine mimicked the negative inotropic ACh-action but not the m-ligands muscarine, pilocarpine or oxotremorine. However, the fact that the ACh-action could be blocked by α-bungarotoxine (α-BTX) but

Fig. 1. – A, Diagram of the circulatory system of Sepia officinalis in ventral view. V=ventricle, AU=auricles, BH=branchial hearts, BHA=branchial heart appendages; arteries: CA/PAO= cephalic and posterior aorta, AFUA=anterior funnel artery, AMA=anterior mantle a., BRA=branchial a., GA=genital a., OA=ophtalmic a., PFUA=posterior funnel a., SA=siphuncle a., TA=ten- tacle a.; veins: AV=arm v., ABV/EBV=afferent and ef- ferent branchial vessels, ACV=anterior cephalic vein., AFV=anterior funnel v., AFIV=anterior fin v., AMV=anterior mantle v., CV=cephalic v., ISV=inksac v., OV=ophthalmic v., PFV=posterior funnel v., PMV=posterior mantle v., RVH=ring vein of head, VC=vena cava, OS/PBS=optic and peribuccal blood si- nus (from Schipp 1987a). B, Innervation of the systemic heart and branchial heart complex of Sepia officinalis by the paired visceral nerve; nervus cardiacus (arrow heads) (after Alexandrowicz 1960). RECEPTOR DIFFERENTIATION IN THE CIRCULATORY SYSTEM OF S. OFFICINALIS 159

Table I. – Effects of intrinsic neurotransmitters of the central organs of the circulatory system of Sepia officinalis L.*

also by the m2-antagonist 4-DAMP and that the classic n-antagonist d-tubocurarine blocked the action of nicotine but not that of ACh has been interpreted as an indication that a G-protein coupled m-receptor could also be present (Hannan & Hall 1993, Pflänzel 1994). In accordance with fluores- cence- and immunohistochemical findings on the occurrence of 5-HT in the auricle nerve endings of S. officinalis recent pharmacological studies revealed a sophisticated system of probably four different 5-HT receptor-subtypes mediating excitatory or inhibitory effects (Lehr & Schipp 2004a, Lehr & Schipp 2004b, Lehr & Schipp 2005) (Fig.3A).A5-HT1-like subtype generating positive chronotropic, inotropic and tonotropic effects is counteracted by a 5-HT4-like subtype mediating negative actions concerning these parameters; both seem to work via the G-protein coupled cAMP

Fig. 2. – A, Activity content of inositolphosphate (IP) and phosphatidylinositol (PI) in HPTLC-eluates of the systemic heart of Sepia officinalis traced by 3H-myoino- sitol 2.5 and 5 min. after stimulation with 4×10-7M noradrenaline (NA), controls (K) with seawater (from Versen α 1999). B, Diagram of the PI-cycle of the presumed 1- like NA-receptor in the systemic heart of Sepia officina- α α lis. 1-like = 1-like receptor type, Chel = chelerythrine, DAG = diacylglycerol, ET-18 = ET-18-OCH3, Gq =G- coupled protein, GDP and GTP = guanosine-di and triphosphate, Ins = myo-inositol, IP = inositol-1-phosphate, IP2 = inositol-1,4-bisphosphate, IP3 = inositol- 1,4,5-triphosphate, NA = noradrenaline, Phorbo-12,13 = phorbol-12,13-diacetate, PI = phosphatidylinositol, PIP = phosphatidylinositol-4-phosphate, PIP2 = phosphatidylinositol-4,5-bisphosphate, PI-PLC = phosphatidylinosi- tolic-specific phospholipase C, PKC = proteine kinase C, U-73122 = inhibitor of phospholipase C 160 R. SCHIPP, T. LEHR

Fig. 3. – A, Diagram of different specific serotonergic agonists and their action on the auricle of Sepia officinalis. While 5-HT 1 and 4 receptors influence the cAMP-dependent second messenger signal transduction way, 5-HT2 receptors are coupled to the PI-response and 5-HT3 receptors are coupled to ion channel. +/– = excitatory/inhibitory, ++/–– = strong excitatory/inhibitory, c = chronotropic, i = inotropic, t = tonotropic, 8-OH = 8-OH-DPAT (5HT1a-agonist), CP = CP-93129 (5-HT1b-agonist), NAN = NAN-190 (5-HT1a antagonist), RS-67333 (5-HT4-agonist), SQ = SQ-91-213 (adenylyl cyclase inhibitor), AlM-5-HT = alpha-methyl-5-HT (5-HT2-agonist), M-CPP = methyl-chlorophenylpiperidin, Ket. = Ketanserin (5-HT2-antagonist), 2-APB = 2-Aminophenylboran (inhibitor of IP3-sensitive channels of sarcoplas- matic reticulum), U = U-73122 (PLC-inhibitor), 1-PBG = 1-Phenylbiguanide (5-HT3 agonist), M-CPBG = meta-Chlo- rophenylbiguanide (5-HT3-agonist), 2-CH3 = 2-methyl-5-HT (5-HT3-agonist), r. Au. = right auricle, Ve. = ventricle. B, Overview of the proposed antagonistic acting 5-HT1 and 5-HT4-like receptor system within the auricle of Sepia officinalis. Both receptors activate or inhibit the adenylyl cyclase as target enzyme via G-proteins. CP-91239 = 5-HT1b-agonist, TFMPP= (5-HT1-agonist), 8-OH-DPAT=5-HT1a-agonist, NAN-190=5-HT1a-antagonist, SQ-22,536 (inhibitor of adenylyl cyclase), RS-67333=5-HT4-agonist (Reprinted from Comparative Biochemistry and Physiology Part C, 138, T Lehr & R Schipp, An antagonistic 5-HT receptor system in the auricles of the systemic heart complex of Sepia officinalis L. (Cephalopoda) shows 5-HT1 and 5-HT4 subtype properties, 213-219, 2004 with permission of Elsevier Publ. RECEPTOR DIFFERENTIATION IN THE CIRCULATORY SYSTEM OF S. OFFICINALIS 161 pathway (Fig. 3B) whereas the primary positive phentolamine and ebrantil, but not by the β-antago- β inotropic effects mediating the 5-HT2-like subtype nist propranolol (Braun 2000). The lack of a - seems to be coupled with the PI-response, since the receptor – which is present in the auricle – has also mechanism could be blocked by the phospholipase been shown by the missing effect of the β-agonist C inhibitor U-73122 and the IP3-receptor antago- isoproterenol. – Surprisingly, serotonin also had no nist 2-aminophenylborane (2-APB). The presumed significant effects on the branchial heart of 5-HT3-like receptor, sensitive to different specific S. officinalis, suggesting that – contrary to the 5-HT3 agonists, is seen as triggering only positive systemic heart – 5-HT receptors do not participate chronotropic actions and could be – as as in verte- in the neuroregulation (Fiedler & Schipp 1990). – brates and in cultured Lymnaea neurones – an ion More recent physio-pharmacological studies by channel (Fozard 1984, Fozard 1989, Walcourt- Gebauer (1998) on the autonomously contractile Ambakederemo & Winlow 1995, Green et al. bulbus muscle, as mentioned above, indicate that in 1996, Lehr & Schipp 2005). this compartment, besides nicotinergic receptors, also receptors of the muscarinergic or of a mixed type are involved in the neuroinhibitory mecha- The branchial heart complex nisms. Furthermore this author and his coworkers give a detailed analysis of nitrinergic mechanisms, As a system with multiple functions the showing that neuronally released NO has inhibi- branchial heart complex consists of the branchial tory effects on the tonus and the contraction force. heart – which contains, besides the autonomous These are mediated by cGMP as second messenger, contractile cardiomyocytes, to a large extent the so probably activating a PKG (Fig. 4 top) (Gebauer called ovoid cells or rhogocytes, they are responsi- et al. 1998). A proof for the complexity of the ble for the catabolism of xenobiotics, excretions neuroregulation of the branchial heart system and and haemocyanin – and the pericardial or branchial its receptor differentiation is the fact that also heart appendage containing the ultrafiltration bar- peptidergic mechanisms seem to be participating, rier of podocytes, the site of the first step of urine as shown by inotropic but not tono- or formation (Fig. 1A) (Schipp & Hevert 1981, chronotropic actions of FMRFamide and some ana- Beuerlein & Schipp 1998, Beuerlein et al. 2000). logues; in vivo these are possibly released from the Physio-pharmacological bioassays on isolated NSV-system of the cephalic vein, as is suggested preparations, on the one hand, revealed the bulbus by branchial heart reactions after electric cordis branchialis, situated at the distal pole of the stimulations of NSV-axons in the perfused double heart (=origine of the A. branchialis) as an area preparations of the vena cephalica/branchial heart with a myogenic automatism and special pace- (Fiedler 1992). maker function for the circulation of the gills, and on the other hand provided findings concerning the catecholaminergic, cholinergic and especially The cephalic aorta nitrinergic receptors (Fiedler & Schipp 1987, Gebauer 1998). In accordance with the histo- Among the numerous putative neurotransmitters chemical localization of the ACh-Esterase within already applied on the aorta cephalica of S. the myocard, ACh has been revealed as an intrinsic officinalis – seen as a model of a high pressure re- neurotransmitter of the branchial heart, with signif- sistance vessel in invertebrates – catecholamines icant negative inotropic and chrono-tropic effects. only showed a significant vasotonus increasing ac- Furthermore, bioassays gave evidence that these tion with a potency range dopamin (DA) > are mediated by a nicotinic receptor, because the noradrenaline > adrenaline (Schipp et al. 1991). ACh-effects could be mimicked by nicotine but not More recent pharmacological studies using specific muscarine, pilocarpine or oxotremorine and could inhibitors and activators of the PLC and PKC sug- be blocked by α-tubocurarine and α-bungarotoxin gest that this vasoconstrictory action is, like in ver- α α ( -BTX) but not by atropine, pirencepine or tebrate arteries, mediated through an 1-like tetraetylammonium (TEA) (Schipp et al. 1986, adrenoreceptor, which seems to be coupled to the Gebauer & Versen 1998). In vertebrates all nico- PI second messenger pathway (Fig. 4 bottom) tinic receptors are pentameric structures which (Schipp et al. 2001). Contrary to the positive function as ligand-gated ion channels (Rang et al. tonotropic effect of 5-HT on the systemic heart, as 2003) but molecular biological studies concerning mentioned above, this neurotransmitter decreases this question in cephalopods are still missing. This the vasotonus of the aorta (Schipp et al. 1991). is also true concerning the monoaminergic recep- This action could be mimicked by the highly spe- tors and their mechanisms of transmission in the cific 5-HT4 agonist RS-67333 and, to a lesser branchial heart. The pharmacological bioassays of extent, by the 5-HT1a agonist 8-OH-DPAT, indicat- Fiedler & Schipp (1990, 1991) indicate that there ing that like in the auricle a 5-HT4-like subtype α is an 1-like receptor, which generates positive seems to be established, which decreases the inotropic- and chronotropic actions of adrenaline intracelluar Ca2+-ion concentration by the cAMP or noradrenaline and that could be blocked by transduction mechanism (Lehr & Schipp 2004b). 162 R. SCHIPP, T. LEHR

Fig. 4. – Top, Diagram of the presumed cholinergic and nitrinergic mechanisms involved in the neuroregulation of the bulbus cordis branchialis of Sepia officinalis L. (+/– = excitatory/inhibitory action, BTX = α-bungarotoxin, GMP = guanylmonophosphate, GTN = glyceroltrinitrate, KNO2 = potassium nitrite, L-NOARG = L-NO-arginine, NO = nitric oxide, NOS = nitric oxide synthase, ODQ = 1H(1,2,4)oxodiazolo-(4,3-a)-quinoxaline, PKG = proteinkinase G, PTIO = (2-(4-carboxyphenyl)-4,4,5,6-tetrametylimidazoline-1-oxyl-3-oxide-K), QNB = quinuclidinylbenzilate, SIN-1 (3-mor- pholinylsydnoneimine), L-SMTC = (s-methyl-L-thiocitrullinchloride), (from Gebauer 1998). Bottom, Diagram of the second messenger mechanisms of the presumed α1-receptor in the myocyte of the cephalic aorta of Sepia officinalis; +/– = excitatory/inhibitory action, α-R = α-like receptor, A = adrenaline, A3-HCl/NPC-15437 = inhibitors of PKC, Calm = calmodulin, DA = dopamine, DAG = diacylglycerol, ER = endoplasmatic reticulum, G-Stroph.=G-Strophantin, IP3 = see legend fig. 2B, LiCl = lithiumchloride, MLCK = myosin light chain kinase, NA = noradrenaline, Phorbol-E 12/13 = activator of the PKC, PI = see legend fig. 2B, PKC = proteinkinase C, PLC = phospholipase C, U-73122 = inhibitor of PLC, W-7-HCl and W-13-HCl = calmodulin antagonists.

ACh and several cholinomimetics showed also that peptidergic receptors are also involved in the vasodilatory effects on the DA-precontracted aorta, neuroregulation of this vessel (Schipp et al. 1991, with a potency range of: carbachol > ACh > Schipp & Fiedler 1994). muscarine; i. e. contrary to its missing effect on the heart and branchial heart muscarine induced also a significant action and under the ACh-antagonists The cephalic vein applied, only TEA, but not D-tubocurarine and α- bungarotoxine (α-BTX) blocked the ACh-induced action. Nicotine had a reduced action with a This largest vein of the circulatory system of S. biphasic concentration-response curve. These officinalis, generating the reflux of blood from the findings were interpreted with the presence of a anterior body areas by obvious peristaltic contrac- “m-like” receptor in the muscle cells of the aorta tions, contains two muscle systems: the peri- (Schipp & Fiedler 1994), but further studies have adventitial longitudinal muscles (PLM) showing to clarify this question. The peptide FMRFamide autonomous longitudinal contractions and the cir- and analogues also induced – contrary to their cular muscle of the tunica media (CMM) which is positive inotropic effects on the heart organs responsible for the peristalsis. These structurally (Jakobs 1991) – a decrease of the muscle tonus, different muscle systems are innervated by suggesting (together with histochemical findings) branches of the paired nervus visceralis, which is RECEPTOR DIFFERENTIATION IN THE CIRCULATORY SYSTEM OF S. OFFICINALIS 163 cholinergic (Schipp 1987b); this is contrary to the tion dependent negative inotropic action which axons of the neurohemal system (NVS) that origi- could be significantly blocked by α-BTX and α- nate in a special postcerebral ganglion and release tubocurarine suggesting the presence of a several neuropeptides into the vessel lumen (Mar- nicotinergic receptor mechanism. The fact that the tin & Voigt 1987, Marschinke 1995, Budelmann et m2-antagonist 4-DAMP inhibited the ACh- and al. 1997). Pharmacological in vitro studies fo- pilocarpine action also was interpreted as meaning cussed on the question about the origin of the peri- that the presumed n-receptor has a different struc- staltic activity of the CMM and revealed for the ture to that of vertebrates (Haas 1997). These find- perfused isolated preparations of the inner vessel ings as well as the positive inotropic action of tube only weak oscillatory contractions that FMRFamide are in an obvious accordance with the changed to a strong and frequent peristalsis in the pharmacological profile of the auricle – described presence of higher ACh-concentrations (threshold above – and support the hypothesis that the paired concentration 10-5M) (Schipp 1987b, Schuck auricle of coleoids has to be seen phylogeneticaly 1988). The fact that this excitatory action of ACh as a specialized compartment of the branchial vein; could be mimicked by nicotine and DMPP but not a hypothesis that is also supported by similarities by muscarine and that it could be blocked by d- of the wall structure as well as ontogenetical tubocurarine and α-BTX indicates that a findings (Boletzky 1987). nicotinergic receptor mechanism seems to generate the peristalsis (von Byern 2001). However, it is not yet clear if these peristalsis inducing effects of CONCLUSIONS ACh and mimetics work via remaining nerve endings or directly on the muscle structures thus suggesting a neurogenic or myogenic automatism. Although it is not easy to fit the neuro- Further studies have to clarify also more precisely pharmacological receptor types and subtypes of in- the receptor subtype and the possible second mes- vertebrates into the terms of the vertebrate classifi- senger mechanisms that must be involved. Cate- cation the overview of the findings concerning the cholamines and 5-HT showed inhibitory actions on receptor differentiation of the circulatory system of the vessel peristalsis, peptides of the FMRFamide Sepia officinalis as presented here, reveals numer- family did not influence it (Schipp 1987b, von ous analogies or possibly homologies to that of Byern 2001). vertebrates. In both systems nearly the same transmitters are involved (Messenger 1996) with an obvious excitatory-inhibitory antagonism between The branchial vein monoamines and ACh (Table I). Furthermore, the findings on S. officinalis give evidence that there Only few studies deal with the neuroregulation are, as in vertebrates, highly sophisticated multiple of medium-sized vessels of the coleoid circulatory receptor differentiations and mechanisms of signal system such as the autonomously contractile transduction. 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Schipp R, Fronk B, Kopsch M, Polenz A 1997. Functio- Berücksichtigung der Signaltransduktions-mechanis- nal morphological aspects of the cephalic aorta of the men des α1-ähnlichen Adrenorezeptors. Thesis cephalopod Sepia officinalis L. Vie Milieu 47 (2): Justus-Liebig-Univ Giessen, Germany. 111-116. Versen B, Gokorsch S, Lücke J, Fiedler A, Schipp R Schipp R, Hevert F 1981. Ultrafiltration in the branchial 1997. Auricular-ventricular interacting mechanisms heart appendage of dibranchiate cephalopods: A com- in the systemic heart of the cuttlefish Sepia officinalis parative ultrastructural and physiological study. J exp (Cephalopoda). Vie Milieu 47: 123-130. Biol 92: 23-35. Versen B, Schipp R 1997. Cytobiological aspects of the Schipp R, Jakobs PM, Fiedler A 1991. Monoaminerg- auricle and the auriculo-ventricular contact in the sys- peptidergic interactions in neuroregulatory control of temic heart of Sepia officinalis L. (Cephalopoda). Tsi- the cephalic Aorta in Sepia officinalis L. (Cephalopo- tologiya 39: 900-906. da). Comp Biochem Physiol 99C (3): 421-429. Schuck A 1988. Automatie und cholinerges Rezeptor- Schipp R, Schmidt HR, Fiedler A 1986. Comparative cy- system der Vena cephalica von Sepia officinalis L. tochemical and pharmacological studies on the choli- Diploma thesis Giessen, Germany. nergic innervation of the branchial heart of the Walcourt-Ambakederemo A, Winlow W 1995. 5-HT re- cephalopod Sepia officinalis. Experientia 42: 23-30. ceptors on identified Lymnaea neurones in culture: Schipp R, Lehr T, Versen B 2001. The α-adrenergic va- Pharmacological Characterization of 5-HT3 Recep- sotonus control and mechanisms of signal transduc- tors. Gen Pharmac 26 (3): 553-561. tion in the cephalic aorta of Sepia officinalis L. Wells MJ, Smith P 1987. The performance of the Octo- (Cephalopoda), unpubl report. pus circulatory system: A triumph of engineering Versen B 1999. Biochemische und physiopharmakolo- over design. Experientia 43: 487-499. gische Untersuchungen zur extrinsischen mono- aminergen Regulation des Zentralherzens von Sepia Received October 3, 2005 officinalis L. (Cephalopoda) unter besonderer Accepted January 16, 2006