Summary
Among four stereotyped manifestations that can be simultaneously quantified in mice treated with apomorphine (APO), two of them (climbing and sniffing) emerge at low APO dosages (below 1 mg/kg) whereas licking and sniffing require APO dosages above 6 mg/kg. However, in mice pretreated (either i.p. or i.c.v.) with sulpiride (especially the levo isomer) or (±)amisulpride in moderate dosage stereotyped licking and sniffing are elicited by APO in much lower dosage (0.75 mg/kg). As a consequence, in mice pretreated with these benzamide derivatives and receiving 0.75 mg/kg APO, a biphasic effect was observed: licking and gnawing progressively appear at low dosages, whereas they are progressively abolished at higher dosages.
This potentiation of the effects of APO by (±)amisulpride is even more obvious (maximal scores increased) with larger test-doses of the dopamine agonist (up to 5 mg/kg). Amisulpride also allows the emergence of the two stereotyped behaviours in mice receiving other dopamine agonists in subthreshold dosages (Dipropyl 5,6-ADTN, dexamphetamine or cocaine). The potentation of APO is still observed after dopamine depletion by reserpine and α-methylparatyrosine, whereas that of dexamphetamine is abolished. In contrast with the benzamide derivatives, haloperidol does not potentiate at any dosage the effect of APO but, at 0.15 mg/kg, suppresses licking and gnawing elicited by 0.75 mg/kg APO in mice pretreated with 6.25 mg/kg amisulpride or veralipride.
Among a series of dopamine antagonists belonging to various chemical classes, only a number of discriminant benzamide derivatives (DBD), previously shown to differentially antagonise several APO-induced behavioural manifestations in rats (sulpiride, amisulpride, tiapride, sultopride, DO 701, LUR 2366 but not metoclopramide) potentiate APO (0.75 mg/kg) regarding licking and gnawing. In contrast, potentiation is not observed, even for a higher test dose of APO, with haloperidol, thioproperazine, pimozide, mezilamine, thioridazine or metoclopramide at any dosage tested.
For the various DBD, the two stereotyped behaviours emerge at dosages at which climbing starts to be inhibited, suggesting that selective blockade of some inhibitory response to APO is responsible for the potentiation. Among other hypothesis the possibility that the peculiar behavioural properties of DBD is related to their differential recognition of two classes of dopaminergic binding sites is discussed.
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References
Andèn NE, Rubvenson A, Fuxe K, Hökfelt T (1967) Evidence for dopamine receptor stimulation by apomorphine. J Pharm Pharmacol 19:627–629
Bartholini G (1976) Differential effect of neuroleptic drugs on dopamine turnover in the extrapyramidal and limbic system. J Pharm Pharmacol 28:429–433
Borenstein P, Gekiere F (1981) Sulpiride, psychosis, and mood. Adv Biol Psychiatr 7:138–153
Carlsson A (1975) Receptor-mediated control of dopamine metabolism. In: Usdin E, Bunney WE (eds) Pre- and postsynaptic receptors. Marcel Dekker, New York, p 49
Chiueh CC, Moore KE (1975) D-amphetamine-induced release of “newly synthetized” and “stored” dopamine from the caudate nucleus in vivo. J Pharmacol Exp Ther 192:642–653
Christensen A, Fjalland B, Moller-Nielsen I (1976) On the supersensitivity of dopamine receptors induced by neuroleptics. Psychopharmacology 48:1–6
Colboc O, Protais P, Costentin J (1983) Pharmacological evidence against the involvement of the D-1 subtype of dopamine receptors in apomorphine-induced hypothermia. Neurosci Lett 39:211–216
Costall B, Naylor RJ, Cannon JG, Lee T (1977) Differential activation by some 2-amino tetralin derivatives of the receptor mechanisms in the nucleus accumbens of rat which mediate hyperactivity and stereotyped biting. Eur J Pharmacol 41:307–319
Costall B, Naylor RJ, Nohria V (1978) Climbing behaviour induced by apomorphine in mice: a potential model for the detection of neuroleptic activity. Eur J Pharmacol 50:39–50
Costentin J, Dubuc I, Protais P (1983) Behavioural data suggesting the plurality of central dopamine receptors. In: Mandel P, De Feudis F (eds) CNS receptors: From molecular pharmacology to behaviour. Raven Press, New York, p 289
Costentin J, Protais P, Schwartz J-C (1975) Rapid and dissociated changes in sensitivities of different dopamine receptors in mouse brain. Nature 257:405–407
Costentin J, Marcais H, Protais P, Baudry M, De la Baume S, Martres MP, Schwartz J-C (1977) Rapid development of hypersensitivity of striatal dopamine receptors induced by alpha-methyl para-tyrosine and its prevention by protein synthesis inhibitors. Life Sci 21:307–314
Dadkar NK, Dohadwalla AN, Bhattacharya BK (1976) Influence of pheniramine and chlorpheniramine on apomorphine-induced compulsive gnawing in mice. Psychopharmacology 48:7–10
Ernst A (1967) Mode of action of apomorphine and dexamphetamine on compulsive gnawing in mice. Psychopharmacology 48:7–10
Fjalland B, Moller-Nielsen I (1974) Enhancement of methylphenidate-induced stereotypies by repeated administration of neuroleptics. Psychopharmacologia 34:105–109
Fuxe K, Agusti LF, Anderson K, Calza L, Benfensti F, Köhler C (1983) Analysis of transmitter-identified neurons by morphometry and quantitative microfluorimetry. Evaluation of the actions of psychoactive drugs, especially sulpiride. In: Ackenheil M, Mutussek N (eds) Special aspects of psychopharmacology. Expansion Scientifique Française, Paris, p 13
Gulat-Marnay C, Lafitte A, Schwartz J-C, Protais P (1985) Effects of discriminant and non-discriminant dopamine antagonists on in vivo binding of 3H-N-propylnorapomorphine in mouse striatum and tuberculum olfactorium. Naunyn-Schmiedeberg's Arch Pharmacol 329:117–122
Haley TJ, McCormick WG (1957) Pharmacological effects produced by intracerbral injection of drugs in the conscious mouse. Br J Pharmacol 12:12–15
Hedley LR, Wallach MB (1983) Potentiation of apomorphine-induced gnawing in mice. Prog Neuropsychopharmacol Biol Psychiatry 5:47–56
Heikkila RE, Orlansky H, Cohen G (1975) Studies on the distinction between uptake inhibition and release of 3H-dopamine in rat brain tissue slices. Biochem Pharmacol 24:847–852
Jenner P, Marsden CD (1981) Substituted benzamide drugs as selective neuroleptic agents. Neuropharmacology 20:1285–1293
Justin-Besancon L, Thominet M, Franceschini J, Laville C, Margarit J, Borenstein P (1978) Propriétés biologiques d'orthoanisamides substitués à fonction-4 amino-5 alkyl-sulfonc. C. R. Acad Sci (Paris) 286:1169–1170
Kebabian JW, Calne DB (1979) Multiple receptors for dopamine. Nature 277:93–96
Laduron PM, Leysen JE (1978) Is the low incidence of extrapyramidal side-effects of antipsychotics associated with antimuscarinic properties? J Pharm Pharmacol 30:120–124
Litchfield JT Jr, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 96:99–115
Marcais H, Protais P, Costentin J (1979) Hypersensitivity of the climbing response to apomorphine induced by a short depression of dopaminergic neurone activity. Neuropharmacology 18:845–849
Marcais H, Protais P, Costentin J, Schwartz JC (1978) A gradual score to evaluate the climbing behaviour elicited by apomorphine in mice. Psychopharmacology 56:233–234
Martres MP, Costentin J, Baudry M, Marcais H, Protais P, Schwartz J-C (1977) Long-term changes in the sensitivity of pre-and post-synaptic dopamine receptors in mouse striatum as evidenced by behavioural and biochemical studies. Brain Res 136:319–337
Martres MP, Sokoloff P, Delandre M, Schwartz JC, Protais P, Costentin J (1984) Selection of dopamine antagonists discriminating various behavioural responses and radioligand binding sites. Naunyn-Schmiedeberg's Arch Pharmacol 325:102–115
Miller RJ, Hiley CR (1974) Anti-muscarinic properties of neuroleptics and drug-induced Parkinsonism. Nature 248:596–598
Mizuchi A, Kitagawa N, Miyachi Y (1983) Regional distribution of sultopride and sulpiride in rat brain measured by radioimmunoassay. Psychopharmacology 81:195–198
Molander L, Randrup A (1976) Effects of thymoleptics on behavior associated with changes in brain dopamine: modification and potentiation of apomorphine-induced stimulation of mice. Psychopharmacology 49:139–144
O'Connor SE, Brown RA (1982) The pharmacology of sulpiride, a dopamine receptor antagonist.Gen Pharmacol 13:185–195
Pedersen V (1967) Potentiation of apomorphine effect (compulsive gnawing behaviour) in mice. Acta Pharmacol (Kbh) 25, suppl 4:63
Protais P, Bonnet JJ, Costentin J (1983a) Pharmacological characterization of the receptors involved in the apomorphine-induced polyphasic modifications of locomotor activity in mice. Psychopharmacology 81:126–134
Protais P, Bonnet JJ, Costentin J, Schwartz JC (1984) Rat climbing behaviour elicited by stimulation of cerebral dopamine receptors. Naunyn-Schmiedeberg's Arch Pharmacol 325:93–101
Protais P, Costentin J, Schwartz JC (1976) Climbing behaviour induced by apomorphine in mice: a simple test for the study of dopamine receptors in striatum. Psychopharmacology 50:1–6
Protais P, Dubuc I, Costentin J (1983b) Pharmacological characteristics of dopamine receptors involved in the dual effect of dopamine agonists on yawning behaviour in rats. Eur J Pharmacol 94:271–280
Puech AJ, Rioux P, Poncelet M, Brochet D, Chermat R, Simon P (1981) Pharmacological properties of new antipsychotic agents: use of animals models. Neuropharmacology 20:1279–1284
Puech AJ, Simon P, Boissier JR (1978) Benzamides and classical neuroleptics: comparison of their action using 6 apomorphine-induced effects. Eur J Pharmacol 50:291–300
Scatton B, Worms P, Zivkovic B, Depoortere H, Bedek J, Bartholini G (1979) On the neuropharmacological spectra of classical (haloperidol) and atypical (benzamide derivatives) neuroleptics. In: Spano PF, Trabucchi M, Corsini GU, Gessa GL (eds) Sulpiride and other benzamides. Italian Brain Research Foundation Press, Milan, p 53
Scheel-Krüger J (1970) Central effects of anticholinergic drugs measured by the apomorphine gnawing test in mice. Acta Pharmacol Toxicol 28:1–16
Schwartz J-C, Costentin J, Martres MP, Protais P, Baudry M (1978) Modulation of receptor mechanisms in the CNS: hyper and hyposensitivity to catecholamines. Neuropharmacology 17: 665–685
Schwartz J-C, Delandre M, Martres MP, Sokoloff P, Protais P, Vasse M, Costentin J, Laibe P, Wermuth CG, Gulat C, Lafitte A (1984) Biochemical and behavioural identification of discriminant benzamide derivatives: new tools to differentiate subclasses of dopamine receptors. In: Usdin E, Carlsson A, Dahlström A, Engel J (eds) Catecholamines, Part B: Neuropharmacology and central nervous system. Alan Liss, New York, p 59
Schwartz J-C, Sokoloff P, Martres MP, Protais P, Costentin J, Bouthenet ML, Sales N (1983) Distinction of dopamine receptors well recognized by antipsychotic agents: binding, autoradiographic and behavioural studies. In: Carlsson A, Lars J, Nilsson G (eds) Symposium on dopamine receptor agonists, Acta Pharmaceutica Swecica Suppl. 1. Swedish Pharmaceutical Press, Stockholm, p 47
Seeman P (1980) Brain dopamine receptors. Pharmacol Rev 32(3):229–313
Sokoloff P, Martres MP, Delandre M, Redouane K, Schwartz J-C (1984) 3H-domperidone binding sites differ in rat striatum and pituitary. Naunyn-Schmiedeberg's Arch Pharmacol 327:221–227
Sokoloff P, Martres MP, Protais P, Costentin J, Schwartz JC (1983) Two distinct classes of dopamine receptor mediating actions of antipsychotics: binding and behavioral studies. In: Segawa T, Yamamura HI, Kuriyama K (eds) Molecular Pharmacology of neurotransmitter receptors. Raven Press, New York, p 163
Sokoloff P, Martres MP, Schwartz J-C (1980) Three classes of dopamine receptors (D-2, D-3, D-4) identified by binding studies with 3H-apomorphine and 3H-domperidone. Naunyn-Schmiedeberg's Arch Pharmacol 315:89–102
Ther L, Schramm H (1962) Apomorphine-Synergismus (Zwangsnagen bei Mäusen als Test zur Differenzierung psychotroper Substanzen). Arch Int Pharmacodyn 138:302–310
Ungerstedt U (1980) Behavioral pharmacology reflection catecholamine neurotransmission. In: Szekeres L (ed) Adrenergic activators and inhibitors, part I. Springer, Berlin Heidelberg New York, pp 499–519
Urbà-Holmgren R, Holmgren B, Anias J (1982) Pre-and postsynaptic dopaminergic receptors involved in apomorphine-induced yawning. Acta Neurobiol Exp 42:115–123
Wiszniowska-Szafraniec GL, Banek K, Reichenberg K, Vetulani J (1983) Facilitation by α-adrenolytics of apomorphine gnawing behaviour: depression of threshold apomorphine concentration in the striatum of the rat. Pharmacol Biochem Behav 19:19–22
Yoshida M, Yokoo H, Kojima H, Suetake K, Anraku S, Inanaga K (1981) The acute effects of sulpiride on the central dopamine turnover in rats: a quantitative histochemical study. Experimentia 37:491–492
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Vasse, M., Protais, P., Costentin, J. et al. Unexpected potentiation by discriminant benzamide derivatives of stereotyped behaviours elicited by dopamine agonists in mice. Naunyn-Schmiedeberg's Arch. Pharmacol. 329, 108–116 (1985). https://doi.org/10.1007/BF00501198
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DOI: https://doi.org/10.1007/BF00501198