Summary
The biochemical and behavioral effects of the putative dopamine autoreceptor antagonists cis-(+)-5-methoxy-1-methyl-2-(n-propylamino)tetralin, (+)-AJ 76 and cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin, (+)-UH 232, were evaluated in various in vivo models in rats. Both compounds produced a marked elevation in brain dopamine synthesis and turnover with only slight effects on the synthesis and turnover of serotonin (5-HT) and noradrenaline being noted. (+)-AJ 76 and (+)-UH 232 also failed to antagonize the decrease in cortical noradrenaline synthesis rate caused by the alpha2 agonist clonidine. The apomorphine-induced decrease in dopamine synthesis rate in gamma-butyrolactone (GBL) treated animals was completely blocked by (+)-AJ 76 and (+)-UH 232 but not by d-amphetamine or methylphenidate. In activity experiments using habituated animals, (+)-AJ 76 and (+)-UH 232 produced locomotor stimulation and weak stereotypies and antagonized the sedative effects of low doses of apomorphine. Locomotor hyperactivity induced by apomorphine or the dopamine agonist DiPr-5,6-ADTN was antagonized by (+)-UH 232 and to a lesser degree by (+)-AJ 76. The locomotor hyperactivity produced by (+)-AJ 76, (+)-UH 232 and methylphenidate was completely prevented by reserpine pretreatment and partially blocked by the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (alpha-MT), whereas d-amphetamine-induced hyperactivity was only antagonized by alpha-MT pretreatment. It is concluded that (+)-AJ 76 and (+)-UH 232 produce behavioral stimulation via a preferential antagonism on central dopamine autoreceptors, an action different from that of all known stimulants including apomorphine, d-amphetamine and methylphenidate. (+)-AJ 76 and (+)-UH 232 possess but weak antagonistic effects on postsynaptic dopamine receptors and only the latter compound is able to induce sedation in rats.
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References
Ahlenius S, Engel J (1971) Effects of small doses of haloperidol on timing behavior. J Pharm Pharmacol 23:301–302
Ålander T, Grabowska-Andén M, Andén N-E (1980) Physiological significance of dopamine autoreceptors as studied following their selective blockade by molindone. J Pharm Pharmacol 32:780–782
Andén N-E (1975) The interaction of neuroleptic drugs with striatal and limbic dopaminergic mechanims. In: Sedvall G, Uvnäs B, Zotterman Y (eds) Antipsychotic drugs, pharmacodynamics and pharmacokinetics. Pergamon, Oxford, pp 217–225
Andén N-E, Corrodi H, Dahlström A, Fuxe K, Hökfelt T (1966) Effects of tyrosine hydroxylase inhibition in the amine levels of central monoamine neurons. Life Sci 5:561–568
Andén N-E, Corrodi H, Fuxe K, Ungersted U (1971) Importance of nervous impulse flow for the neuroleptic induced increase in amine turnover in central dopamine neurons. Eur J Pharmacol 15:193–199
Andén N-E, Grabowska-Andén M (1976) Pharmacological evidence for a stimulation of dopamine neurons by noradrenaline neurons in the brain. Eur J Pharmacol 39:275–282
Azzaro AJ, Ziance RJ, Rutledge CO (1974) The importance of neuronal uptake of amines for amphetamine-induced release of 3H-norepinephrine from isolated brain tissue. J Pharmacol Exp Ther 189:110–118
Braestrup C, Scheel-Krüger J (1976) Methylphenidate-like effects of the new antidepressant drug nomifensine (HOE 984). Eur J Pharmacol 38:305–312
Carlsson A (1975) Receptor-mediated control of dopamine metabolism. In: Usdin E, Bunney WE (eds) Pre- and postsynaptic receptors. Marcel Dekker, New York, pp 49–63
Carlsson A (1978) Mechanism of action of neurodeptic drugs. In: Lipton MA, DiMascio A, Killam KF (eds) Psychopharmacology: A Generation of Progress. Raven Press, New York, pp 1057–1070
Carlsson A, Lindqvist M (1973) Effect of ethanol on the hydroxylation of tyrosine and tryptophan in rat brain in vivo. J Pharm Pharmacol 25:437–440
Carlsson A, Löfberg L (1985) In vivo displacement by 3-PPP enantiomers of N,N-Dipropyl-5,6-ADTN from striatal dopamine receptor binding sites. J Neural Transm 64:173–185
Carlsson A, Fuxe K, Hamburger B, Lindqvist M (1966) Biochemical and histochemical studies on the effects of imipramine-like drugs and (+)-amphetamine on central and peripheral catecholamine neurons. Acta Physiol Scand 67:481–497
Carlsson A, Kehr W, Lindqvist M (1977) Agonist-antagonist interaction on dopamine receptors in brain, as reflected in the rates of tyrosine and tryptophan hydroxylation. J Neural Transm 40:99–113
Costall B, Domeney AM, Naylor RB (1983) Stimulation of rat spontaneous locomotion by low doses of haloperidol and (−)-sulpiride: Importance of animal selection and measurement technique. Eur J Pharmacol 90:307–314
Demarest KT, Lawson-Wendling KL, Moore KE (1983) d-Amphetamine and gamma-butyrolactone alteration of dopamine synthesis in the terminals of nigrostriatal and mesolimbic neurons. Bioch Pharmacol 32:691–697
Dominic JA, Moore KE (1969) Supersensitivity to central stimulant actions of adrenergic drugs following discontinuation of a chronic diet of alpha-methyltyrosine. Psychopharmacologia (Berl) 15:96–101
Feenstra MGP, Rollema H, Mulder TBA, Westerink BHC, Horn AS (1983) In vivo dopamine receptor binding studies with a nonradioactively labelled agonist, di-propyl-5,6-ADTN. Life Sci 32:1313–1323
Felice LJ, Felice JD, Kissinger PT (1978) Determination of catecholamines in rat brain parts by reverse-phase ion-pair liquid chromatography. J Neurochem 31:1461–1465
Ferris RM, Tang FLM, Maxwell RA (1972) A comparison of the capacities of isomers of amphetamine, deoxypipradrol and methylphenidate to inhibit the uptake of tritriated catecholamines into rat cerebral cortex slices, synaptosomal preparations of rat cerebral cortex, hypothalamus and striatum and into adrenergic nerves of rabbit aorta. J Pharmacol Exp Ther 181:407–416
Gerhards HJ, Carenzi A, Costa E (1974) Effects of nomifensine on motor activity, dopamine turnover rate and cyclic 3′,5′-adenosine monophosphate concentrations of rat striatum. Naunyn-Schmiedeberg's Arch Pharmacol 286:49–63
Glowinski J, Axelrod J (1965) Effect of drugs on the uptake, release and metabolism of 3H-norepinephrine in the rat brain. J Pharmacol Exp Ther 149:43–49
Green AL, El Hait MAS (1978) Inhibition of mouse brain monoamine oxidase by (+)-amphetamine in vivo. J Pharm Pharmacol 30:262–263
Hanson LCF (1965) The disruption of conditioned avoidance response following selective depetion of brain catechol amines. Psychopharmacologia (Berl) 8:100–110
Johansson AM, Arvidsson L-E, Hacksell U, Nilsson JLG, Svenson G, Hjorth S, Clark D, Carlsson A, Sanchez D, Andersson B, Wikström H (1985a) Novel dopamine receptor agonists and antagonists with preferential action on autoreceptors. J Med Chem 28:1049–1053
Johansson AM, Arvidson L-E, Nilsson JLG, Sanchez D, Andersson B, Wikström H, Svensson K, Hjorth S, Carlsson A (1985b) Synthesis and pharmacology of the four stereoisomers of 5-hydroxy-1-methyl-2-(di-n-propylamino)tetralin. In: Dahlbom R, Nilsson JLG (eds) Proceedings from the VIIIth International Sympesium on Medicinal Chemistry, vol I. Swedish Pharmacentical Press, Stockholm, pp 447–450
Kehr W (1976) 3-Methoxytyramine as an indicator of impulse-induced dopamine release in rat brain in vivo. Naunyn-Schmiedeberg's Arch Pharmacol 293:209–215
Kuczenski R (1977) Biphasic effect of amphetamine on striatal dopamine dynamics. Eur J Pharmacol 46:249–257
Kuczenski R (1980) Amphetamine-haloperidol interactions on striatal and mesolimbic tyrosine hydroxylase activity and dopamine metabolism. J Pharmacol Exp Ther 215:135–142
Magnusson O, Nilsson LB, Westerlund D (1980) Simultaneous determination of dopamine, dopac and homovanillic acid. Direct injection of supernatants from brain tissue homogenates in a liquid chromatography-electrochemical detection system. J Chromatogr 221:237–247
McMillen BA (1983) CNS stimulants: two distinct mechanisms of action for amphetamine-like drugs. Trends Pharmacol Sci 4:429–432
Persson T, Waldeck B (1970) Is there an interaction between dopamine and noradrenaline containing neurons in the brain? Acta Physiol Scand 78:142–144
Ross SB (1979) The central stimulatory action of inhibitors of the dopamine uptake. Life Sci 24:159–168
Sayers AC, Handley SL (1973) A study of the role of catecholamines in the response to various central stimulants. Eur J Pharmacol 23:47–55
Scheel-Krüger J (1971) Comparative studies of various amphetamine analogues demonstrating different interactions with the metabolism of the catecholamines in the brain. Eur J Pharmacol 14:47–59
Shum A, Sole MJ, van Loon GR (1982) Simultaneous measurement of 5-hydroxytryptophan and 1-dihydroxyphenylalanine by high performance liquid chromatography with electrochemical detection. Measurement of serotonin and catecholamine turnover in discrete brain regions. J Chromatogr 228:123–130
Strömbom U (1975) On the functional role of pre- and postsynaptic catecholamine receptors in brain (Thesis). Acta Physiol Scand, Suppl 431
Strömbom U (1976) Catecholamine receptor agonists: Effects on motor activity and rate of tyrosine hydroxylation in mouse brain. Naunyn-Schmiedeberg's Arch Pharmacol 292:167–176
Strömbom U (1977) Antagonism by haloperidol of locomotor depression induced by small doses of apomorphine. J Neural Transm 40:191–194
Svensson K, Hjorth S, Clark D, Carlsson A, Wikström H, Andersson B, Sanchez D, Johansson AM, Arvidsson L-E, Hacksell U, Nilsson JLG (1986a) (+)-UH 232 and (+)-UH 242: Novel stereoselective dopamine receptor antagonists with preferential action on autoreceptors. J Neural Transm 65:1–27
Svensson K, Carlsson A, Johansson AM, Arvidsson L-E, Nilsson JLG (1986b) A homologous series of N-alkylated cis-(+)-(1S,2R)-5-methoxy-1-methyl-2-aminotetralins: central dopamine receptor antagonists showing profiles ranging from classical antagonism to selectivity for autoreceptors. J Neural Transm 65:29–38
Thornburg JE, Moore KE (1973) The relative importance of dopaminergic and noradrenergic neuronal systems for the stimulation of locomotor activity induced by amphetamine and other drugs. Neuropharmacol 12:853–866
Walters JR, Roth RH (1976) Dopaminergic neurons: An in vivo system for measuring drug interactions with presynaptic receptors. Naunyn-Schmiedeberg's Arch Pharmacol 274:5–14
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Svensson, K., Johansson, A.M., Magnusson, T. et al. (+)-AJ 76 and (+)-UH 232: Central stimulants acting as preferential dopamine autoreceptor antagonists. Naunyn-Schmiedeberg's Arch. Pharmacol. 334, 234–245 (1986). https://doi.org/10.1007/BF00508777
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DOI: https://doi.org/10.1007/BF00508777