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Pharmacological interactions with circling behaviour induced by the piperidinyl indole derivative RU 23686

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Abstract

When administered i.p. from doses of 10 mg/kg, RU 23686 [5-methoxy 3-(4-piperidinyl) 1H-indole hydrochloride], a drug with relatively weak stimulant properties, induces contralateral (C) circling behaviour in rats with a unilateral electrolytic lesion in the striatum and a more complex effect with ipsilateral (1) and/or C circling in rats with a 6-hydroxydopamine (6-OHDA) lesion in the dopamine (DA) nigro-striatal tract. Interactions of RU 23686 with pharmacological agents have been studied in order to investigate the extent to which different neurotransmitters may be implicated in the circling behaviour induced by this compound.

In striatal of 6-OHDA lesioned rats, α methyl p-tyrosine (αMT) did not modify C turns, while in the latter case only I turns were decreased. FLA 63, propranolol, and desipramine were also inactive in rats with a unilateral striatal lesion. Haloperidol reduced the effects of a 10 mg/kg dose of RU 23686 in striatal lesioned rats but was without effect against a dose of 20 mg/kg; in 6-OHDA lesioned rats, haloperidol blocked induced I turns but either did not affect or increased C turns. Phenoxybenzamine and p-chlorophenylalanine (PCPA), but not methysergide, p-chloroamphetamine (PCA), or fluoxetine, reduced the effect of RU 23686 in rats with a striatal lesion. In nigro-striatal lesioned rats, PCPA exhibited a differing effect according to the predominance of I or C turns: in rats with a mainly C response, C turns were decreased and I turns preserved, whereas in rats with a majority of I responses, these were depressed. In both types of lesions, animals reserpinized 48 h before RU 23686 exhibited an increase in their C circling, even in 6-OHDA lesioned animals where I turns predominated. In both rotational models, apomorphine-induced circling was potentiated by RU 23686.

It is concluded that I circling, which is blocked by haloperidol and αMT, could be related to a presynaptic action causing DA release. On the other hand, C turns do not depend on apomorphine-sensitive DA receptors in the striatum. A minor or indirect role of 5-hydroxytryptamine (5-HT) containing areas is suggested from the response to PCPA and the lack of effect of other drugs interfering with 5-HT. Results obtained from interactions with phenoxybenzamine, caffeine, and reserpine and the bimodal response to RU 23686 observed in 6-OHDA lesioned rats could indicate an interference with adrenergic processes.

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Boissier, J.R., Oberlander, C., Dumont, C. et al. Pharmacological interactions with circling behaviour induced by the piperidinyl indole derivative RU 23686. Psychopharmacology 55, 53–60 (1977). https://doi.org/10.1007/BF00432817

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Key words

  • Circling behaviour
  • Nigro-striatal pathway
  • Medial forebrain bundle
  • 6-Hydroxydopamine
  • Indole derivative
  • Neurotransmitters interactions