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Evidence that RU 24969‐induced locomotor activity in C57/B1/6 mice is specifically mediated by the 5‐HT 1B receptor
Author(s) -
Cheetham S.C.,
Heal D.J.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb14010.x
Subject(s) - ritanserin , ketanserin , metergoline , chemistry , methysergide , endocrinology , antagonist , receptor antagonist , agonist , medicine , 5 ht receptor , idazoxan , pharmacology , receptor , serotonin , biochemistry , prazosin
1 The behavioural effects of the 5‐HT 1B receptor agonists, RU 24969 and CGS 12066B, have been investigated in C57/B1/6 mice. 2 RU 24969 (1–30 mg kg −1 ) produced intense and prolonged hyperlocomotion and other behavioural changes. 3 CGS 12066B caused similar effects, but they were much less pronounced, inconsistent and transient irrespective of whether this drug was given i.p. (1–15 mg kg −1 ) or i.c.v. (0.2–40 μg). However, CGS 12066B (7.5 and 15 mg kg −1 ) caused a dose‐related inhibition of RU 24969 (7.5 mg kg −1 )‐induced hyperlocomotion indicating that the former is a 5‐HT 1B partial agonist. 4 RU 24969 (7.5 mg kg −1 i.p.)‐induced hyperlocomotion was inhibited by the (−)‐, but not (+)‐ isomers of pindolol (4 mg kg −1 ) and propranolol (20 mg kg −1 ) but not by metoprolol (10 mg kg −1 ) or ICI 118,551 (5 mg kg −1 ), consistent with an involvement of 5‐HT 1A or 5‐HT 1B receptors. 5 The response was not altered by the selective 5‐HT 1A receptor antagonist, WAY 100135 (5 mg kg −1 , s.c), the 5‐HT 2A /5‐HT 2C receptor antagonist, ritanserin (0.1 mg kg −1 ), the selective 5‐HT 3 receptor antagonist, ondansetron (1 mg kg −1 ) or the non‐selective 5‐HT receptor antagonists methysergide (3 mg kg −1 ) and metergoline (3 mg kg −1 ). 6 Although spiroxatrine (0.1 mg kg −1 ) and ketanserin (1 mg kg −1 ) inhibited RU 24969‐induced hyperlocomotion, these effects were probably due to antagonism of dopamine D 2 receptors and α 1 ‐adrenoceptors respectively. 7 Taken together, these results indicate that RU 24969‐induced hyperlocomotion results specifically from activation of central 5‐HT 1B receptors. 8 Lesioning of 5‐HT neurones with 5,7‐dihydroxytryptamine (75 μg, i.c.v.) or depletion with p ‐chlorophenylalanine (200 mg kg −1 , i.p. for 14 days) had no effect on RU 24969‐induced hyperlocomotion demonstrating that the 5‐HT 1B receptors involved are postsynaptic and that they do not show supersensitivity. 9 The involvement of other monoamine neurotransmitter systems in RU 24969‐induced hyperlocomotion was also examined. The response was inhibited by the α 1 ‐adrenoceptor antagonist, prazosin (1 mg kg −1 ), the dopamine D 1 receptor antagonist, SCH 23390 (0.05 mg kg −1 ) and the dopamine D 2 receptor antagonist, BRL 34778 (0.03 mg kg −1 ), but not by the α 2 ‐adrenoceptor antagonist, idazoxan (1 mg kg −1 ). Lesioning noradrenergic neurones with N‐(2‐chloroethyl)‐ N ‐ethyl‐2‐bromobenzylamine (100 mg kg −1 ) markedly attenuated this behaviour. These results show that the hyperlocomotion is expressed via noradrenergic and dopaminergic neurones acting on α 1 ‐adrenoceptors, D 1 and D 2 receptors. 10 RU 24969 decreased brain concentrations of 5‐hydroxyindoleacetic acid whilst simultaneously increasing 5‐HT, consistent with the reduction of 5‐HT neuronal activity by activation of 5‐HT 1A and 5‐HT 1B autoreceptors. RU 24969 increased brain 3‐methoxy‐4‐hydroxyphenylglycol, but not noradrenaline, concentrations which supports the involvement of noradrenergic neurones in the expression of hyperlocomotion. RU 24969 did not alter dopamine, dihydroxyphenylacetic acid or homovanillic acid concentrations in the nucleus accumbens suggesting that the dopaminergic neurones terminating there are not directly involved.