Evidence that RU 24969‐induced locomotor activity in C57/B1/6 mice is specifically mediated by the 5‐HT1B receptor
Authors: Cheetham S.C. , Heal D.J. 
Published: July 2012

The behavioural effects of the 5‐HT1B receptor agonists, RU 24969 and CGS 12066B, have been investigated in C57/B1/6 mice.
RU 24969 (1–30 mg kg−1) produced intense and prolonged hyperlocomotion and other behavioural changes.
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‐HT1B partial agonist.
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‐HT1A or 5‐HT1B receptors.
The response was not altered by the selective 5‐HT1A receptor antagonist, WAY 100135 (5 mg kg−1, s.c), the 5‐HT2A/5‐HT2C receptor antagonist, ritanserin (0.1 mg kg−1), the selective 5‐HT3 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).
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 D2 receptors and α1‐adrenoceptors respectively.
Taken together, these results indicate that RU 24969‐induced hyperlocomotion results specifically from activation of central 5‐HT1B receptors.
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‐HT1B receptors involved are postsynaptic and that they do not show supersensitivity.
The involvement of other monoamine neurotransmitter systems in RU 24969‐induced hyperlocomotion was also examined. The response was inhibited by the α1‐adrenoceptor antagonist, prazosin (1 mg kg−1), the dopamine D1 receptor antagonist, SCH 23390 (0.05 mg kg−1) and the dopamine D2 receptor antagonist, BRL 34778 (0.03 mg kg−1), but not by the α2‐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 α1‐adrenoceptors, D1 and D2 receptors.
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‐HT1A and 5‐HT1B 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.