Determination of the 5-HT receptor subtype involved in 8-OH-DPAT-induced hyperlocomotion: potential difficulties arising from inadequate pharmacological tools.
Selective 5-HT1A receptor agonists such as 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), flesinoxan, 5-methylurapidil and others, increased locomotor behaviour in rats following s.c. injection. Unfortunately, all available 5-HT1A receptor antagonists are non-selective, a fact which severely hampers their use. The inhibitory effects of (+)- and (-)-pindolol (1-10 mg/kg, -45 min s.c.) on locomotion induced by 8-OH-DPAT were investigated in rats pretreated with the beta-adrenoceptor antagonists, ICI 118,551 and betaxolol (both 1 mg/kg, -45 min s.c.). ICI 118,551 and betaxolol significantly enhanced the response to 8-OH-DPAT. Co-administration of (-)-pindolol (2-10 mg/kg) dose dependently antagonised the hyperlocomotion whereas (+)-pindolol was weakly effective at 10 mg/kg. The partial agonists ipsapirone (1-10 mg/kg, -45 min s.c.) and buspirone (0.1-1 mg/kg, -45 min) antagonised the effects of 8-OH-DPAT. This inhibition may, however, be due to alpha 1-adrenoceptor blockade and DA receptor antagonism, respectively. Finally, although spiroxatrine (0.1 and 1 mg/kg, -45 min s.c.) inhibited the response to 8-OH-DPAT, this inhibition may also be non-specific since spiroxatrine strongly reduced spontaneous locomotor activity. In conclusion, whilst much of our data is consistent with 8-OH-DPAT-induced locomotion being mediated by 5-HT1A receptors, only the data obtained with the pindolol enantiomers provide direct evidence for this. The results also suggest that, under normal circumstances, the 5-HT1A receptor antagonist effect of pindolol may be masked by the facilitating effect of beta-adrenoceptor blockade.
Kalkman
H O
HO
Preclinical Research, Sandoz Pharma Ltd., Basel, Switzerland.
Soar
J
J
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D002065:Buspirone / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D010869:Pindolol / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D004146:Dioxanes; D011743:Pyrimidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013141:Spiro Compounds; D013764:Tetrahydronaphthalenes; C043077:ipsapirone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010869:Pindolol; C018387:spiroxatrine; D006220:Haloperidol; D002065:Buspirone