THE EFFECT OF 5-HT1A RECEPTOR AGONISTS ON LOCOMOTOR-ACTIVITY IN THE GUINEA-PIG

1 The present study examined the effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), flesinoxan, ipsapirone and buspirone, all agonists at the 5-HT1A receptor, on the locomotor activity of guinea-pigs. The effects of these drugs were contrasted with those of the non-selective 5-HT agonist, 5-methoxy-N,N-dimethyl tryptamine (5-MeO-DMT) and the dopamine D-2 antagonist, raclopride. 2 8-OH-DPAT, flesinoxan and 5-MeO-DMT markedly increased the locomotor activity of naive, unhabituated guinea-pigs in a dose-dependent manner. Buspirone also did so, although to a lesser extent and for a shorter time. The doses at which this effect was seen were higher than those normally employed in rats. Ipsapirone and raclopride had no significant effects on locomotor activity. 3 The locomotor activity increasing effect of 1.0 mg kg(-1) 8-OH-DPAT was blocked by the selective 5-HT1A antagonist (S)-UH-301 (3.0 and 10.0 mg kg(-1)), but not by (-)-alprenolol (15.0 mg kg(-1)). Ipsapirone (30.0 mg kg(-1)) and raclopride (3.0 mg kg(-1)) antagonized 8-OH-DPAT-induced locomotor activity but only to a small extent. The 5-HT reuptake inhibitor, zimelidine (10.0 mg kg(-1)) had no effect. 4 The effect of the 5-HT1A agonists in the guinea-pig contrasts with the effects of 8-OH-DPAT on the locomotor activity of unhabituated rats and mice tested in the same apparatus, but are similar to the effects of 8-OH-DPAT on habituated rats, which show a low baseline of activity. 5 These results support the suggestion that 5-HT1A agonists may have an intrinsic activating effect which may be masked by other effects of the drug (e.g. hypothermia, 5-HT syndrome). The rank ordering of the 5-HT1A agonists also suggests that the degree to which the drugs increase locomotor activity is related to their agonist efficacy at the postsynaptic 5-HT1A receptor.