2 SELECTIVE 5-HT1A RECEPTOR ANTAGONISTS, WAY-100-635 AND NDL-249, STIMULATE LOCOMOTION IN RATS ACCLIMATIZED TO THEIR ENVIRONMENT AND ALTER THEIR BEHAVIOR - A BEHAVIORAL-ANALYSIS

The aim was to study firstly the motor effects of a new 5-HT1A antagon ist, NDL-249 8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamine hydroc hloride] and of the reference 5-HT1A antagonist WAY-100 635 -methoxyph enyl)piperazinyl))ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihyd rochloride], in comparison to the 5-HT1A agonist (+/-)-8-OH-DPAT [(8-h ydroxy-2-(di-N-propylamino) tetralin, hereafter 8-OH-DPAT], in rats ac climatised to the automated activity cages; secondly, to study whether the behavioural effects of NDL-249 and 8-OH-DPAT are sensitive to the 5-HT depleting effects of p-chlorophenylalanine (PCPA); thirdly, to c haracterise the nature of the antagonist-induced activation seen in th e automatic activity cages with the aid Of a behavioural observation a nalysis; fourthly, to examine the interaction between the 5-HT1A recep tors mediating the behavioural effects and dopamine (DA) receptors. ND L-249 was found to bind in vitro to rat hippocampal 5-HT1A receptors w ith high affinity and selectivity. In second messenger studies, it was devoid of agonist-like effects. In the locomotor activity studies, ea ch antagonist significantly increased the incidence of horizontal acti vity, peripheral activity and rearing, 8-OH-DPAT, while significantly increasing peripheral and horizontal activities, decreased the inciden ce of rearing. PCPA blocked the motor effects of NDL-249 but did not a ffect those of 8-OH-DPAT. Observational analyses indicated that NDL-24 9 induced significant increases at one or more doses in sniffing, rear ing and locomotion together with a significant reduction in stillness. WAY-100 635 significantly increased the incidence of rearing, intense grooming and vacuous chewing. The significant increases in sniffing, grooming and intense grooming and the significant decrease in stillnes s induced by the DA D-1 agonist, SK&F 38393 nyl-2,3,4,5-tetrahydro-(1H )-3-benzazepine-7,8-diol hydrochloride]. were not altered by concomita nt pre-treatment with NDL-249. Pre-treatment of rats with either the D A D-1 antagonist SCH-23390 (2,3,4,5-tetrahydro-3-methyl-5-phenyl- 1H-3 -benzazepin-7-ol) or the DA D-2 antagonist, raclopride, blocked the re duced stillness and increased sniffing and rearing induced by NDL-249. In conclusion, 5-HT1A antagonists including the new selective antagon ist, NDL-249, induce mild behavioural activation in rats, which is med iated probably indirectly via DA systems.