Functional serotonin (5-hydroxytryptamine, 5-HT) receptors have been divided into three subtypes: 5-HT1-like, 5-HT2 and 5-HT3 (ref. 1). Brain binding sites have been identified for both the 5-HT1 and 5-HT2 subtypes. Receptors of the 5-HT3 type have been characterized on isolated peripheral tissue models such as the rat vagus nerve, guinea-pig ileum and isolated rabbit heart. Using these models, selective 5-HT3 receptor antagonists such as MDL 72222 (ref. 5), ICS 205-930 (ref. 6), GR38032F (ref. 7) and BRL 43694 (ref. 8) have been developed. Recently, GR38032F, MDL 72222 and ICS 205-930 have been shown to have behavioural effects in rodents and primates that undoubtedly reflect an action in the central nervous system (refs 9-11 and unpublished observations), suggesting the existence of 5-HT3 receptors in the brain. Here we report direct evidence for the existence of 5-HT3 receptors in rat brain tissue and their distribution, based on high affinity binding of the potent 5-HT3 receptor antagonist 3H-GR65630 to homogenates of rat entorhinal cortex. Selective 5-HT3 receptor antagonists and agonists inhibited binding of 3H-GR65630 with high affinities which correlated well with their actions on the rat isolated vagus nerve. Binding was differentially distributed throughout the brain with high concentrations in cortical and limbic areas.

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1 This paper describes the pharmacology of the novel 5-hydroxytryptamine3 (5-HT3) receptor antagonist GR38032F. 2 On the isolated vagus nerve and superior cervical ganglion of the rat, R,S-GR38032F behaved as a reversible competitive antagonist of 5-HT-induced depolarization with pKB values of 8.61 + 0.08 (n = 19) and 8.13 + 0.07 (n = 16), respectively. The resolved R-and S-isomers of GR38032F were approximately equipotent as 5-HT antagonists on the rat vagus nerve: the pKB values were 8.95 + 0.05 (n = 16) and 8.63 + 0.08 (n = 17), respectively. R,S-GR38032F was also an effective antagonist of 5-HT on the rabbit isolated vagus nerve: in this case the pKB value was 9.40 + 0.14 (n = 4).3 On the rabbit isolated heart, low concentrations of R,S-GR38032F (3 x 10-1`4l x 10-9M)antagonized the positive chronotropic effect of 5-HT and 2-methyl-5-hydroxytryptamine (2-methyl-5-HT). However, the effects of the compound did not appear consistent with simple reversible competition. 4 On the longitudinal smooth muscle of the guinea-pig ileum, RS-GR38032F caused concentration-dependent parallel rightward displacement of the 2-methyl-5-HT concentrationcontraction response curve; in contrast, a portion of the response to 5-HT appeared resistant to R,S-GR38032F. pKB values estimated from the effects of the compound against 2-methyl-5-HT or the inhibitable portion of the response to 5-HT were 7.31 + 0.06 (n = 8) and 7.33 + 0.13 (n = 8), respectively. Against 2-methyl-5-HT, R-GR38032F seemed more potent (pKB 7.20 + 0.10; n = 6) than S-GR38032F (pKB 6.30 + 0.05; n = 6).5 R,S-GR38032F is highly selective for 5-HT3 receptors, and at concentrations of 3 x 10-6_ 3 x 10-M, had negligible agonist or antagonist activity on other 5-HT or non-5-HT receptorcontaining tissues on which it was tested. 6 The potency and duration of action of R,S-GR38032F in blocking 5-HT3 receptors in vivo were assessed by measuring its ability to antagonize the bradycardic response to 5-HT or 2-methyl-5-HT administered intravenously (i.v.) to anaesthetized animals. For i.v. administration to the rat, the ED50 for R,S-GR38032F against 2-methyl-5-HT (100pgkg-1) was 0.4 (95% confidence limits 0.18-0.87) ygkg-1 (n = 10); the corresponding value for oral administration to this species was 7.0 (3.0-22.0)pgkg-' (n = 8-10 per dose level). R,S-GR38032F was similarly effective in the anaesthetized cat. 7 The present results are discussed with reference to the postulated existence of subtypes of the 5-HT3 receptor.

1To investigate the opiate receptors that mediate antinociception, the activity profiles of opioid analgesic drugs have been determined against different nociceptive stimuli in the mouse and rat.2 In tests that employ heat as the nociceptive stimulus, p-opiate receptor agonists, such as morphine, pethidine and dextropropoxyphene, had steep and parallel dose-response curves and were capable of achieving maximum effects. In addition, the antinociceptive potency ratios of these drugs in heat tests were similar to those for analgesia in man. 3 The K-agonists, such as ethylketazocine, nalorphine, Mr2034 and pentazocine, were essentially inactive against heat nociception except at doses that caused sedation and motor incapacitation. 4 In the writhing and paw pressure tests both j-and a--agonists produced steep and parallel dose-response curves. 5 It is concluded that both t-and K-opiate receptors mediate antinociception in animals and that the interactions of analgesic drugs with these receptors may be classified in terms of their antinociceptive activities against qualitatively different nociceptive stimuli.