A behavioural and biochemical study in mice and rats of putative selective agonists and antagonists for 5‐HT1 and 5‐HT2 receptors

Abstract

1 Radioligand binding techniques have demonstrated the existence of 5-hydroxytryptamine (5-HT) binding subtypes: 5-HT₂, 5-HT_1A and 5-HT_1B. These techniques have also indicated that certain drugs appear to show sub-type specificity: 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT_1A agonist; 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)l-H indole (RU 24969), a 5-HT_1B agonist; and ritanserin, a 5-HT₂ antagonist. (−)−Propranolol is a 5-HT₁ antagonist of uncertain sub-type specificity. 2 An examination has been made in mice and rats of the behavioural and biochemical effects of these drugs to determine whether the binding sites have physiological functions and further characterise the behavioural models. 3 Administration of carbidopa (25 mg kg⁻¹) plus 5-hydroxytryptophan (100 mg kg⁻¹) produced head-twitch behaviour in mice which was antagonized by ritanserin (ED₅₀ = 65 μg kg⁻¹) but not (−)−propranolol (20 mg kg⁻¹). 8-OH-DPAT (1–10 mg kg⁻¹ s.c.) and RU 24949 (5 mg kg⁻¹ i.p.) did not produce head-twitch behaviour. 8-OH-DPAT decreased 5-HTP- but not S-methoxy-N-N-dimethyl-tryptamine (5 mg kg⁻¹)-induced head-twitch by a (−)−propranolol-insensitive mechanism. 4 Locomotor activity produced in mice by RU 24969 (3 mg kg⁻¹) was antagonized by (−)−propranolol (20 mg kg⁻¹) but not the (+)-isomer. (−)−Propranolol did not antagonize the behaviour induced in rats. 5 In mice, both 8-OH-DPAT and RU 24969 markedly inhibited whole brain 5-HT synthesis and this effect was not antagonized by (−)−propranolol. 6 In rats, 8-OH-DPAT (3 mg kg⁻¹ s.c.) produced all the behavioural changes seen after quipazine (25 mg kg⁻¹). (−)−Propranolol inhibited the behaviour changes produced by both agonists, while ritanserin antagonized the behaviour produced by quipazine but not 8-OH-DPAT. It is concluded, therefore, that the 5-HT_1A receptor exists between the 5-HT₂ receptor and the behavioural effectors. 7 8-OH-DPAT (at 20°C ambient temperature) rapidly decreased rat body temperature, an effect antagonized by (−)−propranolol but not ritanserin. Quipazine (at 27°C ambient temperature, but not 20°C) increased body temperature but the effect was not blocked by either antagonist. 8 Ritanserin does not antagonize apomorphine-induced locomotion in either species. 9 We suggest that 5-HT-induced head-twitch behaviour in mice is a useful 5-HT₂ receptor model and the temperature change following 8-OH-DPAT injection in rats may be a 5-HT_1A model. While (−)−propranolol antagonizes 8-OH-DPAT effects in rat, it does not inhibit 8-OH-DPAT effects in mice, and instead antagonizes RU 24969-induced locomotion. Its status as a 5-HT₁ antagonist remains ill-defined.