N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline studies on the role of 5-HT 1A and 5-HT 2 receptors in mediating foot-shock-induced ultrasonic vocalisation in adult rats

Abstract

The role of 5-HT 1A and 5-HT 2 receptors in mediating foot-shock-induced ultrasonic vocalisation has been studied in rats. Furthermore, behavioural effects were correlated to receptor reserves in the brain by means of receptor inactivation with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). The dose-dependent inhibition of ultrasonic vocalisation by the 5-HT precursor, l-5-hydroxy- l-tryptophan (110–450 μmol/kg), was abolished by pretreatment with the 5-HT 1A/1B antagonist, (−)-penbutolol (27 μmol/kg), and the 5-HT 2A/2C antagonist, ritanserin (10 μmol/kg). The inhibitory actions of the 5-HT 1A receptor agonist 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT) and the 5-HT 2A/5-HT 2C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) were reversed by the 5-HT 1A antagonist, (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY-100 635), and the 5-HT 2A antagonist, (±)α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorphenyl)ethyl]-4-piperidine-methanol (MDL 100 151), respectively. Pretreatment with EEDQ (24 h, subcutaneous [s.c.]) inhibited foot-shock-induced ultrasonic vocalisation (effective dose 50=0.95 μmol/kg) and decreased [ 3H]-8-OH-DPAT and [ 3H]-ketanserin binding in the brain. Pretreatment with WAY-100 635 (0.3–20 μmol/kg) 20 min prior to EEDQ administration (1.3 μmol/kg, s.c.) did not reverse the EEDQ-induced inhibition of ultrasonic vocalisation but protected the 5-HT 1A receptors against EEDQ inactivation. Pretreatment with MDL 100 151 (0.83–54 μmol/kg) 20 min prior to EEDQ administration both reversed the EEDQ-induced inhibition of ultrasonic vocalisation and protected the 5-HT 2A receptors against EEDQ inactivation. These findings demonstrate that 5-HT 1A and 5-HT 2 receptors are involved in the regulation of ultrasonic vocalisation in rats. However, the function of 5-HT 1A and 5-HT 2 receptors in this model seems to differ as vocalisation was preserved after protection of 5-HT 2 but not 5-HT 1A receptors.