Role of 5-HT2A and 5-HT2C receptor subtypes in the two types of fear generated by the elevated T-maze.

To study the role of 5-HT2A and 5-HT2C receptor subtypes in anxiety, the behavioral effects of drugs that either block or stimulate these receptors were measured in an animal model of anxiety, the elevated T-maze. One arm of the maze is enclosed by walls and stands perpendicular to the two open arms. Inhibitory (passive) avoidance--representing learned fear--was measured by placing a rat at the end of the enclosed arm and recording the time to leave this arm with the four paws during three consecutive trials. After 30 s, the same animal was placed at the end of one of the open arms and the time to leave this arm with the four paws was recorded. This one-way escape response represents unconditioned fear. The I.P. injection of the preferential 5-HT2C receptor agonists mCPP and TFMPP (0.1-0.8 mg/kg), 25 min before the experimental session enhanced inhibitory avoidance. In contrast, the same drugs either tended to impair (mCPP) or significantly inhibited (TFMPP) one-way escape. The preferential 5-HT2A agonist DOI (0.03-0.3 mg/kg) did not change either inhibitory avoidance or one-way escape. Inhibitory avoidance was impaired by the selective 5-HT2C antagonists SB 200646A (3.0-30 mg/kg) and SDZ SER 082 (0.1-1.0 mg/kg), by the 5-HT2A antagonist SR 46349B (1.0-10.0 mg/kg), and by the mixed 5-HT(2A,2C) antagonist ritanserin (0.3-3.0 mg/kg). However, it was not affected by the selective 5-HT2A antagonist RP 62203 (0.25-4.0 mg/kg). All the 5-HT2 antagonists used were ineffective on one-way escape. Therefore, conditioned fear seems to be tonically facilitated through 5-HT2C receptor stimulation, although the 5-HT2A receptor may also participate in its regulation. Unconditioned fear might be phasically inhibited by 5-HT2C receptor activation.