LAUSR

ABSTRACT The role of 5‐HT2C receptors (5‐HT2CRs) in the regulation of anxiety has been widely acknowledged. However, conflicting results have been reported on whether stimulation of these receptors increases or decreases anxiety. We here investigated the role of 5‐HT2CRs of the dorsal hippocampus (DH) in the mediation of anxiety‐ or panic‐associated defensive behaviors and in the anxiolytic effect of the tricyclic antidepressant imipramine. In the Vogel conflict test, administration of the mixed 5‐HT2CR agonist mCPP into the DH of male Wistar rats was anxiogenic, whereas infusions of the more selective agonists MK‐212 and RO‐600175 were anxiolytic. The 5‐HT2CR antagonist SB‐242084, on the other hand, was anxiogenic. A sub‐effective dose of this antagonist blocked the anxiolytic effect of RO‐600175, but not the increase in anxiety observed with mCPP, indicating that the latter effect was not due to 5‐HT2CR activation. In full agreement with these findings, MK‐212 and RO‐600175 in the DH also inhibited inhibitory avoidance acquisition in the elevated T‐maze, whereas SB‐242084 caused the opposite effect. None of these drugs interfered with escape expression in this test, which has been associated with panic. Chronic administration of imipramine (15 mg/kg, ip, 21 days) caused an anxiolytic effect in the elevated T‐maze and light‐dark transition tests, which was not blocked by previous infusion of SB‐242084 into the DH. Therefore, facilitation of 5‐HT2CR‐mediated neurotransmission in the DH decreases the expression of anxiety‐, but not panic‐related defensive behaviors. This mechanism, however, is not involved in the anxiolytic effect caused by imipramine. HighlightsActivation of 5‐HT2CRs in the DH causes anxiolytic effects.DH 5‐HT2CRs are not involved in the regulation of panic‐related defensive responses.DH 5‐HT2CRs are not recruited for the anxiolytic effect of chronic imipramine.