The effect of 5-HT4 serotonin receptors in the CA3 hippocampal region on D-AP5-induced anxiolytic-like effects: Isobolographic analyses

Abstract

Increasing evidence shows the close relationship between hippocampal glutamatergic and serotonergic systems through the modulation of behavioral responses. This study aimed to investigate the possible involvement of 5-HT4 receptors in the CA3 hippocampal region in anxiolytic-like effects induced by D-AP5 (a competitive antagonist of the glutamate NMDA [N-Methyl-D-aspartate] receptor). Male Wistar rats were placed in the elevated plus maze (EPM) apparatus that is used to assess anxiety-related behaviors, and the percentages of open arm time (%OAT) and open arm entries (%OAE) which are associated with anxiety-related behaviors were measured. The close arm entries (CAE) which is correlated with locomotor activity was also evaluated. The results showed that, intra-CA3 injection of D-AP5 (0.4\u2009µg/rat), RS67333 (1.2\u2009µg/rat; a 5-HT4 receptor agonist), and RS23597-190 (1.2\u2009µg/rat; a 5-HT4 receptor antagonist) increased %OAT and %OAE, indicating the anxiolytic-like effect of these drugs. Also, only RS23597-190 (1.2\u2009µg/rat) decreased CAE. Intra-CA3 injection of sub-threshold dose of RS67333 (0.012\u2009µg/rat) or RS23597-190 (0.012\u2009µg/rat), 5\u2009min before the injection of D-AP5 (0.2\u2009µg/rat) increased %OAT, indicating potentiating the anxiolytic-like effect of D-AP5. The isobolographic analyses also showed the additive or synergistic anxiolytic-like effect of intra-CA3 co-administration of D-AP5 with RS67333 or RS23597-190, respectively. In conclusion, CA3 5-HT4 receptors are involved in D-AP5-induced anxiolytic-like behaviors in rats.