Analysis of mechanisms for memory enhancement using novel and potent 5-HT1A receptor ligands

In light of the involvement of serotonergic 5-HT1A receptors in the mediation of the memory of aversive events, the potent and selective 5-HT1A receptor antagonists, MC18 fumarate and VP08/34 fumarate, were tested in the passive avoidance task (PA), a rodent model of instrumental conditioning. Either alone or in combination with the prototypical agonist 8-OH-DPAT, MC18 fumarate at doses (0.1, 0.3 and 1 mg/kg given 15 min prior to training) exerted a dose-dependent facilitation of PA memory retention. When administered 15 min prior to 8-OH-DPAT (0.3 and 1 mg/kg), MC18 fumarate at a dose of 0.3 mg/kg, enhanced significantly the impairment of PA retention caused by 8-OH-DPAT (1 mg/kg). However, VP08/34 fumarate given at the same doses exerted no statistically effect on PA retention memory. Furthermore, VP08/34 fumarate given 15 min prior to 8-OH-DPAT (0.3 and 1 mg/kg) only slightly enhanced the PA impairment induced by 8-OH-DPAT. In conclusion, the profile of MC18 fumarate is intriguing since it behaves in a manner which differs from both full receptor antagonists such as NAD-299 or partial receptor agonists. The results also illustrate the importance of subtle receptor interaction and probably ligand efficacy in determining the actions of two almost identical 5-HT1A receptor ligands in cognitive function such as instrumental learning.