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 1mg/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 1mg/kg), MC18 fumarate at a dose of 0.3 mg/kg, enhanced significantly the impairment of PA retention caused by 8-OH-DPAT(1mg/kg). However,VP08/34 fumarate given at the same doses exerted nostatistically 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-OHDPAT.In conclusion, the profile of MC18 fumarate isintriguing 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.