Acquisition deficit and time-dependent retrograde amnesia for contextual fear conditioning in agmatine-treated rats

Cumulative evidence indicates that the hippocampus plays a time-limited rol e in contextual learning paradigms. Pharmacological studies have indicated that acquisition of background contextual cues during Pavlovian fear condit ioning is dependent upon hippocampal function, whereas early inactivation o f the hippocampus after training produces retrograde amnesia. When administ ered prior to contextual fear conditioning, agmatine (5 and 10 mg/kg, i.p.) , an endogenous polyamine and N-methyl-D-aspartate (NMDA) receptor ligand f ound at excitatory synapses in the hippocampus, impaired the acquisition of contextual fear (measured as defensive freezing 26 hours later) without a reduction in baseline motor activity during training. Furthermore, ascendin g doses of agmatine were found not to exert analgesic effects on response t hresholds to peripheral shock. This negated the possibility that the observ ed learning deficit resulted from a difference in perceived shock intensity . Post-training agmatine treatment produced a time-dependent impairment of consolidation, with subjects approaching a level of fear equivalent to that of a reference group as the delay of treatment increased (up to 6 hours). Since physiologically high levels of agmatine are able to inhibit NMDA rece ptor activity, these results suggest that polyamine modulation of NMDA rece ptors, most likely within the hippocampus, is required for the acquisition and consolidation of contextual fear stimuli. (C) 2000 Lippincott Williams & Wilkins.