The Role of Neuronal Histamine in Memory Processing

Neuronal histamine(HA) may play a role in memory processing. This hypothesis is based upon evidence that the action of histamine at central H1 and H2 histamine receptor sites has been shown to modulate memory of rats and mice in adversely-motivated tasks. The purpose of this study was to test this hypothesis more thoroughly in mice using two distinct approaches to neuronal HA manipulation. One approach involved the use of new pharmacological agents which act at the histamine H3 receptor. It has been demonstrated that the selective H3 antagonist thioperamide increases HA release in the brain of mice whereas the H3 agonist imetit decreases HA release via modulation of presynaptic H3 autoreceptors. It was expected that an increase in neuronal HA via the autoreceptor mechanism would result in facilitation of memory processing whereas a decrease in HA release would disrupt memory processing. The second approach involved the manipulation of cerebral HA levels via the specific enzyme inhibiting compounds alpha-flouromethylhistidine (alpha-FMH), a potent neuronal HA depleter and metoprine, a histamine-methyl transferase inhibitor which results in accumulation of neuronal HA. Again, effects of increased HA due to metoprine and decreased HA levels due to alpha-FMH were expected to facilitate and disrupt memory processing respectively. One trial inhibitory (passive) avoidance training was employed in each experiment in order to evaluate the effect of each drug on memory. Each compound was tested for effects on memory consolidation and memory retrieval as well as for the presence of state dependent effects. The pattern of effects obtained with thioperamide suggested facilitation of acquisition or memory storage (consolidation) processes, with no effect on the retrieval phase of memory processing. In accordance with those findings, significant disruption of memory occurred when imetit was present during the consolidation phase of memory processing, but not when presented prior to the retrieval phase. These findings suggest that H3 receptor sites play a significant role in the modulation of memory processes via some mechanism which exclusively affects the acquisition or memory consolidation process, while the retrieval of previously laid down memory traces is unaffected