Differential effects of histamine H3 receptor inverse agonist thioperamide, given alone or in combination with the N-methyl-d-aspartate receptor antagonist dizocilpine, on reconsolidation and consolidation of a contextual fear memory in mice

Abstract

Abstract-Albeit there is no doubt that histamine and its H 3 receptors participate in several aspects of learning and memory, such as memory consolidation, nothing is known about their potential involvement in memory reconsolidation. On the basis of previous reports of pro-cognitive effects of histamine H 3 receptor inverse agonists (which augment histamine release), we investigated to what extent the most representative of them, thioperamide, is able to facilitate reconsolidation of a contextually-conditioned fear memory in C57BL/6J mice. We also examined the effects of thioperamide on the stark disruptive effect that the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) typically exerts on both reconsolidation and consolidation. Post-training systemic injections (i.p.) of thioperamide facilitated consolidation at 10 and 20 mg/kg and reversed amnesia induced by an i.p. injection of 0.12 mg/kg dizocilpine at 5, 10 and 20 mg/kg. Importantly, none of the five thioperamide doses (2.5, 5, 10, 20 and 30 mg/kg) given right after reactivation (reexposure to the context in which training took place 48 h earlier) affected reconsolidation, whereas all similarly given doses of dizocilpine (0.03, 0.06 and 0.12 mg/kg) disrupted it more or less equally. By contrast, thioperamide was able to unambiguously reverse the deficit in reconsolidation induced by 0.12 mg/kg dizocilpine at 10 and 20, but not 5 mg/kg. This is the first demonstration of an involvement of the interactive articulation between histamine and NMDA receptors in the mechanisms of memory reconsolidation, which seems to be indifferent to an increase of brain histamine per se. The results suggest a qualitatively different participation of histaminergic signalling in the mechanisms of reconsolidation and consolidation. The precise circuits within which these interactions take place are yet to be identified.

On the transition from reconsolidation to extinction of contextual fear memories

“…Therefore, while context reexposure led to behaviorally defined extinction for all durations, this extinction was apparently NMDA receptor-dependent only for the 30-min condition. Moreover, the reconsolidation impairment with the brief reexposure duration was observed in spite of a significant between-session decline in freezing, as has been previously documented in the literature (Charlier and Tirelli 2011;Brabant et al 2013;Heath et al 2015). Importantly, we observed a similar pattern of freezing reduction even in the animals that received MK-801 after context reexposure, no matter how long the session lasted for (Fig.…”

The histamine H3-receptor inverse agonist Pitolisant improves fear memory in mice

“…The role of histamine transmission is practically unknown in reconsolidation processes. In our laboratory, we have previously demonstrated that thioperamide can block the deficit in reconsolidation produced by dizocilpine in the fear conditioning test [14].…”

“…During the consolidation phase, memories are susceptible to disruption when amnesic treatments are applied shortly after learning such as electroconvulsive shocks [13]. Glutamate transmission and in particular N-methyld-aspartate (NMDA) receptors play a critical role in consolidation of fear memories since the blockade of NMDA receptors impairs memory consolidation [14] whereas NMDA receptor activation facilitates consolidation [15]. In addition, other neurotransmitter systems like histamine can facilitate the consolidation of memories [16].…”

“…In addition, other neurotransmitter systems like histamine can facilitate the consolidation of memories [16]. The systemic injection of H 3 R inverse agonists improve consolidation in the inhibitory avoidance test [17], the social memory test [18,19], the two-trail place recognition task [20] and the fear conditioning task [14].…”

“…As for consolidation, NMDA receptors play an important function in reconsolidation processes [25]. The blockade of NMDA receptors with dizocilpine impairs memory reconsolidation in the fear conditioning task [14,26]. Inversely, activation of these receptors with the partial agonist d-cycloserine facilitates reconsolidation in the same task [26].…”