Histaminergic Neurotransmission as a Gateway for the Cognitive Effect of Oleoylethanolamide in Contextual Fear Conditioning

Abstract

Background:The integrity of the brain histaminergic system is necessary for the unfolding of homeostatic and cognitive processes through the recruitment of alternative circuits with distinct temporal patterns. We recently demonstrated that the fat-sensing lipid mediator oleoylethanolamide indirectly activates histaminergic neurons to exerts its hypophagic effects. The present experiments investigated whether histaminergic neurotransmission is necessary also for the modulation of emotional memory induced by oleoylethanolamide in a contextual fear conditioning paradigm.Methods:We examined the acute effect of i.p. administration of oleoylethanolamide immediately posttraining in the contextual fear conditioning test. Retention test was performed 72 hours after training. To test the participation of the brain histaminergic system in the cognitive effect of oleoylethanolamide, we depleted rats of brain histamine with an i.c.v. injection of alpha-fluoromethylhistidine (a suicide inhibitor of histidine decarboxylase) or bilateral intra-amygdala infusions of histamine H1 or H2 receptor antagonists. We also examined the effect of oleoylethanolamide on histamine release in the amygdala using in vivo microdialysis.Results:Posttraining administration of oleoylethanolamide enhanced freezing time at retention. This effect was blocked by both i.c.v. infusions of alpha-fluoromethylhistidine or by intra-amygdala infusions of either pyrilamine or zolantidine (H1 and H2 receptor antagonists, respectively). Microdialysis experiments showed that oleoylethanolamide increased histamine release from the amygdala of freely moving rats.Conclusions:Our results suggest that activation of the histaminergic system in the amygdala has a “permissive” role on the memory-enhancing effects of oleoylethanolamide. Hence, targeting the H1 and H2 receptors may modify the expression of emotional memory and reduce dysfunctional aversive memories as found in phobias and posttraumatic stress disorder.

The Hyperpolarization-Activated Current Determines Synaptic Excitability, Calcium Activity and Specific Viability of Substantia Nigra Dopaminergic Neurons

“…Animals were housed in humidity- and temperature-controlled room (22–24°C), allowed free access to food (4RF21; Mucedola s.r.l., Milan, Italy) and water, and kept on a 12-h light/dark cycle (lights start at 7:00 AM). Procedures were performed according to a previous report (Provensi et al, 2017 ), with modifications due to the different brain areas involved. One week after arrival, animals were anesthetized with an intraperitoneal (i.p.)…”

Oleoylethanolamide, Neuroinflammation, and Alcohol Abuse

“…Lipopolysaccharide-induced neuroinflammation is associated also with learning and memory deficits in rodents (Sadraie et al, 2018) and it is well known that the effect of alcohol abuse in memory impairments. OEA appears to have a beneficial role in memory consolidation, through activation of PPARα receptors in the periphery (Campolongo et al, 2009; Provensi et al, 2017). OEA may modulate also emotional memory tasks such as the contextual fear conditioning, which appears very relevant as this behavioral paradigm is generally considered to have substantial coincidences with functional and neural mechanisms involved in anxiety and various other mental disorders (Rosen and Schulkin, 1998; Briscione et al, 2014), including alcohol addiction.…”

Neuronal histamine and the memory of emotionally salient events

“…A recent paper by our group proposed a novel role for the central histaminergic system as a gateway between peripheral signals and the elaboration of emotionally salient stimuli by the BLA to provide the appropriate information to be memorized for adequate behavioural responses (Provensi et al, 2017). Oleoylethanolamide (OEA) is released by enterocytes in response to fat intake and indirectly signals satiety to hypothalamic nuclei through sensory fibres of the vagus nerve (Fu et al, 2003).…”

“…OEA requires the integrity of the brain histamine system to fully exert its hypophagic effect (Provensi et al, 2014). Provensi and colleagues demonstrated that OEA also enhances memory expression of contextual fear conditioning, by stimulating histaminergic neurotransmission in the BLA (Provensi et al, 2017). Accordingly, both histamine depletion in the brain by using α‐FMH or intra‐BLA infusion of H 1 or H 2 receptor antagonists prevented the enhanced freezing elicited by OEA (Provensi et al, 2017).…”

“…Provensi and colleagues demonstrated that OEA also enhances memory expression of contextual fear conditioning, by stimulating histaminergic neurotransmission in the BLA (Provensi et al, 2017). Accordingly, both histamine depletion in the brain by using α‐FMH or intra‐BLA infusion of H 1 or H 2 receptor antagonists prevented the enhanced freezing elicited by OEA (Provensi et al, 2017). Hence, the integrity of the brain histaminergic system is necessary for the unfolding of emotional memory processes induced by OEA in a contextual fear conditioning paradigm.…”