Modulation of cannabinoid signaling by hippocampal 5-HT4 serotonergic system in fear conditioning

Abstract

Behavioral studies have suggested a key role for the cannabinoid system in the modulation of conditioned fear memory. Likewise, much of the literature has revealed that the serotonergic system affects Pavlovian fear conditioning and extinction. A high level of functional overlap between the serotonin and cannabinoid systems has also been reported. To clarify the interaction between the hippocampal serotonin (5-HT4) receptor and the cannabinoid CB1 receptor in the acquisition of fear memory, the effects of 5-HT4 agents, arachidonylcyclopropylamide (ACPA; CB1 receptor agonist), and the combined use of these drugs on fear learning were studied in a fear conditioning task in adult male NMRI mice. Pre-training intraperitoneal administration of ACPA (0.1 mg/kg) decreased the percentage of freezing time in both context- and tone-dependent fear conditions, suggesting impairment of the acquisition of fear memory. Pre-training, intra-hippocampal (CA1) microinjection of RS67333, a 5-HT4 receptor agonist, at doses of 0.1 and 0.2 or 0.2 µg/mouse impaired contextual and tone fear memory, respectively. A subthreshold dose of RS67333 (0.005 µg/mouse) did not alter the ACPA response in either condition. Moreover, intra-CA1 microinjection of RS23597 as a 5-HT4 receptor antagonist did not alter context-dependent fear memory acquisition, but it did impair tone-dependent fear memory acquisition. However, a subthreshold dose of the RS23597 (0.01 µg/mouse) potentiated ACPA-induced fear memory impairment in both conditions. Therefore, we suggest that the blockade of hippocampal 5-HT4 serotonergic system modulates cannabinoid signaling induced by the activation of CB1 receptors in conditioned fear.

Focus on cannabinoids and synthetic cannabinoids

“…Indeed, modulation of cannabinoid signaling by interaction with various serotonergic receptors, such as 5-HT2A or 5-HT4 receptors, has been demonstrated. 26,27 These data suggest that the serotonergic system plays a role in anxiety/ depression side effects observed with cannabinoids, and may be a basis for new approaches in the treatment of anxiety disorders.…”

Interaction between hippocampal serotonin and cannabinoid systems in reactivity to spatial and object novelty detection

“…Accumulating evidence suggests that there is an interaction between CB1Rs and the 5-HT neuronal system [2,13]. We previously reported the involvement of 5-HT4 receptors in learning deficits induced by activation of CB1Rs in passive avoidance step-down task [26] and fear conditioning apparatus [27].…”

“…Among the numerous serotonin (5-HT) receptors, the 5-HT4 receptors, appear to be of particular importance in cognitive processes [1][2][3]. High density of 5-HT4 receptors in the limbic system, mainly on the pyramidal neurons of hippocampus, suggests a potential role in learning and memory [4,5].…”

GABA‐ergic agents modulated the effects of histamine on the behaviour of male mice in the elevated plus maze test

“…microinjection of the drug was performed 5 min before the test, and intraperitoneal ( i.p. ) injection of drug was performed 15 min before the test (Nasehi et al., 2016a). Thus, histamine was administered intracerebroventricularly (a volume of 1 μl/mouse) 5 min before testing, but muscimol and bicuculline were administered intraperitoneally (a volume of 10 ml/kg) 15 min before testing.…”

“…microinjection of the drug was performed 5 min before the test, and intraperitoneal (I.P.) injection of drug was performed 15 min before the test (Nasehi et al, 2016a). Thus, histamine was administered intracerebroventricularly…”