Modulation of cannabinoid signaling by hippocampal 5-HT4 serotonergic system in fear conditioning.
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.
Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran.
Mohammad
M
Nasehi
Department of Biology, Faculty of Basic Sciences, Islamic Azad University, Northern Branch, Tehran, Iran.
Maryam
M
Farrahizadeh
Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran.
Mohaddeseh
M
Ebrahimi-Ghiri
Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran Department of Pharmacology School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran Institute for Cognitive Science Studies (ICSS), Tehran, Iran School of Cognitive Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran Medical Genomics Research Center, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran zarinmr@ams.ac.ir.
Mohammad-Reza
MR
Zarrindast
D000814:Aniline Compounds / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D002186:Cannabinoids / Q000378:metabolism*; D003214:Conditioning, Classical / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4 / Q000187:drug effects / Q000378:metabolism*; D058828:Serotonin 5-HT4 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D058832:Serotonin 5-HT4 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D062366:para-Aminobenzoates / Q000008:administration & dosage / Q000494:pharmacology
C084177:3-(piperidine-1-yl)propyl 4-amino-5-chloro-2-methoxybenzoate hydrochloride; D000814:Aniline Compounds; D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D010880:Piperidines; D043884:Receptor, Cannabinoid, CB1; D058828:Serotonin 5-HT4 Receptor Agonists; D058832:Serotonin 5-HT4 Receptor Antagonists; C119324:arachidonylcyclopropylamide; D062366:para-Aminobenzoates; D044422:Receptors, Serotonin, 5-HT4; C107826:RS 67333
5-HT4 serotonin receptor; CA1 region; Cannabinoid; fear conditioning; mice