Effects of a Flavonoid-Rich Fraction on the Acquisition and Extinction of Fear Memory: Pharmacological and Molecular Approaches

Abstract

The effects of flavonoids have been correlated with their ability to modulate the glutamatergic, serotoninergic, and GABAergic neurotransmission; the major targets of these substances are N-methyl-D-aspartic acid receptor (NMDARs), serotonin type1A receptor (5-HT1ARs), and the gamma-aminobutyric acid type A receptors (GABAARs). Several studies showed that these receptors are involved in the acquisition and extinction of fear memory. This study assessed the effects of treatment prior to conditioning with a flavonoid-rich fraction from the stem bark of Erythrina falcata (FfB) on the acquisition and extinction of the conditioned suppression following pharmacological manipulations and on gene expression in the dorsal hippocampus (DH). Adult male Wistar rats were treated before conditioned fear with FfB, vehicle, an agonist or antagonist of the 5-HT1AR, GABAARs or the GluN2B-NMDAR or one of these antagonists before FfB treatment. The effects of these treatments on fear memory retrieval, extinction training and extinction retrieval were evaluated at 48, 72, and 98 h after conditioning, respectively. We found that activation of GABAARs and inactivation of GluN2B-NMDARs play important roles in the acquisition of lick response suppression. FfB reversed the effect of blocking GluN2B-NMDARs on the conditioned fear and induced the spontaneous recovery. Blocking the 5-HT1AR and the GluN2B-NMDAR before FfB treatment seemed to be associated with weakening of the spontaneous recovery. Expression of analysis of DH samples via qPCR showed that FfB treatment resulted in the overexpression of Htr1a, Grin2a, Gabra5, and Erk2 after the retention test and of Htr1a and Erk2 after the extinction retention test. Moreover, blocking the 5-HT1ARs and the GluN2B-NMDARs before FfB treatment resulted in reduced Htr1a and Grin2b expression after the retention test, but played a distinct role in Grin2a and Erk2 expression, according session evaluated. We show for the first time that the serotoninergic and glutamatergic receptors are important targets for the effect of FfB on the conditioned fear and spontaneous recovery, in which the ERK signaling pathway appears to be modulated. Further, these results provide important information regarding the role of the DH in conditioned suppression. Taken together, our data suggest that FfB represents a potential therapy for preventing or treating memory impairments.

Flavones-bound in benzodiazepine site on GABA A receptor: Concomitant anxiolytic-like and cognitive-enhancing effects produced by Isovitexin and 6-C-glycoside-Diosmetin

“…Our results confirm that treatment with 4 mg/kg Diazepam had an anxiolytic-like effect and impaired short-and long-term memory retention evaluated in the training and test session, respectively, in the PM-DAT task and is in accordance with data described by Silva and colleagues (Silva et al, 2016). This effect is well-established in rodents studies in different tasks (de Oliveira et al, 2014(de Oliveira et al, , 2015Silva et al, 2016) and human studies (Rich et al, 2006;Roy-Byrne et al, 1987;Verwey et al, 2005). Moreover, the increase in the total number of entries into any of the arms during testing suggest that the rats treated with Diazepam at the higher dose could not distinguish the aversive arms from the non-aversive arm in the test session in relation to rats treated with flavones (Vicenin-2 and Vitexin), which was interpreted as impaired memory retention, since no drugs were administered before the test session.…”

“…T anticonvulsant, myorelaxant and cognitive-impairing effects (de Oliveira et al, 2014(de Oliveira et al, , 2015Griffin et al, 2013;Rich et al, 2006;Verwey et al, 2005).…”

Protective, Preventive and Enhancing-Memory Effects of the Flavonoidic-Rich Plants or Flavonoidic Molecules: Behavioural, Neurochemical and Pharmacological Correlates

“…Similar results were seen after a single dose treatment with crude extract of Erythrina falcata (CE), pure flavonoids or flavonoid-rich fractions from the stem bark of E. falcata using a one-trial, step-down inhibitory avoidance (IA) [9] or conditioned lick suppression (CLS) [8] tasks.…”

“…Moreover, our data showed, through pharmacological manipulation and genetic analysis, that acquisition of lick suppression is mediated by hydroxytryptamine (serotonin) receptor, subunit 1A (5-HT 1A R), gamma-aminobutyric acid type A receptor (GABA A R) and GluN2B-NMDAR in the dorsal hippocampal formation (dHF). Furthermore, for the first time, we showed by pharmacological and molecular analysis that the fear memory acquisition is modulated by NMDAR and spontaneous recovery of fear memory, verified after treatment with flavonoidic fractions, may be reliant on tri-activation of GluN2A/GluN2B-NMDARs and 5-HT 1A R in the dHF [8]. Conversely, our findings also suggested that spontaneous recovery is not modulated by GABA A Rs.…”

“…Ginkgo biloba improves short and long-term fear memory by modulating dorsal hippocampal formation and prefrontal cortex Studies in our laboratory have characterized the putative neuromodulatory effects of short and long-term treatment with flavonoid-rich plant extracts, from a standardized extract of the green leaves of Ginkgo biloba (EGb) [7,8] on conditioned lick suppression (CLS) in adult healthy Wistar rats. These behavioral effects were associated with differential expression (mRNA and protein) of CAMP responsive element binding protein-1 (CREB-1), grown associated protein-43 (GAP-43) and glial fibrillary acidic protein (GFAP) in the dorsal hippocampus (DH), the prefrontal cortex and the amygdaloid complex.…”