Dataset Information

A time-dependent contribution of hippocampal CB₁ , CB₂ and PPAR? receptors to cannabidiol-induced disruption of fear memory consolidation.

ABSTRACT:

Background and purpose

In preclinical studies, cannabidiol (CBD) mitigates fear memories by facilitating their extinction or interfering with their generalization and reconsolidation. The brain regions and mechanisms underlying these effects, and their temporal window, are still poorly understood. Here, we have investigated related questions in the dorsal hippocampus (DH) during contextual fear consolidation.

Experimental approach

Adult male Wistar rats received CBD (10-30 pmol) intra-DH immediately, 1 or 3 hr after fear conditioning. Effects of CBD on consolidation were inferred behaviourally and by analysing expression of the activity-regulated, cytoskeleton-associated (Arc) protein. The contribution of anandamide, CB₁ , CB₂ , 5-HT_1A , A_2A , and PPAR? receptors was also assessed.

Key results

CBD impaired memory consolidation when given immediately or 1 hr after fear conditioning, but not after 3 hr. Expression of Arc protein in DH was reduced by systemic CBD treatment in both cases. Immediately after fear conditioning, CBD effects were abolished by CB₁ or CB₂ receptor blockade, partly reduced by 5-HT_1A or A_2A antagonism, and remained unchanged after antagonism of PPAR? receptors. One hour after fear conditioning, CBD effects were prevented only by PPAR? receptor antagonism. Also, inhibition of fatty acid amide hydrolase by URB597, impaired memory consolidation when infused immediately, but not 1 hr after fear conditioning.

Conclusions and implications

CBD disrupts memory consolidation up to 1 hr after fear conditioning, allowing an extended window of opportunity to mitigate aversive memories after their acquisition. Our results suggest time-dependent participation of anandamide, CB₁ , CB₂ and PPAR? receptors in the DH, during this process.

SUBMITTER: Raymundi AM

PROVIDER: S-EPMC7024734 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

A time-dependent contribution of hippocampal CB<sub>1</sub> , CB<sub>2</sub> and PPARγ receptors to cannabidiol-induced disruption of fear memory consolidation.

Raymundi Ana Maria AM da Silva Thiago R TR Zampronio Aleksander R AR Guimarães Francisco S FS Bertoglio Leandro J LJ Stern Cristina A J CAJ

British journal of pharmacology 20200121 4

<h4>Background and purpose</h4>In preclinical studies, cannabidiol (CBD) mitigates fear memories by facilitating their extinction or interfering with their generalization and reconsolidation. The brain regions and mechanisms underlying these effects, and their temporal window, are still poorly understood. Here, we have investigated related questions in the dorsal hippocampus (DH) during contextual fear consolidation.<h4>Experimental approach</h4>Adult male Wistar rats received CBD (10-30 pmol) i ...[more]

PMID: 31648363

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Project description:The endocannabinoid system is a key regulator of the response to psychological stress. Inhibitors of monoacylglycerol lipase (MGL), the enzyme that deactivates the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG), exert anxiolytic-like effects in rodent models via 2-AG-dependent activation of CB1 cannabinoid receptors. In the present study, we examined whether the MGL inhibitor JZL184 might modulate persistent predator-induced fear in rats, a model that captures features of human post-traumatic stress disorder. Exposure to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a volatile chemical that is innately aversive to some rodent species, produced in male rats a long-lasting anxiety-like state that was measured 7 days later in the elevated plus maze test. Systemic administration of JZL184 [4, 8 and 16 mg/kg, intraperitoneal (IP)] 4 h before testing caused dose-dependent inhibition of MGL activity and elevation of 2-AG content in brain tissue. Concomitantly, the inhibitor suppressed TMT-induced fear behaviors with a median effective dose (ED50) of 4 mg/kg. A similar behavioral response was observed with another MGL inhibitor, KML29 (4 and 16 mg/kg, IP). Surprisingly, the effect of JZL184 was prevented by co-administration of the CB2 inverse agonist AM630 (5 mg/kg, IP), but not the CB1 inverse agonist rimonabant (1 mg/kg, IP). Supporting mediation of the response by CB2 receptors, the CB2 agonist JWH133 (0.3, 1 and 3 mg/kg, IP) also produced anxiolytic-like effects in TMT-stressed rats, which were suppressed by AM630. Notably, (i) JWH133 was behaviorally ineffective in animals that had no prior experience with TMT; and (ii) CB2 mRNA levels in rat prefrontal cortex were elevated 7 days after exposure to the aversive odorant. The results suggest that JZL184 attenuates the behavioral consequences of predator stress through a mechanism that requires 2-AG-mediated activation of CB2 receptors, whose transcription may be induced by the stress itself.

Dataset Information

A time-dependent contribution of hippocampal CB₁ , CB₂ and PPAR? receptors to cannabidiol-induced disruption of fear memory consolidation.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

A time-dependent contribution of hippocampal CB<sub>1</sub> , CB<sub>2</sub> and PPARγ receptors to cannabidiol-induced disruption of fear memory consolidation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

A time-dependent contribution of hippocampal CB1 , CB2 and PPAR? receptors to cannabidiol-induced disruption of fear memory consolidation.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

A time-dependent contribution of hippocampal CB<sub>1</sub> , CB<sub>2</sub> and PPARγ receptors to cannabidiol-induced disruption of fear memory consolidation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

A time-dependent contribution of hippocampal CB₁ , CB₂ and PPAR? receptors to cannabidiol-induced disruption of fear memory consolidation.