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?⁹-Tetrahydrocannabinol Experience Influences ?FosB and Downstream Gene Expression in Prefrontal Cortex.

ABSTRACT: Introduction: Repeated administration of abused drugs, including ?⁹-tetrahydrocannabinol (THC), induces the stable transcription factor ?FosB in dopaminergic terminal field regions of the mesolimbic system. These studies investigated the effect of prior repeated THC treatment on THC-induced ?FosB expression and regulation of downstream targets in the forebrain. Methods: Mice received THC (10?mg/kg) or vehicle twice daily for 13 days, and then half of each group received a single injection of THC or vehicle 45?min before brain collection. ?FosB messenger RNA (mRNA) and protein were measured by polymerase chain reaction and immunoblotting, respectively. Potential downstream targets of ?FosB induction were measured by immunoblot. Results: THC injection in mice with a history of repeated THC treatment enhanced ?FosB expression as compared with vehicle in the prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala. This change occurred concomitantly with an increase in ?FosB mRNA in the PFC and NAc. THC injection in mice with a history of repeated THC treatment increased expression of cyclin-dependent kinase 5 (Cdk5) and its regulatory protein p35 only in the PFC. This increase in Cdk5 and p35 expression in PFC was also found in mice that had only received repeated THC administration, suggesting that this effect might be due to induction of ?FosB. Extracellular signal-regulated kinase (ERK) phosphorylation was increased in PFC after THC injection in repeated THC-treated mice. Phosphorylation of glycogen synthase kinase-3? (GSK3?), a Cdk5 target, was reduced in PFC after repeated THC treatment regardless of THC history, and phosphorylation of dopamine- and cAMP-regulated phosphoprotein of 32?kDa (DARPP-32) at the Cdk5-regulated threonine 75 site was unchanged. Conclusion: These results suggest that a history of repeated THC administration primes THC-mediated induction of ?FosB in the NAc and PFC, and that expression of both downstream targets of ?FosB (e.g., Cdk5 and p35) and upstream activators (e.g., pERK) in the PFC is dependent on THC history, which might have functional implications in addiction and neuropsychiatric disease.

SUBMITTER: Lazenka MF

PROVIDER: S-EPMC5628572 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Δ9-Tetrahydrocannabinol Experience Influences ΔFosB and Downstream Gene Expression in Prefrontal Cortex.

Lazenka Matthew F MF Kang Minho M De Dipanjana Datta DD Selley Dana E DE Sim-Selley Laura J LJ

Cannabis and cannabinoid research 20170801 1

Introduction: Repeated administration of abused drugs, including Δ9-tetrahydrocannabinol (THC), induces the stable transcription factor ΔFosB in dopaminergic terminal field regions of the mesolimbic system. These studies investigated the effect of prior repeated THC treatment on THC-induced ΔFosB expression and regulation of downstream targets in the forebrain. Methods: Mice received THC (10 mg/kg) or vehicle twice daily for 13 days, and then half of each group received ...[more]

PMID: 29082320

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Project description:BackgroundAggressive behavior is an ancient and conserved trait, habitual for most animals in order to eat, protect themselves, compete for mating and defend their territories. Genetic factors have been shown to play an important role in the development of aggression both in animals and humans, displaying moderate to high heritability estimates. Although such types of behaviors have been studied in different animal models, the molecular architecture of aggressiveness remains poorly understood. This study compared gene expression profiles of 16 prefrontal cortex (PFC) samples from aggressive and non-aggressive cattle breeds: Lidia, selected for agonistic responses, and Wagyu, selected for tameness.ResultsA total of 918 up-regulated and 278 down-regulated differentially expressed genes (DEG) were identified, representing above-chance overlap with genes previously identified in studies of aggression across species, as well as those implicated in recent human evolution. The functional interpretation of the up-regulated genes in the aggressive cohort revealed enrichment of pathways such as Alzheimer disease-presenilin, integrins and the ERK/MAPK signaling cascade, all implicated in the development of abnormal aggressive behaviors and neurophysiological disorders. Moreover, gonadotropins, are up-regulated as natural mechanisms enhancing aggression. Concomitantly, heterotrimeric G-protein pathways, associated with low reactivity mental states, and the GAD2 gene, a repressor of agonistic reactions associated with PFC activity, are down-regulated, promoting the development of the aggressive responses selected for in Lidia cattle. We also identified six upstream regulators, whose functional activity fits with the etiology of abnormal behavioral responses associated with aggression.ConclusionsThese transcriptional correlates of aggression, resulting, at least in part, from controlled artificial selection, can provide valuable insights into the complex architecture that underlies naturally developed agonistic behaviors. This analysis constitutes a first important step towards the identification of the genes and metabolic pathways that promote aggression in cattle and, providing a novel model species to disentangle the mechanisms underlying variability in aggressive behavior.

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?⁹-Tetrahydrocannabinol Experience Influences ?FosB and Downstream Gene Expression in Prefrontal Cortex.

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Δ<sup>9</sup>-Tetrahydrocannabinol Experience Influences ΔFosB and Downstream Gene Expression in Prefrontal Cortex.

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Dataset Information

?9-Tetrahydrocannabinol Experience Influences ?FosB and Downstream Gene Expression in Prefrontal Cortex.

Publications

Δ<sup>9</sup>-Tetrahydrocannabinol Experience Influences ΔFosB and Downstream Gene Expression in Prefrontal Cortex.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

?⁹-Tetrahydrocannabinol Experience Influences ?FosB and Downstream Gene Expression in Prefrontal Cortex.