Role of epigenetic regulatory enzymes in animal models of mania induced by amphetamine and paradoxical sleep deprivation

Abstract

It is known that bipolar disorder has a multifactorial aetiology where the interaction between genetic and environmental factors is responsible for its development. Because of this, epigenetics has been largely studied in psychiatric disorders. The present study aims to evaluate the effects of histone deacetylase inhibitors on epigenetic enzyme alterations in rats or mice submitted to animal models of mania induced by dextro‐amphetamine or sleep deprivation, respectively. Adult male Wistar rats were subjected to 14 days of dextro‐amphetamine administration, and from the eighth to the fourteenth day, the animals were treated with valproate and sodium butyrate in addition to dextro‐amphetamine injections. Adult C57BL/6 mice received 7 days of valproate or sodium butyrate administration, being sleep deprived at the last 36 hr of the protocol. Locomotor and exploratory activities of rats and mice were evaluated in the open‐field test, and histone deacetylase, DNA methyltransferase, and histone acetyltransferase activities were assessed in the frontal cortex, hippocampus, and striatum. Dextro‐amphetamine and sleep deprivation induced hyperactivity and increased histone deacetylase and DNA methyltransferase activities in the animal's brain. Valproate and sodium butyrate were able to reverse hyperlocomotion induced by both animal models, as well as the alterations on histone deacetylase and DNA methyltransferase activities. There was a positive correlation between enzyme activities and number of crossings for both models. Histone deacetylase and DNA methyltransferase activities also presented a positive correlation between theirselves. These results suggest that epigenetics can play an important role in BD pathophysiology as well as in its treatment.

Enlightened: addressing circadian and seasonal changes in photoperiod in animal models of bipolar disorder

“… Animal model Key features Behavioral characteristics of model BD patterns References Pharmacological Amphetamine (AMPH) Acute/chronic peripheral administration ↑ locomotor activity related to DA, some evidence for cycling from depression Mania + cycling (?) [ 88 – 95 ] Cocaine Chronic peripheral administration ↑ locomotor activity related to DA, time-dependent sensitization Mania + cycling (?) [ 96 ] Fenproporex Converted to AMPH in vivo, acute and chronic peripheral administration ↑ locomotor activity Mania [ 97 ] GBR 12909, an inhibitor of the DA transporter (DAT) Acute peripheral administration ↑ activity and perseverative patterns of locomotion for several hours Mania [ 98 ] Ouabain Acute icv administration ↑ activity, ↓ reversal learning Mania [ 99 – 101 ] Environmental Sleep deprivation Sleep deprivation (SD) using the platform method with testing afterwards, vary duration and frequency of SD After sleep deprivation: ↑ activity, insomnia, ↑ irritability, ↑ aggression, ↑ sexual behavior, evidence of sensitization to repeated SD Mania [ 102 , 103 ,] Genetically selected strains Black Swiss mice Mania-like phenotype observed in mice from Taconic Biosciences but not Charles River Labs Hyperactive, ↓ immobility in FST, ↑ response to AMPH, ↑ aggression, ↑ saccharin preference Mania [ 104 ] Hyperactive (HYPER) rat Derived from a single litter of Sprague–Dawley rats that were discovered to be hyperactive at night.…”

Transcriptome Changes in Three Brain Regions during Chronic Lithium Administration in the Rat Models of Mania and Depression

“…Moreover, these behaviors were reversed by the administration of mood stabilizers, including lithium [40,43]. This chronic amphetamine-induced mania model showed recently good face, predictive and construct validity in modeling mania in Wistar rats [44][45][46][47].…”

Association of Polymorphism within the Putative miRNA Target Site in the 3′UTR Region of the DRD2 Gene with Neuroticism in Patients with Substance Use Disorder

“…Additionally, stimulants such as methamphetamine are more typical and are attributed to paranoidal psychoses [ 99 , 100 ], whereas alcohol usually aggravates depression and may relate to a “double diagnosis” (alcohol addiction and bipolar disorder) [ 101 ]. It is probable that the selected SUD MANIA patients in the current study were also characterized by an additional specific vulnerability, such as neuroticism, personality traits, or epigenetic factors [ 102 ], which influenced their clinical manic view in cannabinoid, stimulant, and alcohol addiction.…”