Cocaine-induced changes in behaviour and DNA methylation in rats are influenced by inter-individual differences in spontaneous exploratory activity

Abstract

Background: Individual differences in behavioural traits influence susceptibility to addictive disorders. Drug addiction involves changes in gene expression, proposed to occur via DNA methylation (DNAm). Aims: To investigate DNAm changes in reward-related brain structures (nucleus accumbens (NAc), lateral habenula (LHb)) in response to cocaine exposure in rats differing in spontaneous exploratory activity. Methods: Rats were observed in the exploration box and categorised as high- (HE) or low explorers (LE). Rats were administered vehicle or cocaine (12 mg/kg, i.p.) for 7 days, followed by a 14-day withdrawal period and cocaine challenge (7 mg/kg); horizontal locomotor activity was recorded. Brain tissue was dissected after 24 h; we analysed messenger RNA (mRNA) and activity levels of epigenetic DNA modifiers (DNMTs and TETs) as well as mRNA and promoter methylation levels at selected genes previously linked to addictive behaviours. Results: The cocaine challenge dose stimulated locomotor activity in both LE- and HE rats only when administered after a repeated cocaine schedule, suggesting development of behavioural sensitisation. Quantitative polymerase chain reaction analyses demonstrated higher basal expression of Dnmt3a, Tet2 and Tet3 in the LHb of HE- vs. LE rats, and we observed differential effects of cocaine exposure on the expression and activity of epigenetic DNA modifiers in the NAc and LHb of HE- and LE rats. Furthermore, cocaine exposure differentially altered promoter methylation levels of A2AR, Ppp1cc, and Taar7b in the NAc and LHb of HE- and LE rats. Conclusions: DNAm might play a role in the HE- and LE phenotypes as well as mediate behavioural effects of LE- and HE rats in response to drugs of abuse.

Neuroprotective Effect of Piracetam against Cocaine-Induced Neuro Epigenetic Modification of DNA Methylation in Astrocytes

“…Addiction has been shown to be an altered DNA methylation signature in animal models, leading to changes in neuronal and brain activity following acute and chronic drug exposure [ 20 , 31 ]. Evidence from mammalian studies suggests that chronic cocaine administration interferes with DNA methylation dynamics and that gene expression in the brain may alter vulnerability to drug abuse [ 32 , 33 ]. However, cocaine-induced epigenetic modification of DNA methylation and cross-talk with mtDNA-mediated impairment in astrocytes is unknown.…”

Substance use disorders: a comprehensive update of classification, epidemiology, neurobiology, clinical aspects, treatment and prevention

“…Clinical studies based on blood cells have found that individuals who consume drugs show epigenetic changes that appear to relate to the frequency of use in a dose dependent man ner 113 . However, drug independent changes in addiction vulner ability triggered by adverse childhood experiences or other environ mental factors might have also contributed to the epigenetic modifi cations reported in individuals with SUDs 120 .…”

DNA Epigenetics in Addiction Susceptibility

“…As drug exposure itself has been known to induce time-dependent DNA epigenetic changes in brain reward regions, the drug intake differences over time may therefore have contributed to differential methylation in the susceptible animals (Massart et al, 2015;Brown and Feng, 2017;Ploense et al, 2018;Sakharkar et al, 2019). However, a recent study (Vaher et al, 2020) provided evidence of drug dose-independent DNA epigenetic changes in addiction vulnerability. This was demonstrated in rats that were pre-screened for differences in exploratory behavior in a familiar environment [i.e., high and low explorers (Mällo et al, 2007)]; a behavioral phenotype that is similar to novelty-seeking and is concomitant with differential responding to substances of abuse (Alttoa et al, 2007).…”

“…This was demonstrated in rats that were pre-screened for differences in exploratory behavior in a familiar environment [i.e., high and low explorers (Mällo et al, 2007)]; a behavioral phenotype that is similar to novelty-seeking and is concomitant with differential responding to substances of abuse (Alttoa et al, 2007). Cocaine intraperitoneal injections administered passively by an experimenter (i.e., each animal received identical drug doses) differentially regulated the expression of Dnmt3b and Tet3 in the NAc of high-and lowexploring rats, leading to phenotype-specific DNA methylation signatures at genes implicated in addiction (Vaher et al, 2020). Furthermore, these differences were only present after cocaine exposure, demonstrating that DNA epigenetic changes associated with addiction behavioral phenotypes may be drug dose independent.…”