Heterozygote Dopamine Transporter Knockout Rats Display Enhanced Cocaine Locomotion in Adolescent Females

Abstract

Cocaine is a powerful psychostimulant that is one of the most widely used illicit addictive. The dopamine transporter (DAT) plays a major role in mediating cocaine’s reward effect. Decreases in DAT expression increase rates of drug abuse and vulnerability to comorbid psychiatric disorders. We used the novel DAT transgenic rat model to study the effects of cocaine on locomotor behaviors in adolescent rats, with an emphasis on sex. Female rats showed higher response rates to cocaine at lower acute and chronic doses, highlighting a higher vulnerability and perceived gender effects. In contrast, locomotor responses to an acute high dose of cocaine were more marked and sustained in male DAT heterozygous (HET) adolescents. The results demonstrate the augmented effects of chronic cocaine in HET DAT adolescent female rats. Knockout (KO) DAT led to a level of hyperdopaminergia which caused a marked basal hyperactivity that was unchanged, consistent with a possible ceiling effect. We suggest a role of alpha synuclein (α-syn) and PICK 1 protein expressions to the increased vulnerability in female rats. These proteins showed a lower expression in female HET and KO rats. This study highlights gender differences associated with mutations which affect DAT expression and can increase susceptibility to cocaine abuse in adolescence.

Dopamine Transporter Knockout Rats Display Epigenetic Alterations in Response to Cocaine Exposure

“…We observed a strong effect of cocaine on these epigenetic enzymes in a sexand genotype-dependent manner. These results support our previous study [11], which showed robust sex differences in response to cocaine administration in DAT transgenic rats. Additionally, these data highlight the impact of partial or full DAT mutation on epigenetic enzymes and subsequent effects on cocaine-related behavior.…”

“…Cocaine was administered intraperitoneally (ip) for 8 days. The cocaine dose (0 or 10 mg/kg) was chosen based on previous publications [11,[68][69][70]. Saline 0.9% solution was used as vehicle.…”

“…In the current study, we investigated the expression of KDM6B and BRD4 in the PFC of male and female DAT transgenic rats in response to chronic cocaine administration using qRT-PCR. We hypothesize that KDM6B and BRD4 may play a vital role in mediating the heightened response to cocaine in DAT HET and KO rats as well as the impact of sex differences [11].…”

“…More precisely, the DA transporter (DAT), which plays an important role in regulating intracellular and extracellular DA levels [2,3], has been studied widely for its role in various neurological diseases, including cocaine use disorder (CUD) [4][5][6][7]. Moreover, previous studies using DAT Knockout (KO) mice [8][9][10] and a recent study from our group using DAT KO rats [11] support the hypothesis that DA levels and the DAT mediate response to cocaine, as well as highlighting the impact of sex. Additionally, excessive DA signaling has been related to altered gene expression [12].…”

Hyperdopaminergia in rats is associated with reverse effort-cost dependent performance

“…However, the observed tendency to δ lower value in DAT-HT rats can be interpreted as some motor facilitation of operant responding. Several papers have shown differences in locomotion of DAT-HT versus -WT littermates (Cristiana et al, 2020; Manoni et al, 2022; Pardo et al, 2022), so further studies are needed to better investigate the behaviour of heterozygous rats.…”