Amphetamine Stimulation throughout Embryogenesis Promotes Long-lasting Epigenetic Modification in the Dopamine Transporter in Adult Animals

Rosemary Brecht^*
*Correspondence: Rosemary Brecht, Department of Wildlife Resources, Utah State University, Logan, Utah, USA, Email:

Introduction

The use of amphetamine, a powerful stimulant has been a subject of extensive research and debate for decades due to its widespread recreational and medicinal use. One of the central mechanisms through which amphetamine exerts its effects is the modulation of dopamine neurotransmission in the brain. While much is known about the acute and chronic effects of amphetamine on the brain's reward system and its impact on behavior less attention has been given to the potential long-lasting consequences of amphetamine exposure during early development. Emerging research suggests that exposure to amphetamines during embryogenesis may lead to lasting epigenetic modifications in the Dopamine Transporter (DAT), a key protein responsible for regulating dopamine levels in the brain. This article explores the current state of knowledge regarding amphetamine-induced epigenetic modifications during embryogenesis their potential consequences in adult animals, and the broader implications for understanding addiction, neurodevelopmental disorders, and epigenetic mechanisms.

Description

Amphetamines, including methamphetamine and its derivatives, are known to readily cross the placenta and affect the developing embryo. In pregnant women who use amphetamines, these compounds can reach the developing foetus exposing it to their pharmacological effects. This early exposure has been linked to various adverse outcomes including preterm birth, low birth weight and developmental abnormalities. During embryogenesis, the epigenome undergoes dynamic changes that play a crucial role in shaping cellular identity and function. Epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNA regulation, can influence gene expression patterns thereby affecting developmental processes. It is within this context that amphetamine exposure during embryogenesis may exert its long-lasting effects on the developing brain [1].

Recent research has uncovered evidence suggesting that amphetamine exposure during embryogenesis can lead to alterations in epigenetic marks within the dopaminergic system. Studies in animal models have demonstrated changes in DNA methylation patterns and histone modifications in genes related to dopamine signalling, including DAT. These epigenetic modifications are thought to persist into adulthood, potentially influencing the functioning of the dopaminergic system and related behaviors. The Dopamine Transporter (DAT) is a critical protein involved in the regulation of dopamine levels in the brain [2]. DAT is primarily responsible for the reuptake of extracellular dopamine into presynaptic neurons, thus terminating dopamine signalling and maintaining proper neurotransmission. Dysregulation of DAT function has been implicated in various neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and substance use disorders.

The DAT gene, also known as SLC6A3 encodes the DAT protein. The expression of DAT is tightly regulated to ensure precise control of dopamine reuptake. Epigenetic modifications, including DNA methylation and histone acetylation, play a pivotal role in modulating DAT gene expression. Changes in the epigenetic landscape of the DAT gene can lead to alterations in DAT protein levels, potentially influencing dopamine homeostasis in the brain. Dopaminergic signalling is essential for various cognitive and emotional functions, including reward processing, motivation and motor control. DAT by regulating dopamine reuptake modulates the duration and intensity of dopamine signalling at synapses [3]. Dysregulated DAT function can lead to aberrant dopamine levels, which are implicated in psychiatric disorders such as schizophrenia and addiction.

Amphetamine exposure during embryogenesis has been associated with epigenetic modifications in the dopaminergic system. These modifications can impact DAT gene expression and function, potentially leading to lasting changes in dopamine signalling in adult animals. Studies have shown that amphetamine exposure during embryogenesis can lead to altered DNA methylation patterns in the promoter region of the DAT gene. Hyper methylation of the DAT promoter is associated with decreased gene expression, leading to reduced DAT protein levels. This reduction in DAT function may result in elevated extracellular dopamine levels, which could contribute to behavioral alterations seen in adult animals exposed to amphetamines in utero [4].

In addition to DNA methylation, amphetamine exposure has been linked to changes in histone modifications within the dopaminergic system. Histone modifications, such as acetylation and methylation can influence chromatin accessibility and gene expression. Amphetamine-induced alterations in histone acetylation patterns may contribute to long-lasting changes in the expression of genes involved in dopamine signalling, including DAT. The epigenetic modifications induced by amphetamine exposure during embryogenesis can have profound behavioral consequences in adult animals. These consequences are mediated through alterations in the dopaminergic system, affecting reward processing, impulsivity, and susceptibility to substance abuse. Amphetamineinduced epigenetic modifications may lead to changes in reward circuitry in the brain. Altered DAT function can result in prolonged dopamine signaling at synapses, which may contribute to heightened sensitivity to rewarding stimuli. This increased reward sensitivity could predispose adult animals to seek out rewarding substances and behaviors, potentially increasing the risk of addiction [5].

Conclusion

Amphetamine exposure during embryogenesis can induce long-lasting epigenetic modifications in the Dopamine Transporter (DAT) and other components of the dopaminergic system. These modifications have significant implications for behavior in adult animals, including altered reward processing, increased impulsivity, and susceptibility to substance abuse. Understanding the epigenetic mechanisms underlying these effects provides valuable insights into addiction, neurodevelopmental disorders, and the developmental origins of behavioral dysfunction. Moreover, it opens up new avenues for therapeutic interventions aimed at mitigating the long-term consequences of early amphetamine exposure on the brain. Further research in this field promises to deepen our understanding of the complex interplay between early-life experiences, epigenetics, and brain function.

Acknowledgement

None.

Conflict of Interest

None.

References

1. Hansen, Freja H., Tina Skjørringe, Saiqa Yasmeen and Natascha V. Arends, et al. “Missense dopamine transporter mutations associate with adult parkinsonism and ADHD.” J Clin Investig 124 (2014): 3107–3120.

Google Scholar, Crossref, Indexed at

2. Herborg, Freja, Katherine L. Jensen, Sasha Tostoy and Natascha V. Arends, et al. “Identifying dominat-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease.” JCI Insight 6 (2021): e151496.

Google Scholar, Crossref, Indexed at

3. Masoud, S.T., L.M. Vecchio, Y. Bergeron and M.M. Hossain, et al. “Increased expression of the dopamine transporter leads to loss of dopamine neurons, oxidative stress and l-DOPA reversible motor deficits.” Neurobiol Dis 74 (2015): 66–75.

Google Scholar, Crossref, Indexed at

4. Ross, Emily J., Devon L. Graham, Kelli M. Money and Gregg D. Stanwood, et al. “Developmental consequences of fetal exposure to drugs: What we know and what we still must learn.” Neuropsychopharmacology 40 (2015): 61–87.

Google Scholar, Crossref, Indexed at

5. Weaver, Ian C.G., Nadia Cervoni, Frances A. Champagne and Ana C. D’Alessio, et al. “Epigenetic programming by maternal behavior.” Nat Neurosci 7 (2004): 847–854.

Google Scholar, Crossref, Indexed at