Neurobiology, molecular pathways, and environmental influences in antisocial traits and personality disorders

Abstract

Personality disorders (PDs) are psychiatric conditions characterized by enduring patterns of cognition, emotion, and behaviour that deviate significantly from cultural norms, causing distress or impairment. The aetiology of PDs is complex, involving both genetic and environmental factors. Genetic studies estimate the heritability of PDs at 30%-60%, implicating genes involved in neurotransmitter regulation, such as those for serotonin transporters and dopamine receptors. Environmental factors, including childhood trauma and chronic stress, interact with genetic predispositions to induce epigenetic modifications like DNA methylation and histone modifications, contributing to PD development. Neurobiological research has identified structural and functional abnormalities in brain regions related to emotional regulation and social cognition, such as the amygdala, prefrontal cortex, and limbic system. These abnormalities are linked to impaired emotion processing and interpersonal functioning in PDs. This review focuses on how environmental factors shape maladaptive behaviours and endophenotypes central to many PDs. It explores the interaction between the Ras-ERK, p38, and mTOR molecular pathways in response to environmental stimuli, and examines the role of oxidative stress and mitochondrial metabolism in these processes. Also reviewed are various types of PDs and existing animal models that replicate key endophenotypes, highlighting changes in neurotransmitters and neurohormones. Identifying molecular biomarkers can lead to the development of "enviromimetic" drugs, which mimic environmental influences to activate molecular pathways, facilitating targeted, personalized treatments based on the molecular profiles of individuals with PDs. Ultimately, understanding the molecular mechanisms of PDs promises to enhance diagnostic accuracy, prognosis, and therapeutic outcomes for affected individuals.

Keywords: Nootropics and enviromimetic drugs; Oxidative stress; Personality disorders; Ras-ERK and P38 pathway; Tetrahydrobiopterin (BH(4)).