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REVIEW ARTICLE

The imprisoned brain: An integrated neurobiological view of substance dependence

André Demambre Bacchi1*
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1 Department of Medicine, Faculty of Health Sciences, Federal University of Rondonópolis, Rondonópolis, Mato Grosso, Brazil
Advanced Neurology, 025090018 https://doi.org/10.36922/AN025090018
Received: 25 February 2025 | Revised: 2 May 2025 | Accepted: 9 May 2025 | Published online: 27 May 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Substance dependence is a complex neurobiological condition characterized by progressive dysfunction in reward processing, impulse control, and habit formation. This narrative review integrates key findings on the neural mechanisms underlying addiction, emphasizing the transition from impulsive reward-driven drug use to compulsive habitual consumption. The mesocorticolimbic dopaminergic system plays a central role in addiction, with repeated substance exposure inducing neuroadaptive changes that shift control from the nucleus accumbens to the dorsal striatum, reinforcing compulsive drug-seeking behavior. In addition, glutamatergic plasticity strengthens drug-cue associations, whereas inhibitory control deficits in the prefrontal cortex exacerbate impulsivity. Genetic and epigenetic factors modulate individual vulnerability and influence dopamine receptor expression, synaptic plasticity, and sensitivity to reinforcement. The opioid and endocannabinoid systems further contribute by disinhibiting dopamine release, amplifying craving, and increasing relapse risk. Understanding these neurobiological mechanisms highlights addiction as a condition rooted in maladaptive neural plasticity, rather than a simple failure of willpower. This perspective informs potential therapeutic strategies that target the underlying dysregulation of neurotransmitter systems and behavioral control circuits. By integrating findings from neuroimaging, molecular genetics, and behavioral neuroscience, this review provides a comprehensive framework for understanding the mechanisms sustaining addiction and the persistent challenges of relapse.

Keywords
Substance-related disorders
Dopamine
Impulsivity
Compulsive behavior
Neuroplasticity
Reward system
Funding
None.
Conflict of interest
The author declares no conflicts of interest.
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