Abstract

REVIEW OF PHARMACOLOGICAL MECHANISMS UNDERLYING ADDICTION TO SUBSTANCES LIKE OPIOIDS, PSYCHOSTIMULANTS, OR ALCOHOL, AND POTENTIAL PHARMACOTHERAPIES FOR ADDICTION TREATMENT

Yashika Bhatia* and Maheep Wadhwa

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Abstract

Addiction to substances such as opioids, psychostimulants, and alcohol is a chronic and relapsing neurobiological disorder characterized by compulsive drug-seeking and use despite harmful consequences. This behavior stems from profound dysregulation in brain circuits involved in reward, motivation, stress, and executive control. Central to addiction is the mesolimbic dopamine system, often referred to as the brain’s reward pathway. This system originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens (NAc), playing a critical role in reinforcing behaviors essential for survival, such as eating and social interaction. Drugs of abuse hijack this system, causing a surge in dopamine release in the NAc, which produces intense euphoria and reinforces drug-taking behavior. Over time, repeated drug exposure leads to neuroadaptations, including downregulation of dopamine receptors and reduced dopamine signaling, which diminish the brain’s response to natural rewards and increase the drive to seek drugs. In addition to dopamine, glutamate signaling plays a pivotal role in addiction. Glutamate, the brain’s primary excitatory neurotransmitter, mediates synaptic plasticity and learning processes in regions such as the prefrontal cortex (PFC) and the NAc. Chronic drug use disrupts glutamate homeostasis, leading to hyperexcitability in these regions and impairing cognitive control over drug-seeking behavior. The PFC, which governs decision-making and impulse control, becomes hypoactive, while the NAc and other limbic regions become hyperactive, creating an imbalance that drives compulsive drug use. Stress systems, particularly the hypothalamic-pituitary-adrenal (HPA) axis, further exacerbate addiction by enhancing cravings and relapse vulnerability. Stress hormones like corticotropin-releasing factor (CRF) and cortisol amplify the rewarding effects of drugs and weaken inhibitory control, making individuals more susceptible to relapse during periods of stress or withdrawal Pharmacotherapies for addiction target these neurobiological mechanisms to restore balance and reduce drug-seeking behavior. For opioid addiction, medications like methadone and buprenorphine act as partial agonists at opioid receptors, stabilizing withdrawal symptoms and reducing cravings without producing the intense high of illicit opioids. Naltrexone, an opioid receptor antagonist, blocks the effects of opioids and alcohol, reducing their rewarding properties. For alcohol use disorder, acamprosate modulates glutamate and GABA signaling to alleviate withdrawal symptoms and cravings, while disulfiram discourages drinking by causing unpleasant effects when alcohol is consumed. Emerging treatments focus on novel targets, such as glutamate modulators (e.g., memantine) and CRF antagonists, which aim to restore synaptic plasticity and reduce stress-induced relapse. Despite these advances, addiction treatment remains challenging due to the complexity of the disorder, which involves overlapping genetic, neurobiological, and environmental factors. Personalized approaches that combine pharmacotherapy with behavioral interventions, such as cognitive-behavioral therapy (CBT) and contingency management, show promise in addressing the multifaceted nature of addiction. This review explores the pharmacological mechanisms underlying addiction to opioids, psychostimulants, and alcohol, highlighting current and emerging pharmacotherapies and their efficacy. By elucidating these mechanisms, this review aims to contribute to the development of more effective interventions for addiction, ultimately improving outcomes for individuals affected by this debilitating condition.

Keywords: CBT, CRF antagonists, psychostimulants, relapsing disorder, opioid epidemic.