Antidepressant Agomelatine Dampens Nicotine-Driven Brain Changes in Rats

Nicotine is the engine of tobacco addiction, and one of its most stubborn effects is the way it reprograms the brain’s movement and reward circuitry. A new open-access study in BMC Pharmacology and Toxicology reports that agomelatine, an atypical antidepressant already prescribed for major depressive disorder, blunts a well-established animal model of that reprogramming: nicotine-induced locomotor sensitization in male rats. The work, carried out by Susana Barbosa-Méndez and Alberto Salazar-Juárez at the Instituto Nacional de Psiquiatría in Mexico City, adds a clinically approved drug to the short list of compounds that interfere with the neurobehavioral footprint of repeated nicotine exposure.

Locomotor sensitization is a cornerstone paradigm in addiction neuroscience. When an animal receives repeated doses of a psychostimulant such as nicotine, its spontaneous movement in response to the drug does not stay constant; instead, the locomotor response grows progressively stronger with each exposure. This escalation is thought to mirror long-lasting neuroadaptations in the mesolimbic dopamine system, the same circuitry that mediates craving and drug seeking in humans. Because sensitization can persist for weeks after the last dose, researchers use it as a measurable proxy for the latent brain changes that make relapse so likely. A drug that suppresses the expression of sensitization is therefore considered a candidate for reducing the neural drive behind addiction.

Agomelatine occupies a distinctive pharmacological niche. Unlike classical antidepressants that primarily target monoamine reuptake, agomelatine is a melatonergic agent: it activates MT1 and MT2 melatonin receptors while blocking serotonin 5-HT2B and 5-HT2C receptors. This dual profile underlies its antidepressant and sleep-regulating effects and has made it attractive for disorders in which circadian disruption and mood pathology overlap. Importantly for the present study, the same laboratory had previously shown that agomelatine decreases the reinforcing and neurochemical effects of cocaine in Wistar rats, raising the question of whether its anti-addiction properties extend to nicotine, a drug with a very different primary mechanism acting through nicotinic acetylcholine receptors.

To find out, the researchers turned to the nicotine locomotor sensitization paradigm, one of the most widely used behavioral screens in preclinical addiction research. In this model, rats are given repeated nicotine administrations across several days while their horizontal movement is recorded in activity monitors. The design allowed the team to separate two distinct questions: whether agomelatine changes the acute locomotor activation produced by nicotine itself, and whether it interferes with the expression of sensitization, the amplified response that emerges after repeated dosing. The distinction matters clinically, because the expression phase is thought to reflect the established neuroadaptations that persist into withdrawal and craving.

The results were clear on both fronts. When agomelatine was administered at a dose of 10 milligrams per kilogram intraperitoneally during the expression phase and during nicotine withdrawal, it attenuated the expression of locomotor sensitization induced by multiple doses of nicotine. In practical terms, rats that had been sensitized by repeated nicotine no longer showed the exaggerated locomotor response once they received agomelatine. The drug also shortened the duration of the locomotor effects and reduced overall locomotor activity after binge nicotine administration, meaning that both the intensity and the time course of nicotine’s behavioral impact were blunted.

These findings fit into a broader mechanistic picture. Nicotine’s sensitizing effects depend heavily on dopamine release in the nucleus accumbens and on glutamatergic and serotonergic modulation of ventral tegmental area neurons. By antagonizing 5-HT2C receptors, agomelatine indirectly enhances dopaminergic and noradrenergic tone in frontal regions, while its melatonergic activity may normalize circadian signaling that is disrupted in addiction. The authors note that the drug’s prior success against cocaine-induced sensitization and reinforcement, combined with the present nicotine data, suggests a convergent action on shared final pathways of psychostimulant sensitization rather than on nicotine’s specific receptor target.

The clinical context gives the result its urgency. Smoking remains the leading preventable cause of death worldwide, and current cessation pharmacotherapies, including nicotine replacement, varenicline, and bupropion, leave a substantial fraction of smokers unable to quit permanently. Because agomelatine is already approved for depression in many countries, has a known safety profile, and addresses the mood and sleep disturbances that often accompany nicotine withdrawal, a repurposing strategy is attractive. If sensitization in rodents reflects the human phenomena of craving and relapse, a drug that suppresses sensitization expression could theoretically reduce the pull of cigarette cues during abstinence.

The authors are careful, however, about the limits of the present evidence. Their conclusions state that the results support the need for further preclinical studies before proposing agomelatine for clinical trials in smoking cessation. The study was conducted exclusively in male rats, so sex differences, which are well documented in nicotine reinforcement, remain unexplored. The dose was delivered intraperitoneally, a route that does not translate directly to human oral dosing, and the behavioral endpoint was locomotion rather than drug self-administration or relapse-like behavior, which are closer analogues of human addiction.

Methodological rigor in the study was supported by ethical approval from the Institutional Animal Care and Bioethics Committee under protocols CICUAL/0003/2022 and CEI/C/IC22177015/2022, conducted in compliance with the NIH Guide for the Care and Use of Laboratory Animals. The work was funded by grants INP-2000-2040 and CI-IC092020.2, and the authors declared no competing interests. The article was received in April 2026, accepted in October 2026, and published on 13 October 2026 as an open-access contribution to BMC Pharmacology and Toxicology, making the full dataset available to the research community without paywall.

For the field of addiction pharmacotherapy, the study is a proof of concept rather than a prescription. It demonstrates that a melatonergic antidepressant with serotonergic antagonist properties can reach into the neural machinery of nicotine sensitization, a finding that invites follow-up work with self-administration models, female subjects, and withdrawal-related measures such as anhedonia and anxiety. If those experiments confirm and extend the present results, agomelatine could join a small group of repurposed psychiatric drugs being tested not for their original indication but for their ability to weaken the grip that nicotine exerts on the addicted brain.

Subject of Research: Effects of the melatonergic antidepressant agomelatine on nicotine-induced locomotor sensitization in male rats

Article Title: Agomelatine attenuates the expression of nicotine-induced locomotor sensitization in male rats

Article References: Barbosa-Méndez, S., & Salazar-Juárez, A. (2026). Agomelatine attenuates the expression of nicotine-induced locomotor sensitization in male rats. BMC Pharmacology and Toxicology. https://doi.org/10.1186/s40360-026-01260-7

Image Credits: AI Generated

DOI: 10.1186/s40360-026-01260-7

Keywords: agomelatine, nicotine, locomotor sensitization, addiction, melatonin receptors, serotonin receptors, smoking cessation, psychostimulant, preclinical study, rats, neuropharmacology, antidepressant