Repeated administration of the synthetic cannabinoid AKB48 induces serotonergic neuroadaptation in male and female mice: behavioural and immunohistochemical evidence.
Giorgia Corli, Fabrizio De Luca, Sabrine Bilel, Marta Bassi, Elisa Roda, Rosa Maria Gaudio, Liana Fattore, Carlo Alessandro Locatelli, Matteo Marti
Neuropharmacology February 1, 2026 DOI: 10.1016/j.neuropharm.2025.110758 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Behavioral and immunohistochemical study Peer reviewed |
|---|---|
| Population | Male and female mice |
| Interventions | AKB48 2C-I 25I-NBOMe |
| Topics | Serotonin |
| Keywords | 25i-nbome pubchem cid 2c-i pubchem cid 5-ht2a receptors Akb48 pubchem cid Hallucinogens Immunohistochemistry Sert Serotoninergic system Synthetic cannabinoids |
| Citations | 1 |
| Key points | Repeated AKB48 administration worsens the response to serotoninergic hallucinogens, with sex-dependent differences in duration and neuroplasticity at 5-HT2A receptors and serotonin transporter. |
Abstract
In the last years, Synthetic Cannabinoids (SCBs) have established themselves as one of the largest and most popular groups of Novel Psychoactive Substances (NPS), being frequently detected in biological samples of patients involved in intoxication and death cases. To date, compelling evidence on the potential interaction between SCBs and non-cannabinoid neurotransmission systems has emerged, with reference to a high-level overlap between endocannabinoid and serotoninergic system. Their long-term effect on serotoninergic pathways is still to be elucidated. Using a behavioural and immunohistochemical approach, we investigated the neuroplasticity at 5-HT2A serotoninergic receptors and serotonin transporter in the cerebellum and cortex induced by repeated AKB48 administration in male and female mice. Further, pharmacological response to the serotoninergic compounds 2C-I or 25I-NBOMe has been studied. The repeated exposure to AKB48 results in a worsening effect on the visual sensorimotor, sensory gating, and motor reactivity response to synthetic hallucinogens, that appears to be generally more prolonged in male with respect to AKB48-treated female mice. Interestingly, the effect has been related to cerebellar and cortical neuroplasticity at serotoninergic neurotransmission system, that involves both 5-HT2A and SERT, that occurs more markedly and rapidly in female with respect to male mice. This data highlight the interaction between SCBs and psychedelic drugs that may be relevant to their long-term effects and psychiatric sequelae potentially related to their consumption.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cites 24
- Activation of Serotonin 2A Receptors Underlies the Psilocybin-Induced Effects on Oscillations, N170 Visual-Evoked Potentials, and Visual Hallucinations Journal of Neuroscience June 19, 2013
- Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways Current Topics in Behavioral Neurosciences 2017
- Psilocybin Biases Facial Recognition, Goal-Directed Behavior, and Mood State Toward Positive Relative to Negative Emotions Through Different Serotonergic Subreceptors Biological Psychiatry May 9, 2012
- Designer drugs: mechanism of action and adverse effects Archives of Toxicology April 1, 2020
- Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs). Neuropharmacology December 1, 2015
and 19 more in the library