Brain acid sphingomyelinase controls addiction-related behaviours in a sex-specific way.
Liubov S Kalinichenko, Iulia Zoicas, Anne-Marie Bienia, Clara Bühner, Julia Robinson, Joshua Kütemeyer, Annika Labonte, Thadshajiny Raveendran, Lena Warth, Irena Smaga, Malgorzata Filip, Volker Eulenburg, Cosima Rhein, Anna Fejtova, Erich Gulbins, Johannes Kornhuber, Christian P Müller
Neurobiology of disease March 1, 2025 DOI: 10.1016/j.nbd.2025.106800 via PubMed
Summary
Overexpression of acid sphingomyelinase (ASM) in the forebrain affects addiction-related behaviors differently in male and female mice. In males, forebrain ASM overexpression increased alcohol consumption in a free-choice paradigm and reduced conditioned place preference (CPP) for alcohol and cocaine, but not for amphetamine, ketamine, or high-fat/carbohydrate food. In females, it increased binge-like alcohol drinking while moderate consumption remained unchanged, and enhanced CPP for amphetamine but not other substances. These findings suggest ASM plays a sex-specific role in the reinforcing effects of certain addictive substances, offering potential molecular targets for drug- and sex-specific therapies.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male and female mice with forebrain ASM overexpression |
| Intervention | forebrain ASM overexpression |
| Topics | Addiction Ketamine Serotonin |
| Keywords | Acid sphingomyelinase Alcohol Amphetamine Cocaine Conditioned place preference |
| Citations | 4 |
| Key finding | Forebrain ASM overexpression alters alcohol consumption and conditioned place preference for alcohol, cocaine, and amphetamine in a sex-specific manner in mice. |
Abstract
Addiction is a chronic and severe mental disorder with high gender- and sex-specificity. However, the pathogenesis of this disorder is not fully elucidated, and no targeted pharmacotherapy is available. A growing body of evidence points out the potential involvement of the ceramide system in the pathophysiology of addiction. A pathogenic pathway for several mental disorders based on the overexpression of an enzyme involved in ceramide formation, acid sphingomyelinase (ASM), was recently proposed. Here we show a crucial role of ASM specifically overexpressing in the forebrain for various types of addiction-related behaviours in a drug- and sex-specific way. In male mice, a forebrain ASM overexpression led to enhanced alcohol consumption in a free-choice paradigm. It also diminished the reinforcing properties of alcohol and cocaine, but not that of amphetamine, ketamine, or a natural reinforcer fat/carbohydrate-rich food in the conditioned place preference (CPP) test in males. In female mice, a forebrain ASM overexpression enhanced alcohol binge-like drinking, while moderate alcohol consumption was preserved. ASM overexpression in females contributed to CPP establishment for amphetamine, but not for other psychoactive substances. Altogether, this study shows a specific involvement of forebrain ASM in the development of conditioned reinforcing effects of different types of substances with addictive properties in a sex-specific way. Our data enlarge the current knowledge on the specific molecular mechanisms of dependence from various drugs of abuse and might serve as a basis for the development of drug- and sex-specific targeted therapy.