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Neutral sphingomyelinase controls acute and chronic alcohol effects on brain activity

Wank I, Mittmann C, Kreitz S, Chestnykh D, Mühle C, Kornhuber J, et al.

Neuropharmacology, 2024 Apr 16;253:109948.
PMID: 38636728 DOI: 10.1016/j.neuropharm.2024.109948

Alcohol consumption is a widespread phenomenon throughout the world. However, how recreational alcohol use evolves into alcohol use disorder (AUD) remains poorly understood. The Smpd3 gene and its coded protein neutral sphingomyelinase (NSM) are associated with alcohol consumption in humans and alcohol-related behaviors in mice, suggesting a potential role in this transition. Using multiparametric magnetic resonance imaging, we characterized the role of NSM in acute and chronic effects of alcohol on brain anatomy and function in female mice. Chronic voluntary alcohol consumption (16 vol% for at least 6 days) affected brain anatomy in WT mice, reducing regional structure volume predominantly in cortical regions. Attenuated NSM activity prevented these anatomical changes. Functional MRI linked these anatomical adaptations to functional changes: Chronic alcohol consumption in mice significantly modulated resting state functional connectivity (RS FC) in response to an acute ethanol challenge (i.p. bolus of 2 g kg-1) in heterozygous NSM knockout (Fro), but not in WT mice. Acute ethanol administration in alcohol-naïve WT mice significantly decreased RS FC in cortical and brainstem regions, a key finding that was amplified in Fro mice. Regarding direct pharmacological effects, acute ethanol administration increased the regional cerebral blood volume (rCBV) in many brain areas. Here, chronic alcohol consumption otherwise attenuated the acute rCBV response in WT mice but enhanced it in Fro mice. Altogether, these findings suggest a differential role for NSM in acute and chronic functional brain responses to alcohol. Therefore, targeting NSM may be useful in the prevention or treatment of AUD.
New ways to cope with depression-study protocol for a randomized controlled mixed methods trial of bouldering psychotherapy (BPT) and mental model therapy (MMT)

Kind L, Luttenberger K, Leßmann V, Dorscht L, Mühle C, Müller CP, et al.

Trials, 2023 Sep 22;24(1):602.
PMID: 37736688 DOI: 10.1186/s13063-023-07629-x

BACKGROUND: Due to the growing gap between the demand and supply of therapeutic services for people suffering from depression, with this study, we are investigating the effectiveness and factors of influence of new approaches in group treatments for depression. Two previous studies have already identified bouldering psychotherapy (BPT) as an effective option. It combines psychotherapeutic interventions with action- and body-oriented bouldering exercises. Mental model therapy (MMT) is a new cognitive-behavioral approach for treating depression. It focuses on identifying cognitive distortions, biases in decision making, and false assumptions and aims to correct and replace them with useful mental models. We aim to investigate the effectiveness of the interventions compared with a control group (CG) and to assess the factors of influence in a mixed methods approach.
METHODS: The study is being conducted as a randomized controlled intervention trial. Adult participants with unipolar depression are being randomized into three groups (BPT, MMT, or CG), and the first two groups are undergoing a 10-week treatment phase. CG follows their individual standard treatment as usual. A priori power analysis revealed that about 120 people should be included to capture a moderate effect. The primary outcome of the study is depression rated with the Montgomery and Asberg Depression Rating Scale (MADRS) before (t0), directly after (t1), and 12 months after the intervention phase (t2). Data are being collected via questionnaires, computer-assisted video interviews, and physical examinations. The primary hypotheses will be statistically analyzed by mixed model ANOVAs to compare the three groups over time. For secondary outcomes, further multivariate methods (e.g., mixed model ANOVAs and regression analyses) will be conducted. Qualitative data will be evaluated on the basis of the qualitative thematic analysis.
DISCUSSION: This study is investigating psychological and physical effects of BPT and MMT and its factors of influence on outpatients suffering from depression compared with a CG in a highly naturalistic design. The study could therefore provide insight into the modes of action of group therapy for depression and help to establish new short-term group treatments. Methodological limitations of the study might be the clinical heterogeneity of the sample and confounding effects due to simultaneous individual psychotherapy.
TRIAL REGISTRATION: ISRCTN, ISRCTN12347878. Registered 28 March 2022, https://www.isrctn.com/ISRCTN12347878 .
Sex-specific pleiotropic changes in emotional behavior and alcohol consumption in human α-synuclein A53T transgenic mice during early adulthood

Kalinichenko LS, Kohl Z, Mühle C, Hassan Z, Hahn A, Schmitt EM, et al.

J Neurochem, 2024 Mar;168(3):269-287.
PMID: 38284431 DOI: 10.1111/jnc.16051

Point mutations in the α-synuclein coding gene may lead to the development of Parkinson's disease (PD). PD is often accompanied by other psychiatric conditions, such as anxiety, depression, and drug use disorders, which typically emerge in adulthood. Some of these point mutations, such as SNCA and A30T, have been linked to behavioral effects that are not commonly associated with PD, especially regarding alcohol consumption patterns. In this study, we investigated whether the familial PD point mutation A53T is associated with changes in alcohol consumption behavior and emotional states at ages not yet characterized by α-synuclein accumulation. The affective and alcohol-drinking phenotypes remained unaltered in female PDGF-hA53T-synuclein-transgenic (A53T) mice during both early and late adulthood. Brain region-specific activation of ceramide-producing enzymes, acid sphingomyelinase (ASM), and neutral sphingomyelinase (NSM), known for their neuroprotective properties, was observed during early adulthood but not in late adulthood. In males, the A53T mutation was linked to a reduction in alcohol consumption in both early and late adulthood. However, male A53T mice displayed increased anxiety- and depression-like behaviors during both early and late adulthood. Enhanced ASM activity in the dorsal mesencephalon and ventral hippocampus may potentially contribute to these adverse behavioral effects of the mutation in males during late adulthood. In summary, the A53T gene mutation was associated with diverse changes in emotional states and alcohol consumption behavior long before the onset of PD, and these effects varied by sex. These alterations in behavior may be linked to changes in brain ceramide metabolism.
Adult alcohol drinking and emotional tone are mediated by neutral sphingomyelinase during development in males

Kalinichenko LS, Mühle C, Jia T, Anderheiden F, Datz M, Eberle AL, et al.

Cereb Cortex, 2023 Jan 05;33(3):844-864.
PMID: 35296883 DOI: 10.1093/cercor/bhac106

Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior.
Fulltext Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects

Kalinichenko LS, Mühle C, Jia T, Anderheiden F, Datz M, Eberle AL, et al.

Mol Psychiatry, 2021 Dec;26(12):7403-7416.
PMID: 34584229 DOI: 10.1038/s41380-021-01304-w

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone-brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental-physical co-morbidity trias of alcohol abuse-depression/anxiety-bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental-physical co-morbidity trias.
Associations of Menstrual Cycle and Progesterone-to-Estradiol Ratio With Alcohol Consumption in Alcohol Use Disorder: A Sex-Separated Multicenter Longitudinal Study

Hoffmann S, Gerhardt S, Mühle C, Reinhard I, Reichert D, Bach P, et al.

Am J Psychiatry, 2024 May 01;181(5):445-456.
PMID: 38196336 DOI: 10.1176/appi.ajp.20230027

OBJECTIVE: Alcohol use disorder (AUD) constitutes a critical public health issue and has sex-specific characteristics. Initial evidence suggests that progesterone and estradiol might reduce or increase alcohol intake, respectively. However, there is a need for a better understanding of how the menstrual cycle in females and the ratio of progesterone to estradiol in females and males influence alcohol use patterns in individuals with AUD.
METHODS: In this sex-separated multicenter longitudinal study, the authors analyzed 12-month data on real-life alcohol use (from 21,460 smartphone entries), menstrual cycle, and serum progesterone-to-estradiol ratios (from 667 blood samples at four individual study visits) in 74 naturally cycling females and 278 males with AUD between 2020 and 2022, using generalized and general linear mixed modeling.
RESULTS: Menstrual cycle phases were significantly associated with binge drinking and progesterone-to-estradiol ratio. During the late luteal phase, females showed a lower predicted binge drinking probability of 13% and a higher predicted marginal mean of progesterone-to-estradiol ratio of 95 compared with during the menstrual, follicular, and ovulatory phases (binge drinking probability and odds ratios vs. late luteal phase, respectively: 17%, odds ratio=1.340, 95% CI=1.031, 1.742; 19%, odds ratio=1.523, 95% CI=1.190, 1.949; and 20%, odds ratio=1.683, 95% CI=1.285, 2.206; difference in progesterone-to-estradiol ratios, respectively: -61, 95% CI=-105.492, -16.095; -78, 95% CI=-119.322, -37.039; and -71, 95% CI=-114.568, -27.534). In males, a higher progesterone-to-estradiol ratio was related to lower probabilities of binge drinking and of any alcohol use, with a 10-unit increase in the hormone ratio resulting in odds ratios of 0.918 (95% CI=0.843, 0.999) and 0.914 (95% CI=0.845, 0.988), respectively.
CONCLUSIONS: These ecologically valid findings suggest that high progesterone-to-estradiol ratios can have a protective effect against problematic alcohol use in females and males with AUD, highlighting the progesterone-to-estradiol ratio as a promising treatment target. Moreover, the results indicate that females with AUD may benefit from menstrual cycle phase-tailored treatments.