Adult alcohol drinking and emotional tone are mediated by neutral sphingomyelinase during development in males

Abstract

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.

Behavioural effects of APH199, a selective dopamine D4 receptor agonist, in animal models

“…A number of factors limits our study. First, all our experiments were performed only in male rodents, even though sex differences may play a significant role in behavioural responses to pharmacological challenges (Kalinichenko et al 2021(Kalinichenko et al , 2022. Research showed that the results of many behavioural tests, including FST, EPM, OF, amphetamine-and apomorphine-induced locomotion, varied significantly not only after pharmacological interventions, but also during baseline activity (Simpson et al 2012;Knight et al 2021).…”

“…Behaviour was recorded automatically by the TSE Systems software using infrared sensors. The apparatus measured parameters for each compartment separately (Kalinichenko et al 2021(Kalinichenko et al , 2022.…”

“…In order to measure the basal level (Bl) of place preference in a pre-test, animals were administered with the VEH and placed in the central chamber of CPP with a free choice of moving between all three compartments for 20 min. We applied a counterbalanced study design whereby half of the animals were conditioned to their preferred chamber and another half to the non-preferred (Kalinichenko et al 2021(Kalinichenko et al , 2022. Before the conditioning trial, mice were administered with either APH199 (0.1 or 0.5 mg/kg) or VEH, 20 min in advance.…”

“…APH199, VEH and alcohol solutions were prepared and administered as described above (see Drug preparation). The concentration of 2 g/kg for alcohol was chosen based on the previous studies that demonstrated a prominent rewarding effect but without causing sedation (Easton et al 2013;Kalinichenko et al 2021Kalinichenko et al , 2022. The illumination level of CPP boxes was 20 lx.…”

“…In this experiment, male C57BL/6 J mice (N = 36, n = 12/group) received injections with only SAL or alcohol (2 g/kg) immediately before the conditioning trial, whilst APH199 (0.5 or 5 mg/kg) or VEH (10 ml/kg, I.P.) was administered 20 min before each preference test (T1, T2, T3) (Kalinichenko et al 2021(Kalinichenko et al , 2022.…”