Ceramides affect alcohol consumption and depressive‐like and anxiety‐like behavior in a brain region‐ and ceramide species‐specific way in male mice

Abstract

Depression and alcohol dependence are associated with increased plasma ceramide concentrations in humans. Pharmacological increase in C16 ceramide concentrations in the dorsal hippocampus (DH) induced a depressive-like phenotype in naïve mice. However, the effects of C16 ceramide on alcohol consumption and anxiety-like behavior as well as the behavioral effects of other ceramide species are yet unknown. Therefore, we investigated whether repeated infusion of ceramides with different fatty acid chain lengths (C8, C16, and C20) into the DH and the basolateral amygdala (BLA) alter alcohol consumption, emotional behavior, and tissue monoamine levels. Our results revealed that C16, but not C8 and C20, ceramide altered alcohol drinking and emotional behavior in a brain region-specific way without altering tissue noradrenaline, dopamine, and serotonin levels in the prefrontal cortex, ventral striatum, and dorsal mesencephalon. In more detail, C16 ceramide increased alcohol consumption when infused into the BLA, but not when infused into the DH. Furthermore, C16 ceramide induced a depressive-like phenotype when infused into the DH, but a predominantly anxiogenic-like phenotype (in a non-social, but not a social context) when infused into the BLA. In turn, alcohol drinking normalized C16 ceramide-induced depressive-like and anxiogenic-like phenotypes. This study demonstrates a complex ceramide species-specific and brain region-specific modulation of alcohol consumption and emotional behavior in mice and provides the framework for future studies investigating the involvement of distinct ceramide species in the regulation of emotional behavior.

The Forebrain-Specific Overexpression of Acid Sphingomyelinase Induces Depressive-Like Symptoms in Mice

“…The serum was extracted and stored at −80 • C until it was assayed. Brains were removed, snap-frozen and stored at −80 • C. Several regions in the forebrain (i.e., frontal cortex, dorsal striatum, septum, amygdala, hypothalamus, dorsal hippocampus, and ventral hippocampus), midbrain (ventral mesencephalon) and hindbrain (cerebellum) were dissected from coronal brain slices as described in previous studies [15,21]. In one hemisphere (counterbalanced between mice), we analyzed Asm activity in all dissected brain regions.…”

“…Sphingomyelin SM16:0, SM18:0, SM18:1, SM20:0, SM22:0, SM24:0, SM24:1, SM26:0, and SM26:1 and ceramide Cer16:0, Cer16:1, Cer18:0, Cer18:1, Cer20:1, Cer22:0, and Cer24:0, however, were not altered by chronic corticosterone administration [20], suggesting that specific stressors might alter sphingolipid metabolism in a different way. The direct involvement of ceramide in the pathogenesis of depression was demonstrated in naïve mice, which developed a depressive-like phenotype after infusion of ceramide Cer16 but not Cer8 or Cer20 into the dorsal hippocampus [2,21]. Interestingly, Cer16 induced a predominantly nonsocial anxiogenic-like phenotype when infused into the basolateral amygdala, suggesting that ceramides alter depressive-like and anxiety-like behavior in a brain region-and ceramide species-specific way [21].…”

“…The direct involvement of ceramide in the pathogenesis of depression was demonstrated in naïve mice, which developed a depressive-like phenotype after infusion of ceramide Cer16 but not Cer8 or Cer20 into the dorsal hippocampus [2,21]. Interestingly, Cer16 induced a predominantly nonsocial anxiogenic-like phenotype when infused into the basolateral amygdala, suggesting that ceramides alter depressive-like and anxiety-like behavior in a brain region-and ceramide species-specific way [21].…”

Neutral ceramidase is a marker for cognitive performance in rats and monkeys

“…The ceramide rheostat is a crucial mechanism of cell membrane integrity determining synaptic appearance and signaling [40]. High abundance of ceramides, their precursors and metabolites in the brain [41] determines the specific involvement of these molecules in the pathogenesis of several psychiatric disorders [2,7,[9][10][11][12][13][14][15][16][17][18][19][20]. Recent data show that the ceramide system also contributes to the mechanisms of memory performance both under physiological conditions [26][27][28][29] and in patients with neurodegenerative disorders associated with cognitive decline [17,19,21,22].…”

“…One of them, the sphingomyelinase pathway, is based on the enzymes mediating ceramide generation from sphingomyelin, such as acid and neutral sphingomyelinases, and enzymes catalyzing ceramide degradation to sphingosine, such as acid and neutral ceramidases (AC and NC) [2][3][4]. The alterations in the levels and activities of all members of ceramide metabolism are involved in the pathogenesis of psychiatric disorders, such as depression [7][8][9][10], addiction [9,[11][12][13][14][15], as well as neurodegenerative disorders, such as Alzheimer's and Parkinson's disorder [16][17][18][19][20], and other disorders associated with memory loss [21,22].…”