: Prolonged social isolation triggers neuropsychiatric impairments linked to brain neurotransmitter imbalances. This study investigated the impact of social isolation on sensory perception, affective states, and the levels of amino acid neurotransmitters and endocannabinoids within the medial prefrontal cortex (mPFC) of both male and female adolescent mice. Furthermore, we evaluated the therapeutic efficacy of S-adenosylmethionine (SAMe), a methyl donor with established antidepressant properties, in mitigating these alterations. Single-housed (SH) male mice developed mechanical allodynia, cold hyperalgesia, depression-like behavior, and general malaise, alongside significantly decreased GABA levels in the mPFC. SAMe treatment effectively ameliorated these symptoms, restoring GABAergic tone and increasing glycine and glutamate levels. In contrast, SH female mice exhibited anxiety-like behavior and pain hypersensitivity without depression-like traits. Their neurochemical profile was characterized by decreased GABA but increased levels of glutamate and specific endocannabinoids/acylethanolamides (2-AG, PEA, and LEA) in the mPFC. In females, SAMe treatment successfully reversed anxiety-like behavior and pain hypersensitivity, normalized glutamate, LEA, and GABA levels, and increased glycine and DHG. Our findings demonstrate that while social isolation-induced neuropsychiatric and neurochemical alterations are sex-dependent, the development of sensory hypersensitivity and the therapeutic responsiveness to SAMe are consistent across sexes. By restoring GABAergic homeostasis and modulating excitatory and endocannabinoid signaling in the mPFC, SAMe emerges as a promising pharmacological intervention for treating the complex psychiatric and sensory sequelae induced by chronic social stress.
Adolescent social isolation drives sex-dependent shifts in medial prefrontal cortex endocannabinoid tone and excitatory/inhibitory balance: the protective role of a methyl donor
Mosca, Laura;
2026-01-01
Abstract
: Prolonged social isolation triggers neuropsychiatric impairments linked to brain neurotransmitter imbalances. This study investigated the impact of social isolation on sensory perception, affective states, and the levels of amino acid neurotransmitters and endocannabinoids within the medial prefrontal cortex (mPFC) of both male and female adolescent mice. Furthermore, we evaluated the therapeutic efficacy of S-adenosylmethionine (SAMe), a methyl donor with established antidepressant properties, in mitigating these alterations. Single-housed (SH) male mice developed mechanical allodynia, cold hyperalgesia, depression-like behavior, and general malaise, alongside significantly decreased GABA levels in the mPFC. SAMe treatment effectively ameliorated these symptoms, restoring GABAergic tone and increasing glycine and glutamate levels. In contrast, SH female mice exhibited anxiety-like behavior and pain hypersensitivity without depression-like traits. Their neurochemical profile was characterized by decreased GABA but increased levels of glutamate and specific endocannabinoids/acylethanolamides (2-AG, PEA, and LEA) in the mPFC. In females, SAMe treatment successfully reversed anxiety-like behavior and pain hypersensitivity, normalized glutamate, LEA, and GABA levels, and increased glycine and DHG. Our findings demonstrate that while social isolation-induced neuropsychiatric and neurochemical alterations are sex-dependent, the development of sensory hypersensitivity and the therapeutic responsiveness to SAMe are consistent across sexes. By restoring GABAergic homeostasis and modulating excitatory and endocannabinoid signaling in the mPFC, SAMe emerges as a promising pharmacological intervention for treating the complex psychiatric and sensory sequelae induced by chronic social stress.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
