Maternal immune activation impairs endocannabinoid signaling in the mesolimbic system of adolescent male offspring

Endocannabinoid-dependent decrease of GABAergic transmission on dopaminergic neurons is associated with susceptibility to cocaine stimulant effects in pre-adolescent male MAOA hypomorphic mice exposed to early life stress

“…Remarkably, repeated in vivo cocaine exposure enables a 2AG-mediated DSI, expressed by VTA dopamine neurons only in MAOA Neo ES mice that cannot be ascribed to a larger number of CB1Rs, or a greater effect produced upon their activation. Conversely, the observation that 2AG phasic signal is enhanced in either time and/or space at these inhibitory afferents impinging upon VTA dopamine neurons is consistent with previous reports showing that DSI strength is determined by 2AG degradation rate (Melis et al, 2013(Melis et al, , 2014Pan et al, 2009;Santoni et al, 2023;Yoshida et al, 2011). Since MAOA Neo ES mouse dopamine neurons per se do not express DSI (Fig.…”

“…These results confirm the absence of a 2AG tone at these synapses in MAOA Neo ES mice repeatedly exposed in vivo to cocaine, and suggest a deficient clearance operated by MAGL, which could only be unveiled upon dopamine neuron depolarization. Our data also support that MAGL determines both the strength and the duration of retrograde synaptic signal (Melis et al, 2013(Melis et al, , 2014Pan et al, 2009;Santoni et al, 2023;Yoshida et al, 2011), being DSI expressed by dopamine cells in all experimental groups at a subthreshold duration of depolarization (3 s) in the presence of JZL184 (Fig. 5E), which abates endocannabinoid-dependent synaptic plasticity (Schlosburg et al, 2010), being DSI magnitude in MAOA Neo ES mice reduced in the presence of JZL184.…”

The PPARα Agonist Fenofibrate Reduces the Levels of Proinflammatory Cytokines in a Maternal Immune Activation Model of Schizophrenia

“…2 In our previous studies, we reported behavioral impairments correlated with an altered mesolimbic dopamine transmission both in the first and second generation [16,17]. We showed how inflammation caused by MIA alters the endocannabinoid signaling, which negatively influences the dopamine system, eventually leading to schizophrenia-like phenotype in adulthood [18]. In addition, we demonstrated that activation of peroxisome proliferator-activated receptor-α (PPARα) with the clinically available agonist fenofibrate attenuates the neurodevelopmental disturbances induced by MIA in rat offspring [19].…”

“…As previously described [18,74] sera and brain tissue homogenates were assayed for cytokines, chemokines and CSFs using a Luminex xMAP-based multiplex bead-based immunoassay, the Bio-Plex ProTM Rat Cytokine Group I Panel 23-Plex (Bio-Rad Laboratories, Inc., USA), which detects cytokines: [Interleukins (IL)-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12(p70), IL-13, IL-17A, IL-18, interferon (IFN)γ, tumor necrosis factor (TNF)α; chemokines: monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein (MIP)1α, MIP-3α, regulated on activation normal T cells expressed and secreted (RANTES), keratinocyte derived chemokine (GRO/KC or CXCL1), and growth factors: granulocytes macrophage colony-stimulating factor (GM)-CSF, granulocyte (G)-CSF, macrophage (M)-CSF and vascular endothelial growth factor (VEGF)].…”