Ventral tegmental area dopamine neurons control reward-driven learning, and their dysregulation can lead to psychiatric disorders. Tonic and phasic activity of these dopaminergic neurons depends on cholinergic tone and activation of nicotinic acetylcholine receptors (nAChRs), particularly those containing the ␤2 subunit (␤2*-nAChRs). Nuclear peroxisome proliferator-activated receptors type-␣ (PPAR␣) tonically regulate ␤2*-nAChRs and thereby control dopamine neuron firing activity. However, it is unknown how and when PPAR␣ endogenous ligands are synthesized by dopamine cells. Using ex vivo and in vivo electrophysiological techniques combined with biochemical and behavioral analysis, we show that activation of ␣7-nAChRs increases in the rat VTA both the tyrosine phosphorylation of the ␤2 subunit of nAChRs and the levels of two PPAR␣ endogenous ligands in a Ca 2ϩ -dependent manner. Accordingly, in vivo production of endogenous PPAR␣ ligands, triggered by ␣7-nAChR activation, blocks in rats nicotine-induced increased firing activity of dopamine neurons and displays antidepressant-like properties. These data demonstrate that endogenous PPAR␣ ligands are effectors of ␣7-nAChRs and that their neuromodulatory properties depend on phosphorylation of ␤2*-nAChRs on VTA dopamine cells. This reveals an autoinhibitory mechanism aimed at reducing dopamine cell overexcitation engaged during hypercholinergic drive. Our results unveil important physiological functions of nAChR/PPAR␣ signaling in dopamine neurons and how behavioral output can change after modifications of this signaling pathway. Overall, the present study suggests PPAR␣ as new therapeutic targets for disorders associated with unbalanced dopamine-acetylcholine systems.

Background:In utero exposure to maternal viral infections is associated with a higher incidence of psychiatric disorders with a supposed neurodevelopmental origin, including schizophrenia. Hence, immune response factors exert a negative impact on brain maturation that predisposes the offspring to the emergence of pathological phenotypes later in life. Although ventral tegmental area dopamine neurons and their target regions play essential roles in the pathophysiology of psychoses, it remains to be fully elucidated how dopamine activity and functionality are disrupted in maternal immune activation models of schizophrenia.Methods:Here, we used an immune-mediated neurodevelopmental disruption model based on prenatal administration of the polyriboinosinic-polyribocytidilic acid in rats, which mimics a viral infection and recapitulates behavioral abnormalities relevant to psychiatric disorders in the offspring. Extracellular dopamine levels were measured by brain microdialysis in both the nucleus accumbens shell and the medial prefrontal cortex, whereas dopamine neurons in ventral tegmental area were studied by in vivo electrophysiology.Results:Polyriboinosinic-polyribocytidilic acid-treated animals, at adulthood, displayed deficits in sensorimotor gating, memory, and social interaction and increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex. In polyriboinosinic-polyribocytidilic acid rats, dopamine neurons showed reduced spontaneously firing rate and population activity.Conclusions:These results confirm that maternal immune activation severely impairs dopamine system and that the polyriboinosinic-polyribocytidilic acid model can be considered a proper animal model of a psychiatric condition that fulfills a multidimensional set of validity criteria predictive of a human pathology.

The results obtained reveal a significant decrease in endothelial function of ex-ELBW subjects compared to controls, underlining a probable correlation with preterm birth and low birth weight. Taken together, these results suggest that an ELBW may underlie the onset of early circulatory dysfunction predictive of increased cardiovascular risk.

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