In addition to dopamine neurons, there is a rich heterogeneity of glutamate and GABA neurons in the different anatomical subdomains of the VTA, and neurotransmitter co-release (e.g., dopamine -glutamate, GABA-glutamate, GABA-dopamine) from VTA neurons is common. Exciting VTA dopamine neurons with well-chosen rhythms can produce mania-like behaviors in the day and euthymia at night. The VTA an important source of dopamine, regulates goal- and reward-directed and social behaviors, as well as wakefulness and sleep. Some of these gene manipulations alter excitation-inhibition (E-I) balance, and/or elevate catecholamines, suggesting common themes that could underlie the emergence of some types of mania.Д«oth these themes come together in the ventral tegmental area (VTA). In mice, pathological hyperactivity and elevated mood can be generated by various gene mutations and deletions: e.g., ClockО”19, REV-erbО±, ErbB4 tyrosine kinase deletion in noradrenergic locus ceruleus cells, GSK-3ОІ overexpression, dopamine transporter knockdown, SHANK2 knockout, SHANK3 overexpression, ANK3 disruptions, ionotropic glutamate/AMPA receptor GluA1 knockout, ionotropic glutamate/kainate GluK2 knockout, phospholipase c Оі1 knockout, histidine triad nucleotide-binding protein 1 knockout, glutamate-cysteine ligase modifier unit knockout, and the Na/K-ATPase О±3 Myshkin (Myk/+) mutation. In the extreme, however, decreased or failed inhibition from VTA Vgat neurons produces mania-like qualities (hyperactivity, hedonia, decreased sleep).Дuring the mania phase of bipolar disorder, patients sleep little and have elevated mood (e.g., increased energy and hyperactivity, impulsivity, decreased depression). Inputs inhibiting VTA Vgat neurons intensify wakefulness (increased activity, enhanced alertness and motivation), qualities useful for acute survival. VTA Vgat neurons help set an animalвЂ™s (and perhaps humanвЂ™s) mental and physical activity levels. Optically or chemogenetically inhibiting VTA Vgat terminals in the LH elevated locomotion and decreased immobility time during the tail suspension and forced swimming tests. The mania like-behaviors mostly depended on dopamine, because giving D1/D2/D3 receptor antagonists reduced these behaviors, but also partially on VTA Vgat projections to the lateral hypothalamus (LH). Low doses of diazepam partially reduced the hyperlocomotion and fully recovered the immobility time during tail suspension. Lithium salts and lamotrigine, however, had no effect.

The mania-like behaviors, including the sleep loss, were reversed by valproate, and re-emerged when treatment was stopped. Furthermore, after sleep deprivation, mice with lesioned VTA Vgat neurons did not catch up on lost sleep, even though they were starting from a sleep-deprived baseline, suggesting that sleep homeostasis was bypassed. Lesioning or chemogenetically inhibiting VTA GABAergic (VTA Vgat) neurons generated persistent wakefulness with mania-like qualities: locomotor activity was increased sensitivity to D-amphetamine was heightened immobility times decreased on the tail suspension and forced swim tests and sucrose preference increased. But any roles of non-dopamine VTA neurons in psychiatric illness have been little explored. Hyperactivation of dopamine neurons generates behavioral pathologies. The ventral tegmental area (VTA), an important source of dopamine, regulates goal- and reward-directed and social behaviors, wakefulness, and sleep.

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