The nucleus accumbens (NAc) is the major component of the ventral striatum that regulates stress-induced depression. The NAc receives dopaminergic inputs from the ventral tegmental area (VTA), and the role of VTA-NAc neurons in stress response has been recently characterized. The NAc also receives glutamatergic inputs from various forebrain structures including the prelimbic cortex (PL), basolateral amygdala (BLA), and ventral hippocampus (vHIP), whereas the role of those glutamatergic afferents in stress response remains underscored. In the present study, we investigated the extent to which descending glutamatergic neurons activated by stress in the PL, BLA, and vHIP project to the NAc. To specifically label the input neurons into the NAc, fluorescent-tagged cholera toxin subunit B (CTB), which can be used as a retrograde neuronal tracer, was injected into the NAc. After two weeks, the mice were placed under restraint for 1 h. Subsequent histological analyses indicated that CTB-positive cells were detected in 170~680 cells/mm² in the PL, BLA, and vHIP, and those CTB-positive cells were mostly glutamatergic. In the PL, BLA, and vHIP regions analyzed, stress-induced c-Fos expression was found in 20~100 cells/mm². Among the CTB-positive cells, 2.6% in the PL, 4.2% in the BLA, and 1.1% in the vHIP were co-labeled by c-Fos, whereas among c-Fos-positive cells, 7.7% in the PL, 19.8% in the BLA, and 8.5% in the vHIP were co-labeled with CTB. These results suggest that the NAc receives a significant but differing proportion of glutamatergic inputs from the PL, BLA, and vHIP in stress response.
Animals ; Basolateral Nuclear Complex ; Cholera Toxin ; Depression ; Hippocampus ; Mice ; Neurons* ; Nucleus Accumbens* ; Prosencephalon ; Ventral Striatum ; Ventral Tegmental Area

Ventral tegmental area (VTA) is an important relay station of signal transmission in the reward system. The plasticity of VTA dopaminergic neurons directly influences actions of other regions of the reward system. Studies concerning the plasticity of VTA dopaminergic neurons focus mainly on synaptic plasticity, while much less attention has been given to the plasticity of intrinsic excitability of the neurons. The aim of the present study was to investigate the effect of high-frequency stimulation (HFS) on the plasticity of excitability of VTA neuron. Whole-cell patch-clamping was performed on VTA dopaminergic neurons in midbrain slices bathed with PTX, AP-5 and CNQX, and HFS was introduced to cell soma. The result showed that, after HFS induction the pharmacologically isolated neurons showed increased input resistance and firing frequency, as well as decreased rheobase. Meanwhile, the steady-state whole-cell current decreased, and the hyperpolarization-activated current (I(h)) decreased. These results suggest that HFS on soma induces a long-term potentiation of excitability in VTA dopaminergic neurons, and the underlying mechanism involves the changes of membrane current.
Animals ; Dopaminergic Neurons ; cytology ; Long-Term Potentiation ; Patch-Clamp Techniques ; Ventral Tegmental Area ; physiology

Protein O-GlcNAcylation is a post-translational modification that links environmental stimuli with changes in intracellular signal pathways, and its disturbance has been found in neurodegenerative diseases and metabolic disorders. However, its role in the mesolimbic dopamine (DA) system, especially in the ventral tegmental area (VTA), needs to be elucidated. Here, we found that injection of Thiamet G, an O-GlcNAcase (OGA) inhibitor, in the VTA and nucleus accumbens (NAc) of mice, facilitated neuronal O-GlcNAcylation and decreased the operant response to sucrose as well as the latency to fall in rotarod test. Mice with DAergic neuron-specific knockout of O-GlcNAc transferase (OGT) displayed severe metabolic abnormalities and died within 4-8 weeks after birth. Furthermore, mice specifically overexpressing OGT in DAergic neurons in the VTA had learning defects in the operant response to sucrose, and impaired motor learning in the rotarod test. Instead, overexpression of OGT in GABAergic neurons in the VTA had no effect on these behaviors. These results suggest that protein O-GlcNAcylation of DAergic neurons in the VTA plays an important role in regulating the response to natural reward and motor learning in mice.
Animals ; Dopaminergic Neurons/physiology* ; GABAergic Neurons/physiology* ; Mice ; Nucleus Accumbens/metabolism* ; Reward ; Ventral Tegmental Area/metabolism*

Dopaminergic neurons in the ventral tegmental area (VTA) play an important role in cognition, emergence from anesthesia, reward, and aversion, and their projection to the cortex is a crucial part of the "bottom-up" ascending activating system. The prelimbic cortex (PrL) is one of the important projection regions of the VTA. However, the roles of dopaminergic neurons in the VTA and the VTA^DA-PrL pathway under sevoflurane anesthesia in rats remain unclear. In this study, we found that intraperitoneal injection and local microinjection of a dopamine D1 receptor agonist (Chloro-APB) into the PrL had an emergence-promoting effect on sevoflurane anesthesia in rats, while injection of a dopamine D1 receptor antagonist (SCH23390) deepened anesthesia. The results of chemogenetics combined with microinjection and optogenetics showed that activating the VTA^DA-PrL pathway prolonged the induction time and shortened the emergence time of anesthesia. These results demonstrate that the dopaminergic system in the VTA has an emergence-promoting effect and that the bottom-up VTA^DA-PrL pathway facilitates emergence from sevoflurane anesthesia.
Anesthesia ; Animals ; Dopaminergic Neurons/metabolism* ; Rats ; Receptors, Dopamine D1/metabolism* ; Sevoflurane/pharmacology* ; Ventral Tegmental Area/metabolism*

Acamprosate reduces the craving for alcohol by decreasing glutamate activity and increasing gamma-aminobutyric acid (GABA) action in patients with alcohol dependence. Acamprosate has tolerable side effects that include diarrhea, headache, dizziness and pruritus. In this study, we report acamprosate-induced extrapyramidal symptoms in an elderly patient with no history of neurologic disease. Severe extrapyramidal symptoms developed two days after the administration of acamprosate and improved over one week after the acamprosate was stopped. Extrapyramidal symptoms are commonly associated with dopamine receptor antagonists. However, there have been several reports of extrapyramidal symptoms occurring with drugs targeting other systems, including GABA, glutamate and serotonin. Acamprosate may decrease dopamine levels in the ventral tegmental area mediated by glutamatergic action and thus cause extrapyramidal symptoms. We suggest that acamprosate carries the risk of causing extrapyramidal symptoms.
Aged* ; Alcoholism* ; Diarrhea ; Dizziness ; Dopamine ; Dopamine Antagonists ; gamma-Aminobutyric Acid ; Glutamic Acid ; Headache ; Humans ; Pruritus ; Serotonin ; Ventral Tegmental Area

No abstract available.
Alcohol-Related Disorders/physiopathology ; Behavior, Addictive/*physiopathology ; Brain/physiopathology/radiography ; Humans ; Internet ; Magnetic Resonance Imaging ; Ventral Tegmental Area/metabolism

Mongolian gerbil (Meriones unguiculatus) has been as an model animal for studing the neurologic disease because of the long-term survival in the condition of water-deprived desert condition. In order to accomplish the this research, first of all another divided the laboratory animals 10groups. In this study of the long term water deprived condition investigated catecholamine synthetic enzymes, tyrosine hydroxylase(TH), dopamine-beta-hydroxylase (DBH), and phenylethanolamine-N- methyltransferase(PNMT) in the brain by using immunohistochemical stain. The results obtained in this study were summarized as following. 1. It were observed TH-IR cells in substantia nigra pars compacta, ventral tegmental area and substantia nigra pars reticular of Midbrian. Most of them were presented in pars compacta and ventral tegmental area, but a few in pars reticular. TH-IR cell decreased until the 5th water-deprived day, increased from the 10th water-deprived day to the 15th water-deprived day and redecreased in the 20th water-deprived day 2. In locus ceruleus and rubrospinal tract were observed TH-IR cells and a few DBH-IR cell. Therefore there was composed of dopaminergic neuron and noradrenergic neuron. 3. The quantity of dopamin in serum were decreased until the 4th water-deprived day, increased from the 5th water-deprived day, redecreased on the 15th water-deprived day and reincreased from the 20th water-deprived day.
Adrenergic Neurons ; Animals ; Animals, Laboratory ; Brain ; Dopaminergic Neurons ; Gerbillinae* ; Locus Coeruleus ; Mesencephalon* ; Pons* ; Substantia Nigra ; Tyrosine ; Ventral Tegmental Area

Recent studies suggest that alterations in glutamate receptor subunit levels in mesocorticolimbic dopamine areas could account for neural adaptations in response to psychostimulant drugs. Although many drugs of abuse induce changes in ionotropic glutamate receptor subunits in mesocorticolimbic dopamine areas, the changes of ionotropic glutamate receptor subunits by repeated nicotine treatment in these areas are not known. To answer this question, we injected male Sprague-Dawley rats twice daily with nicotine (0.4 mg/kg) or saline (1 ml/kg) for 10 days. The immunoreactivity of NR1, GluR1, and GluR2 glutamate receptor subunits was examined 16~18 h after the last injection of saline or nicotine. Repeated nicotine treatment significantly increased NR1 levels in the ventral tegmental area (VTA). In addition, repeated nicotine treatment showed a tendency towards an increase in GluR1 levels in the VTA as well as in striatum. However, there was no significant change in glutamate receptor subunits in other areas including nucleus accumbens (NAc). These results demonstrate that repeated nicotine treatment increases NR1 levels in VTA similarly to other drugs of abuse, suggesting that elevated glutamate receptor subunits in the VTA, but not NAc may be involved in the excitation of mesocorticolimbic dopamine neurons by nicotine.
Dopamine* ; Glutamic Acid* ; Humans ; Male ; Neurons ; Nicotine* ; Nucleus Accumbens ; Rats, Sprague-Dawley ; Receptors, Glutamate* ; Street Drugs ; Ventral Tegmental Area

A current hypothesis of sleep-wake regulation proposes that the sleep process starts with the activation of sleep-promoting neurons located in the preoptic area of the anterior hypothalamus. This activation leads to the inhibition of wake-promoting neurons located in the posterior hypothalamus, basal forebrain, and mesopontine tegmentum, which, in turn removes inhibition from the sleep-promoting structures(i.e., disinhibition) to initiate the sleep process. Mutual inhibition between these wake- and sleep-promoting neurons results in switching properties that define discrete wakeful and sleep states with sharp transitions between them. Wake-promoting nuclei include the orexinergic lateral hypothalamic/perifornical area, the histaminergic tuberomammillary nucleus, the cholinergic pedunculopontine tegmental nucleus, the noradrenergic locus coeruleus, the 5-hydroxytryptaminergic raphe nuclei, and possibly the dopaminergic ventral tegmental area. The major sleep-promoting nucleus is the GABAergic ventrolateral preoptic nucleus of the hypothalamus. The regulation of sleep is classically viewed as the dual interaction of circadian(SCN-based) and homeostatic processes, and the propensity to be asleep or awake at any given time is a consequence of a sleep debt and its interaction with signals from the SCN circadian clock. To better understand the mechanisms of sleep and wakefulness, the focus of pharmacotherapy is on targeting specific therapies to the particular defect in sleep-wake regulation.
Circadian Clocks ; Circadian Rhythm ; Drug Therapy* ; Hypothalamic Area, Lateral ; Hypothalamus ; Hypothalamus, Anterior ; Hypothalamus, Posterior ; Locus Coeruleus ; Neuroanatomy* ; Neurons ; Pedunculopontine Tegmental Nucleus ; Preoptic Area ; Prosencephalon ; Raphe Nuclei ; Sleep Wake Disorders ; Ventral Tegmental Area ; Wakefulness

BACKGROUND: The terminal destruction of the striatal dopaminergic axon can produce the retrograde degeneration of nigral dopaminergic neurons. An analyses of the postsynaptic dopamine D1 & D2 receptors and the DOPAC/DA level, revealed that this model mimics the early course of Parkinson's disease in humans. We evaluated the time course of the retrograde dopaminergic neuronal degeneration and the pattern of dopaminergic neuronal loss in the substantia nigra after various doses of 6-hydroxydopamine (6-OHDA) injections in the striatum of rats. METHODS: Different doses of 6- OHDA (0.0, 1.25, 2.5, 5, 10 ug/ul in 3.5 ul of saline) were unilaterally injected into the right striatum of rats using a stereotaxic frame. Structural and functional deficits were quantified and compared using apomorphine-induced rotations and tyrosine hydroxylase-immunoreactive (TH-IR) cell numbers in the substantia nigra pars compacta (SNpc) at 3, 6, 9 weeks after lesioning. RESULTS: Striatal 6-OHDA lesions produced dose-dependent decreases in TH-IR cell numbers in SNpc at 3 weeks (-3.8%, 17.9%, 41.2%, 58.5%, 69.9% cell loss compared with the contralesional side respectively), where the ventrolateral portion of the SNpc were more affected. As time progressed, nigral cell loss was significantly increased in all dosage groups and the lesion extended to the medial side of the SNpc and the ventral tegmental area. Apomorphine-induced rotations did not correlate well with nigral TH-IR cell loss. CONCLUSIONS: Intrastriatal injections of 6-OHDA, results in time-dependent and dose-dependent progressive degeneration of nigral dopaminergic neurons. We conclude that this rat model can be useful for the evaluation of further neuroprotective and neurotrophic therapies.
Animals ; Apoptosis ; Axons ; Cell Count ; Cell Death ; Dopamine* ; Dopaminergic Neurons ; Humans ; Models, Animal ; Oxidopamine* ; Parkinson Disease ; Rats* ; Retrograde Degeneration ; Substantia Nigra ; Tyrosine ; Ventral Tegmental Area