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*

µ-opioid receptor (MOR) is a class of opioid receptors with a high affinity for enkephalins and beta-endorphin. In hippocampus, activation of MOR is known to enhance the neuronal excitability of pyramidal neurons, which has been mainly attributed to a disinhibition of pyramidal neurons via activating Gαi subunit to suppress the presynaptic release of GABA in hippocampal interneurons. In contrast, the potential role of MOR in hippocampal astrocytes, the most abundant cell type in the brain, has remained unexplored. Here, we determine the cellular and subcellular distribution of MOR in different cell types of the hippocampus by utilizing MOR-mCherry mice and two different antibodies against MOR. Consistent with previous findings, we demonstrate that MOR expression in the CA1 pyramidal layer is co-localized with axon terminals from GABAergic inhibitory neurons but not with soma of pyramidal neurons. More importantly, we demonstrate that MOR is highly expressed in CA1 hippocampal astrocytes. The ultrastructural analysis further demonstrates that the astrocytic MOR is localized in soma and processes, but not in microdomains near synapses. Lastly, we demonstrate that astrocytes in ventral tegmental area and nucleus accumbens also express MOR. Our results provide the unprecedented evidence for the presence of MOR in astrocytes, implicating potential roles of astrocytic MOR in addictive behaviors.
Animals ; Antibodies ; Astrocytes* ; Behavior, Addictive ; beta-Endorphin ; Brain ; Carisoprodol ; Enkephalins ; gamma-Aminobutyric Acid ; Hippocampus ; Interneurons ; Mice ; Microscopy, Electron ; Neurons ; Nucleus Accumbens ; Presynaptic Terminals ; Pyramidal Cells ; Receptors, Opioid ; Synapses ; Ventral Tegmental Area

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

BACKGROUND: The melanocortin 4 receptor (MC4R) is involved in the regulation of homeostatic energy balance by the hypothalamus. Recent reports showed that MC4R can also control the motivation for food in association with a brain reward system, such as dopamine. We investigated the expression levels of MC4R and the dopamine D2 receptor (D2R), which is known to be related to food rewards, in both the hypothalamus and brain regions involved in food rewards. METHODS: We examined the expression levels of D2R and MC4R by dual immunofluorescence histochemistry in hypothalamic regions and in the bed nucleus of the stria terminalis (BNST), the central amygdala, and the ventral tegmental area of transgenic mice expressing enhanced green fluorescent protein under the control of the D2R gene. RESULTS: In the hypothalamic area, significant coexpression of MC4R and D2R was observed in the arcuate nucleus. We observed a significant coexpression of D2R and MC4R in the BNST, which has been suggested to be an important site for food reward. CONCLUSION: We suggest that MC4R and D2R function in the hypothalamus for control of energy homeostasis and that within the brain regions related with rewards, such as the BNST, the melanocortin system works synergistically with dopamine for the integration of food motivation in the control of feeding behaviors.
Amygdala ; Animals ; Arcuate Nucleus ; Brain* ; Dopamine* ; Eating* ; Feeding Behavior ; Fluorescent Antibody Technique ; Homeostasis ; Hypothalamus ; Mice ; Mice, Transgenic ; Motivation ; Obesity ; Receptor, Melanocortin, Type 4* ; Receptors, Dopamine D2* ; Reward ; Ventral Tegmental Area

A complex set of brain based systems modulate feeding to maintain constant body weight. The adipose derived-hormone, leptin, plays a crucial role in this control by acting on diverse leptin receptor (LepRb)-expressing neurons in the hypothalamus and brainstem to modify behavior and metabolism. In addition to controlling energy expenditure and satiety, leptin controls motivation and the reward value of food by regulating two interconnected systems: hypocretin (HCRT) neurons and the mesolimbic dopamine (MLDA) system. Modest/acute decreases in leptin levels, as associated with mild caloric restriction, increase MLDA activity and overall food-seeking behavior; in contrast, severe starvation or complete leptin deficiency blunt MLDA activity, along with motivation and associated behaviors. Lateral hypothalamic (LHA) LepRb neurons project to dopamine (DA) neurons in the ventral tegmental area, where neurotensin (NT) release augments MLDA function; these LepRb(NT) cells also innervate HCRT neurons to control Hcrt expression and inhibit HCRT neurons. Ablation of LepRb in these cells abrogates the control of HCRT cells by leptin and decreases activity and MLDA function. We propose that this neural pathway regulates the MLDA, activity, and motivation in response to leptin and nutritional status.
Body Weight ; Brain ; Brain Stem ; Caloric Restriction ; Dopamine ; Energy Metabolism ; Hypothalamus ; Leptin ; Metabolism ; Motivation ; Neural Pathways ; Neurons ; Neurotensin ; Nutritional Status ; Obesity ; Orexins ; Receptors, Leptin ; Reward ; Starvation ; Ventral Tegmental Area

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

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

All drugs of abuse, like neural rewarding behaviors such as sex and eating, increase extra-cellular dopamine (DA) levels in the nucleus accumbens (NA), which is a part of the common reward mesolimbic pathway from the ventral tegmental area (VTA) to the NA. As addiction progresses from initial use to obsessive compulsive use, the neurobiology shifts from a DA-based behavioral system to a predominantly glutamate-based one, still relying on DA. A DA release in the prefrontal cortex (PFC) and amygdala in the relapse stimulates glutamate transmission between the PFC and amygdala and glutamate release in the pathway from the PFC to the NA core, constituting a "final common pathway" for drug-seeking behavior. Dysfunction of critical PFC structures results in drug craving and impaired decision making. Inhalation and smoking are the routes of administration that allow the most rapid delivery of drugs to the brain, while intravenous injection maximizes the bioavailability of a drug. The pharmacokinetic properties of a drug that dispose the user to increased self-administration include rapid absorption, rapid entry into the central nervous system, high bioavailability, short half-life, small volume of distribution, and high free drug clearance. The pharmacokinetic properties associated with drug dependence are a long half-life, low free drug clearance, and presence of the drug at high enough concentrations and for a sufficient time to permit tolerance to develop. Pharmacokinetics and pharmacodynamics play an important role in predicting the dependence and abuse potential of drugs.
Absorption ; Amygdala ; Biological Availability ; Brain ; Central Nervous System ; Decision Making ; Dopamine ; Drug-Seeking Behavior ; Eating ; Glutamic Acid ; Half-Life ; Inhalation ; Injections, Intravenous ; Neurobiology ; Nucleus Accumbens ; Prefrontal Cortex ; Recurrence ; Reward ; Smoke ; Smoking ; Street Drugs ; Substance-Related Disorders ; 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