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*

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*

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

OBJECTIVE: To observe the protein expression of growth associated protein-43 (GAP-43) in midbrain ventral tegmental area in morphine withdrawal rats at different time, and to evaluate the effect of GAP-43 on morphine withdrawal memory. METHODS: Rat models of morphine dependent 1 week, 2 weeks and 4 weeks were established by morphine hydrochloride intraperitoneal injection with increasing doses to establish natural withdrawal. The protein expression of GAP-43 in midbrain ventral tegmental area was observed by immunohistochemical staining and the results were analyzed by Image-Pro Plus 5.1 image analysis system. RESULTS: With prolongation of dependent time, the expression of GAP-43 was decreased then increased in midbrain ventral tegmental area. CONCLUSION GAP-43 could play a role in morphine withdrawal memory in midbrain ventral tegmental area.
Animals ; Behavior, Animal/drug effects* ; Disease Models, Animal ; Female ; GAP-43 Protein/metabolism* ; Immunohistochemistry ; Male ; Mesencephalon/metabolism* ; Morphine/adverse effects* ; Morphine Dependence/metabolism* ; Naloxone/pharmacology* ; Rats ; Rats, Sprague-Dawley ; Substance Withdrawal Syndrome/metabolism* ; Time Factors ; Ventral Tegmental Area/metabolism*

In vivo fast cyclic voltammetry (FCV) was used to investigate dopamine (DA) release from amygdala (Amy) of female rats in different phases of estrus cycle, ovaricectomized (OVX) rats and male rats. Tyrosine hydroxylase (TH) immunohistochemistry was employed to measure the numbers of immunoreactive neurons in ventral tegmental area (VTA) of midbrain in the rats. We also observed the effect of intracerebroventricular injection of phytoestrogen-soy isoflavones on DA release from the Amy. The results are as follows: DA release from the Amy of proestrus female rats was apparently higher than that in estrus, metaestrus, diestrus female rats and OVX rats. Amy DA release and the numbers of the TH immunoreactive neurons in VTA showed a significant sex difference. DA release from Amy of female and OVX rats increased significantly within 5 min after i.c.v injection of soy isoflavones, which elicited no effects in male rats. The above-mentioned results suggest that endogenous estrogen may play an important role in regulating the activity of DA neurons in mid-limbic systems, and that soy isoflavones exert an estrogen-like effect on the dopaminergic systems in the Amy.
Amygdala ; metabolism ; physiology ; Animals ; Dopamine ; metabolism ; Estrogens ; physiology ; Female ; Isoflavones ; pharmacology ; Male ; Neurons ; physiology ; Ovariectomy ; Parkinson Disease ; metabolism ; Phytoestrogens ; Plant Preparations ; pharmacology ; Rats ; Rats, Wistar ; Soybeans ; chemistry ; Ventral Tegmental Area ; metabolism

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

OBJECTIVE: This study investigates the effects of chronic alcohol exposure on rat brain THmRNA expression, TH (tyrosine hydroxylase) acitivity, and TPH (tryptophan hydroxylase) activity which are important in synthesis of dopamine and serotonin and other components of both the dopaminergic and serotonergic systems of the rat brain. METHODS: Rats were fed a liquid diet containing alcohol for 4 weeks. We investigated effects of chronic alcohol exposure on dopaminergic systems as follows. We evaluated expression of THmRNA in LC, VTA and substantia nigra by using in-situ hybridization and measured activity of TH by using immunoassay. We used HPLC for simultaneous measurement of dopamine, DOPAC and HVA in the cerebral cortex, striatum, hypothalamus, hippocampus, mid brain, hind brain, and cerebellum. Also we investigated serotonergic systems as follows. We evaluated expression of TH mRNA in the dorsal raphe nucleus by using radioprobe and measured the activity of TPH by using enzyme immunoassay. We used HPLC for simultaneous measurement of 5-HT and 5-HIAA in the cerebral cortex, striatum, hypothalamus, hippocampus, mid brain, hind brain, and cerebellum. RESULTS: Alcohol exposure for 4 weeks increased the expression of TH mRNA in the ventral tegmental area and the locus ceruleus but not in the substantia nigra. The 4 weeks of alcohol exposure did not cause significant changes in levels of dopamine and metabolites in the different areas of the brain, nor was it associated with changes in the maximal binding and affinity (Kd) of anterior striatal dopamine D2 receptor. Alcohol exposure for 4 weeks had no effect on the expression of TPH mRNA or on the activity of TPH in the dorsal raphe nucleus and the hypothalamus. CONCLUSION: We reported at first that chronic alcohol exposure could increase TH mRNA in the locus ceruleus. In a previous study of acute alcohol treatment, there is increase of dopamine metabolism but in this study, we did not observe any changes in dopamine metabolism in the different areas of the brain. Also we did not see any significant changes in the synthesis and metabolism of serotonin after 4 weeks of chronic alcohol exposure compared with control. Therefore, synthesis and metabolism of serotonin was affected in the acute phase. And, as previous reports have suggested, any changes caused by alcohol returned to previous levels via adaptation and regulatory mechanisms.
3,4-Dihydroxyphenylacetic Acid ; Animals ; Brain ; Cerebellum ; Cerebral Cortex ; Chromatography, High Pressure Liquid ; Diet ; Dopamine ; Hippocampus ; Hydroxyindoleacetic Acid ; Hypothalamus ; Immunoassay ; Immunoenzyme Techniques ; Locus Coeruleus ; Metabolism ; Raphe Nuclei ; Rats* ; Receptors, Dopamine D2 ; Rhombencephalon ; RNA, Messenger ; Serotonin ; Substantia Nigra ; Synaptic Transmission* ; Ventral Tegmental Area

OBJECTIVETo investigate the effect of M(5) muscarinic receptor subtype on the locomotor sensitization induced by heroin priming, and it's effect on the FosB expression in the nucleus accumbens (NAc) and the hippocampus in the heroin sensitized rats.

METHODSLocomotor activity was measured every 10 min for 1 h after subcutaneous injection of heroin. FosB expression was assayed by immunohistochemistry, and the antisense oligonucleotides (AS-ONs) targeting M(5) muscarinic receptor was transferred with the lipofectin.

RESULTSMicroinjection of AS-ONs targeting M(5) muscarinic receptor in the ventral tegmental area (VTA) blocked the expression of behavioral sensitization induced by heroin priming in rats. Meanwhile, the expression of FosB-positive neurons in either the NAc or the dentate gyrus (DG) of the hippocampus increased in heroin-induced locomotor sensitized rats. The enhancement of FosB-positive neurons in the NAc or DG could be inhibited by microinjection of M(5) muscarinic receptor AS-ONs into the VTA before the heroin-induced locomotor sensitization was performed. In contrast, microinjection of M(5) muscarinic receptor sense oligonucleotide (S-ONs) into the VTA did not block the expression of behavioral sensitization or the expression of FosB in the NAc or DG in the heroin sensitized rats.

CONCLUSIONBlocking M(5) muscarinic receptor in the VTA inhibits the expression of heroin-induced locomotor sensitization, which is associated with the regulation of FosB expression in the NAc and hippocampus neurons. M(5) muscarinic receptor may be a useful pharmacological target for the treatment of heroin addiction.

Acetylcholine ; metabolism ; Animals ; Brain ; drug effects ; metabolism ; physiopathology ; Heroin ; adverse effects ; Heroin Dependence ; drug therapy ; metabolism ; physiopathology ; Hippocampus ; drug effects ; metabolism ; Immunohistochemistry ; Male ; Microinjections ; Motor Activity ; drug effects ; physiology ; Narcotics ; adverse effects ; Neural Pathways ; drug effects ; metabolism ; physiopathology ; Neurons ; drug effects ; metabolism ; Nucleus Accumbens ; drug effects ; metabolism ; physiopathology ; Oligonucleotides, Antisense ; pharmacology ; Proto-Oncogene Proteins c-fos ; drug effects ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, Muscarinic M5 ; antagonists & inhibitors ; genetics ; metabolism ; Synaptic Transmission ; drug effects ; physiology ; Ventral Tegmental Area ; drug effects ; metabolism ; physiopathology