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*

As a kind of mental illness, depression produces great difficulties in clinical diagnosis and treatment, and has a high disability rate. It is urgent to clarify the mechanism of depression to find potential therapeutic targets and effective clinical treatment methods. As a deacetylase, silent mating type information regulator 2 homolog 1 (SIRT1) is involved in many biological processes such as cell aging, cancer, and cardiovascular disease. In recent years, more and more studies have found that SIRT1 gene plays an important role in the pathogenesis of depression, but the mechanism is still unclear. Therefore, this review mainly summarizes the relevant research progress on the role and mechanism of SIRT1 gene in the hippocampus, prefrontal cortex, amygdala, hypothalamic suprachiasmatic nucleus, and nucleus accumbens in depression, in order to provide new ideas for exploring the mechanism and prevention of depression.
Cellular Senescence ; Depression/genetics* ; Hippocampus/metabolism* ; Humans ; Nucleus Accumbens ; Sirtuin 1/metabolism*

BACKGROUNDOpiate addiction remains intractable in a large percentage of patients, and relapse is the biggest hurdle to recovery. Many studies have identified a central role of the nucleus accumbens (NAc) in addiction. Deep brain stimulation (DBS) has the advantages of being reversible, adjustable, and minimally invasive, and it has become a potential neurobiological intervention for addiction. The purpose of our study was to investigate whether high-frequency DBS in the NAc effectively attenuates the reinstatement of morphine seeking in morphine-primed rats.

METHODSA morphine-dependent group of rats was given increasing doses of morphine during conditioned place preference training. A control group of rats was given equal volumes of saline. After the establishment of this model, withdrawal syndromes were precipitated in these two groups by administering naloxone, and the differences in withdrawal symptoms between the groups were analyzed. Electrodes for DBS were implanted in the bilateral shell of the NAc in the experimental group. The rats were stimulated daily in the NAc for 5 hours per day over 30 days. Changes in the conditioned place preference test and withdrawal symptoms in the rats were investigated and place navigation studies were performed using the Morris water maze. The data were assessed statistically with one-way analysis of variance (ANOVA) followed by Tukey's tests for multiple post hoc comparisons.

RESULTSHigh-frequency stimulation of the bilateral NAc prevented the morphine-induced reinstatement of morphine seeking in the conditioned place preference test. The time spent in the white compartment by rats following 30 days of DBS ((268.25 ± 25.07) seconds) was not significantly different compared with the time spent in the white compartment after relapse was induced by morphine administration ((303.29 ± 34.22) seconds). High-frequency stimulation of the bilateral NAc accelerated the innate decay of drug craving in morphine-dependent rats without significantly influencing learning and memory.

CONCLUSIONBilateral high-frequency stimulation of the shell of the NAc may be useful as a novel therapeutic modality for the treatment of severe morphine addiction.

Animals ; Electric Stimulation ; Male ; Morphine ; toxicity ; Morphine Dependence ; therapy ; Nucleus Accumbens ; metabolism ; Rats ; Rats, Sprague-Dawley

A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 (DISC1), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation (DISC1-N
Animals ; Interneurons/metabolism* ; Mice ; Mice, Transgenic ; Nerve Tissue Proteins/metabolism* ; Neurons/metabolism* ; Nucleus Accumbens/metabolism* ; Parvalbumins/metabolism*

Adverse experiences in early life have long-lasting negative impacts on behavior and the brain in adulthood, one of which is sleep disturbance. As the corticotropin-releasing hormone (CRH)-corticotropin-releasing hormone receptor 1 (CRHR1) system and nucleus accumbens (NAc) play important roles in both stress responses and sleep-wake regulation, in this study we investigated whether the NAc CRH-CRHR1 system mediates early-life stress-induced abnormalities in sleep-wake behavior in adult mice. Using the limited nesting and bedding material paradigm from postnatal days 2 to 9, we found that early-life stress disrupted sleep-wake behaviors during adulthood, including increased wakefulness and decreased non-rapid eye movement (NREM) sleep time during the dark period and increased rapid eye movement (REM) sleep time during the light period. The stress-induced sleep disturbances were accompanied by dendritic atrophy in the NAc and both were largely reversed by daily systemic administration of the CRHR1 antagonist antalarmin during stress exposure. Importantly, Crh overexpression in the NAc reproduced the effects of early-life stress on sleep-wake behavior and NAc morphology, whereas NAc Crhr1 knockdown reversed these effects (including increased wakefulness and reduced NREM sleep in the dark period and NAc dendritic atrophy). Together, our findings demonstrate the negative influence of early-life stress on sleep architecture and the structural plasticity of the NAc, and highlight the critical role of the NAc CRH-CRHR1 system in modulating these negative outcomes evoked by early-life stress.
Animals ; Mice ; Corticotropin-Releasing Hormone/metabolism* ; Nucleus Accumbens/metabolism* ; Receptors, Corticotropin-Releasing Hormone/metabolism* ; Sleep ; Sleep Wake Disorders ; Stress, Psychological/complications*

AIMTo establish the rat model of morphine-induced conditioned place preference (CPP) and to investigate the effects of morphine psychical dependence on the levels of neurosteroids in rat brain.

METHODSRats were ip administered morphine 5 mg x kg(-1) for 10 days to induce CPP in morphine group. The concentrations of dehydroepiandrosterone (DHEA), pregnenolone (PREG), allopregnanolone (AP), dehydroepiandrosterone sulfate (DS) and pregnenolone sulfate (PS) in nucleus accumbens (Nac), hypothalamus (Ht), amygdale (A) and plasma of rats were determined with liquid chromatography-negative atmospheric pressure ionization mass spectrometry (LC-MS).

RESULTSTrained with morphine for 10 days resulted in the acquisition of CPP in morphine group with the time that the rats spent in drug-pairing room was longer than that of control group. Compared with control group, morphine treatment could significantly decrease the contents of DHEA in Nac and plasma, decrease that of PREG in Ht.

CONCLUSIONMorphine could induce the CPP in rats and affected the contents of some neurosteroids in rat brain, which suggests that endogenous neurosteroids might he related to the development of morphine dependence.

Amygdala ; metabolism ; Animals ; Brain ; metabolism ; Conditioning, Operant ; physiology ; Dehydroepiandrosterone ; blood ; metabolism ; Dehydroepiandrosterone Sulfate ; blood ; metabolism ; Hypothalamus ; metabolism ; Male ; Morphine Dependence ; metabolism ; Nucleus Accumbens ; metabolism ; Pregnanolone ; blood ; metabolism ; Pregnenolone ; blood ; metabolism ; Rats ; Rats, Sprague-Dawley

To define the molecular basis of ethanol dependence, changes in the phosphorylation of cAMP response element binding protein (CREB) in the nucleus accumbens of rats after acute and chronic ethanol administration were detected using immunohistochemistry. The results demonstrate that the expression of phospho-CREB (p-CREB) protein in the rat nucleus accumbens significantly increased after 15 min of acute ethanol exposure, reaching a peak at 30 min after ethanol administration. The increment remained after 1 or 6 h of ethanol exposure compared to the control rats. In contrast, chronic intake of ethanol solution obviously decreased the expression of p-CREB protein compared to the control rats. The decrement remained 24 h or 72 h after ethanol withdrawal, and returned to the control levels after 7 d of ethanol withdrawal. The results suggest that an acute ethanol administration led to an increase in the phosphorylation of CREB in the nucleus accumbens, but chronic ethanol administration produced a decrement, which is possibly one of the molecular mechanisms of alcohol dependence.
Alcoholism ; metabolism ; physiopathology ; Animals ; Cyclic AMP Response Element-Binding Protein ; chemistry ; metabolism ; Ethanol ; pharmacology ; Male ; Nucleus Accumbens ; metabolism ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Substance Withdrawal Syndrome ; metabolism ; physiopathology ; Substance-Related Disorders ; metabolism ; physiopathology

The intense associative memories that develop between cocaine-paired contexts and rewarding stimuli make addiction hard to cure by contributing to cocaine seeking and relapse. So it's of great importance to examine the neurobiological basis of addiction memory. Cocaine conditioned place preference (CPP) used in this study is a form of Pavlovian conditioning which can establish associations between drug and contextual factors. c-Fos and Zif268 are commonly used immediate early gene (IEG) makers to identify neurons that are activated after a stimulus or behavioral conditioning. This study was designed to reveal neuronal c-Fos, Zif268 expression pattern in 10 brain regions following cocaine context-associated reward memory retrieval in mice, combining animal behavioral study and immunofluorescence method. C57BL/6 mice were randomly divided into 3 groups: Saline retrieval, Cocaine retrieval, and No retrieval of cocaine groups. Cocaine retrieval and No retrieval of cocaine underwent CPP training (one side paired with cocaine, and the other side with saline) except that No retrieval of cocaine group didn't undergo CPP test. Saline retrieval group received saline injections (i.p) on both sides. The results showed that: Neuronal c-Fos, Zif268 protein expression levels in nucleus accumbens (NAc) core both were elevated in Cocaine retrieval group compared with those in Saline retrieval (Control) group during cocaine context-associated reward memory retrieval. Zif268 protein expression level in basolateral amygdala (BLA) was also elevated in Cocaine retrieval group compared with that in control mice. Elevation was not seen in other regions such as hippocampus, prefrontal cortex (PFC). Thus, NAc core and BLA were activated during cocaine context-associated reward memory retrieval. The results suggest that neurons that are activated in NAc core and BLA are crucial basis of cocaine context-associated reward memory.
Animals ; Basolateral Nuclear Complex ; cytology ; Cocaine ; pharmacology ; Conditioning (Psychology) ; Early Growth Response Protein 1 ; metabolism ; Hippocampus ; Memory ; Mice ; Mice, Inbred C57BL ; Neurons ; metabolism ; Nucleus Accumbens ; metabolism ; Prefrontal Cortex ; Proto-Oncogene Proteins c-fos ; metabolism ; Reward

OBJECTIVE: To explore the effect of electroacupuncture on heroin seeking behavior and FosB expression in relevant brain regions. METHODS: Rat model of heroin relapse behaviors was developed with progressive fixed ratio program,and model rats were randomly divided into 3 groups: a restraint group, a needle retention group, and a electroacupuncture group. The heroin seeking behavior was elicited by a small dose of heroin. FosB expression in relevnt brain region was assessed with immunohistochemical technique. RESULTS: Tests on reinstatement of drug seeking behavior induced by heroin priming showed that compared with the restraint group, active pokes in the electroacupuncture group decreased significantly(P<0.05). Compared with the restraint group, the expression of FosB positive nuclei in Acd, Pcg and CeA of rats brain both in the electroacupuncture group and the needle retention group (P<0.05) decreased significantly. In LC, the expression of FosB positive nuclei in the needle retention group decreased significantly compared with the restraint group (P<0.05). CONCLUSION Continuous acupuncture and needle retention attentuate the reinstatement of heroin-seeking behaviors induced by heroin priming, and the inhibitory effect may be mediated partially by the expression of FosB in relevant regions which are involved in the process of heroin addiction.
Amygdala ; metabolism ; Animals ; Behavior, Animal ; Brain ; metabolism ; Electroacupuncture ; methods ; Heroin Dependence ; metabolism ; psychology ; therapy ; Male ; Nucleus Accumbens ; metabolism ; Proto-Oncogene Proteins c-fos ; biosynthesis ; Random Allocation ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the changes in CREB (cAMP response element binding protein) in hippocampus, PFC (prefrontal cortex) and NAc (nucleus accumbens) during three phases of morphine induced CPP (conditioned place preference) in rats, and to elucidate the role of CREB during the progress of conditioned place preference.

METHODSMorphine induced CPP acquisition, extinction and drug primed reinstatement model was established, and CREB expression in each brain area was measured by Western Blot methods.

RESULTSEight alternating injections of morphine (10 mg/kg) induced CPP, and 8 d saline extinction training that extinguished CPP. CPP was reinstated following a priming injection of morphine (2.5 mg/kg). During the phases of CPP acquisition and reinstatement, the level of CREB expression was significantly changed in different brain areas.

CONCLUSIONIt was proved that CPP model can be used as an effective tool to investigate the mechanisms underlying drug-induced reinstatement of drug seeking after extinction, and that morphine induced CPP and drug primed reinstatement may involve activation of the transcription factor CREB in several brain areas, suggesting that the CREB and its target gene regulation pathway may mediate the basic mechanism underlying opioid dependence and its drug seeking behavior.

Analgesics, Opioid ; pharmacology ; Animals ; Blotting, Western ; Conditioning (Psychology) ; Conditioning, Operant ; drug effects ; Cyclic AMP Response Element-Binding Protein ; biosynthesis ; Hippocampus ; metabolism ; Male ; Morphine ; pharmacology ; Nucleus Accumbens ; metabolism ; Prefrontal Cortex ; metabolism ; Rats ; Rats, Sprague-Dawley ; Time Factors