Evidence and explanation for the involvement of the nucleus accumbens in pain processing

The nucleus accumbens(NAc)is a subcortical brain structure known primarily for its roles in pleasure,reward,and addiction.Despite less focus on the NAc in pain research,it also plays a large role in the mediation of pain and is effective as a source of analgesia.Evidence for this involvement lies in the NAc’s cortical connections,functions,pharmacology,and therapeutic targeting.The NAc projects to and receives information from notable pain structures,such as the prefrontal cortex,anterior cingulate cortex,periaqueductal gray,habenula,thalamus,etc.Additionally,the NAc and other pain-modulating structures share functions involving opioid regulation and motivational and emotional processing,which each work beyond simply the rewarding experience of pain offset.Pharmacologically speaking,the NAc responds heavily to painful stimuli,due to its high density ofμopioid receptors and the activation of several different neurotransmitter systems in the NAc,such as opioids,dopamine,calcitonin gene-related peptide,γ-aminobutyric acid,glutamate,and substance P,each of which have been shown to elicit analgesic effects.In both preclinical and clinical models,deep brain stimulation of the NAc has elicited successful analgesia.The multi-functional NAc is important in motivational behavior,and the motivation for avoiding pain is just as important to survival as the motivation for seeking pleasure.It is possible,then,that the NAc must be involved in both pleasure and pain in order to help determine the motivational salience of positive and negative events.

Effect of Aqueous Extract of <i>Phoenix dactylifera</i>Pollen on Dopamine System of Nucleus Accumbens in Male Rats

Background: Dopamine has been known to facilitate male sexual function. Methods: The effect of aqueous extract (140 mg/kg) of Phoenix dactylifera date palm pollen on sexual behavior and determining of dopamine transmission in the nucleus accumbens was studied in male rats using in vivo microdialysis. Results: Releasing of dopamine increased significantly in the nucleus accumbens when a receptive female was introduced behind a screen (p 0.001). During copulation, dopamine increased markedly in control and treated rats. Phoenix dactylifera Date Palm Pollen enhanced the orientation of males towards females by increasing mounting and ano-genital investigatory behavior. Improving of sexual behavior and dopamine release was higher in treated rats in comparison with control (p 0.001). Conclusion: These results indicate a neurochemical basis for interaction between dopaminergic agents and male sexual behavior. Therefore, Phoenix dactylifera Date Palm Pollen seems to act as a dopamine agonist and to cure male infertility. It can be used as an aphrodisiac that leads to further increases in dopamine release.

Role of prefrontal cortex-nucleus accumbens glutamatergic projection in heroin reward and motivation

OBJECTIVE Glutamatergic projections from prefrontal cortex(PFc) to nucleus accumbens(NAc) regulate the dopamine(DA) release in NAc.However,it is not clear whether this circuit is effective for the reward and motivation of heroin addiction.Our study investigates the effects of metabotropic glutamate receptor 2/3(mGluR2/3) and the projections from ventromedial prefrontal cortex(vmPFc) to the NAc shell on the reward and motivation of heroin-addicted rats.METHODS First,rats were trained to selfadministration for 14 d.On the 15 thday,parts of rats were injected with mGluR 2/3 agonist LY379268(0.1,0.3 and 1.0 mg·kg-1,ip) systematically and another parts of rats were bilaterally microinjected with LY379268(0.3 and 1.0 g·L^(-1))at the volume of 0.5 μL into the ventral tegmental area(VTA),NAc core or NAc shell,respectively.All rats were followed by heroin self-administration testing under fixed ratio 1(FR1) schedule or progressed ratio(PR) schedule to observe the effect of LY379268 on the heroin reward or motivation.Second,rats were injected chemogenetic glutamatergic virus(pAAV-CaMKIIa-hM3 D(Gq)-mCherry or pAOV-CaMKIIa-hM4 D(Gi)-mCherry-3 Flag) or negative control virus in vmPFc,and trained to heroin self-administration for 14 d.On the 15 thday,rats were bilateral y microinjected with clozapine-N-oxide(CNO,1 mmol·L^(-1),0.5 μL) into NAc shell and tested the effect on the heroin reward or motivation.Finally,rats were injected optogenetical glutamatergic virus(AAV2/9-CaM KⅡ-hChR2-EYFP) or negative control virus in vmPFc,implanted 16 channel photoelectrode in ipsilateral NAc shell,and trained to heroin selfadministration for 14 d.On the 15 thday,rats were tested heroin reward under FR1 procedure with blue light stimulation in the wavelength of470 nm,frequency of 25 HZ and power of 5 mW.Each stimulation lasting for 1 h and interval for1 h.The spike changes before and after stimulation in NAc Shel neural nerve was recorded.RESULTS LY379268 cloud dose-dependent attenuated the heroin reward or motivation and the local effective site was mainly in the NAc shell.Chemogenetic results showed activation or inactivation the projection from vmPFc to NAc shell enhanced or attenuated the heroin reward and motivation,respectively.Optogenetical stimulation the same projection also enhanced the heroin reward,and a tonic neuronal firing at the nerve of NAc shell was observed during the light stimulation session.CONCLUSION mGluR2/3 activation in the NAc shell is involved in the inhibition of heroin reward and motivation.Activation the projection from PFc to NAc shell can enhance the effects on heroin reward and motivation.

Framework for internal sensation of pleasure using constraints from disparate findings in nucleus accumbens

It is necessary to find a mechanism that generates first-person inner sensation of pleasure to understand what causes addiction and associated behaviour by drugs of abuse.The actual mechanism is expected to explain several disparate findings in nucleus accumbens(NAc),a brain region associated with pleasure,in an interconnected manner.Previously,it was possible to derive a mechanism for natural learning and explain:(1)Generation of inner sensation of memory using changes generated by learning;and(2)Long-term potentiation as an experimental delayed scaled-up change by the same mechanism that occur during natural learning.By extending these findings and by using disparate third person observations in NAc from several studies,present work provides a framework of a mechanism that generates internal sensation of pleasure that can provide interconnected explanations for:(1)Ability to induce robust long-term depression(LTD)in NAc from naïve animals;(2)Impaired ability to induce LTD in“addicted”state;(3)Attenuation of postsynaptic potentials by cocaine;and(4)Reduced firing of medium spiny neurons in response to cocaine or dopamine.Findings made by this work are testable.

Nucleus accumbens stereotactic surgery: Achieving accuracy through area M

The nucleus accumbens(NA), a major pleasure center of the human brain, is a limbic-motor interface involved in several neurological and psychiatric disorders. During the last decade, this nucleus is also a deep brain stimulation target for selected patients. Purpose of this paper is to comment on the article entitled "Stereotactic anatomy of the human nucleus accumbens: from applied mathematics to microsurgical accuracy" which was recently published in "Surgical and Radiologic Anatomy" and is one of the latest articles on NA anatomy and surgery. The described results included a probabilitybased guide for in vivo(side-depended) stereotactic localization of the human NA and a standard for the NA, specific stereotactic zone of the human brain(which can be used in combination for an accurate stereotactic NA targeting). Furthermore, two specific stereotactically standard NA areas were found which could be used as abundant stereotactic guides for targeting of the anterior limb of the internal capsule, with electrode's contact 0(lowest) placed in the vicinity of the NA. However, the most important finding of this paper was standard area M(Mavridis' area), which is the most reliable stereotactically standard area of the human NA, regardless of side or gender, useful for highly accurate stereotacticNA targeting.

Differential Effects of Voluntary Ethanol Consumption on Dopamine Output in the Nucleus Accumbens Shell of Roman High- and Low-Avoidance Rats: A Behavioral and Brain Microdialysis Study

The Roman high(RHA) and low-Avoidance (RLA) rats were selectively bred for rapid vs poor acquisition of two-way active avoidance behavior. These lines differ in numerous behavioral traits, with RLA rats being more fearful/anxious than RHA rats, and the latter being novelty-seekers and showing larger intake of, and preference for, addictive substances including ethanol (ETH). Moreover, several differences in central dopaminergic, serotonergic, and GABAergic functions have been reported in these two lines. Since those neural systems are involved in the regulation of ETH consumption, it was considered of interest to investigate: 1) the differences in ETH intake and preference between RHA and RLA rats, 2) the effects of ETH on DA release in the shell of the nucleus accumbens (AcbSh) using brain microdialysis. ETH solutions of increasing concentrations (2% - 10%) were presented on alternate days in a free choice with water. To examine ETH intake and preference stability, animals were subsequently switched to daily presentations of 10% ETH for 10 consecutive days. RHA rats consumed significantly larger amounts of ETH and displayed higher ETH preference than did RLA rats throughout the acquisition and maintenance phases. Following chronic exposure to ETH the animals were habituated to a restricted access to ETH schedule (2% ETH, 2 h per day × 4 days) before surgical implantation of a dialysis probe in the AcbSh. Under these experimental conditions, voluntary ETH intake (2%, 1 h, p.o.) produced a significant increase in accumbal DA output in RHA rats but not in their RLA counterparts. Finally, the i.p. administration of ETH (0.25 g/kg) to na?ve Roman rats produced a significant increment in accumbal DA output only in RHA rats. These results indicate that the mesolimbic dopaminergic system of RHA rats is more responsive to the effects of ETH than that of RLA rats.

Targeting cAMP in D1-MSNs in the nucleus accumbens, a new rapid antidepressant strategy

Studies have suggested that the nucleus accumbens(NAc)is implicated in the pathophysiology of major depression;however,the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated.Here,we identified a specific reduction of cyclic adenosine monophosphate(cAMP)in the subset of dopamine D1 receptor medium spiny neurons(D1-MSNs)in the NAc that promoted stress susceptibility,while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors.Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons(D2-MSNs)of depressed mice,however,the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs.We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration,but not a lower dose.The fast onset property of crocin was verified through multicenter studies.Moreover,crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN.These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc,and provide a potential rapid antidepressant drug candidate,crocin.

The Nucleus Accumbens CRH–CRHR1 System Mediates Early-Life Stress-Induced Sleep Disturbance and Dendritic Atrophy in the Adult Mouse

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.

Brain region-specific roles of brain-derived neurotrophic factor in social stress-induced depressive-like behavior

Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response.Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region–specific,particularly involving the corticolimbic system,including the ventral tegmental area,nucleus accumbens,prefrontal cortex,amygdala,and hippocampus.Determining how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress psychopathology.In this review,we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of depression.We focused on associated molecular pathways and neural circuits,with special attention to the brain-derived neurotrophic factor–tropomyosin receptor kinase B signaling pathway and the ventral tegmental area–nucleus accumbens dopamine circuit.We determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature,severity,and duration of stress,especially in the above-mentioned brain regions of the corticolimbic system.Therefore,BDNF might be a biological indicator regulating stress-related processes in various brain regions.

Extracellular Signal-Regulated Kinase in Nucleus Accumbens Mediates Propofol Self-Administration in Rats

Clinical and animal studies have indicated that propofol has potential for abuse, but the specific neurobi- ological mechanism underlying propofol reward is not fully understood. The purpose of this study was to inves- tigate the role of extracellular signal-regulated kinase （ERK） signal transduction pathways in the nucleus accumbens （NAc） in propofol self-administration. We tested the expression of p-ERK in the NAc following the maintenance of propofol self-administration in rats. We also assessed the effect of administration of SCH23390, an antagonist of the D1 dopamine receptor, on the expression of p-ERK in the NAc in propofol self-administering rats, and examined the effects of intra-NAc injection of U0126, an MEK inhibitor, on propofol reinforcement in rats. The results showed that the expression of p-ERK in the NAc increased significantly in rats maintained on propofol, and pre-treatment with SCH23390 inhibited the propofol self- administration and diminished the expression of p-ERK in the NAc. Moreover, intra-NAc injection of U0126 （4 μg/ side） attenuated the propofol self-administration. The data suggest that ERK signal transduction pathways coupledwith D1 dopamine receptors in the NAc may be involved in the maintenance of propofol self-administration and its rewarding effects.

Projections from D2 Neurons in Different Subregions of Nucleus Accumbens Shell to Ventral Pallidum Play Distinct Roles in Reward and Aversion

The nucleus accumbens shell(NAcSh) plays an important role in reward and aversion. Traditionally, NAc dopamine receptor 2-expressing(D2) neurons are assumed to function in aversion. However, this has been challenged by recent reports which attribute positive motivational roles to D2 neurons. Using optogenetics and multiple behavioral tasks, we found that activation of D2 neurons in the dorsomedial NAcSh drives preference and increases the motivation for rewards, whereas activation of ventral NAcSh D2 neurons induces aversion. Stimulation of D2 neurons in the ventromedial NAcSh increases movement speed and stimulation of D2 neurons in the ventrolateral NAc Sh decreases movement speed. Combining retrograde tracing and in situ hybridization, we demonstrated that glutamatergic and GABAergic neurons in the ventral pallidum receive inputs differentially from the dorsomedial and ventral NAcSh. All together, these findings shed light on the controversy regarding the function of NAcSh D2 neurons, and provide new insights into understanding the heterogeneity of the NAcSh.

CCL2/CCR2 Contributes to the Altered Excitatory-inhibitory Synaptic Balance in the Nucleus Accumbens Shell Following Peripheral Nerve Injury-induced Neuropathic Pain

The medium spiny neurons(MSNs)in the nucleus accumbens(NAc)integrate excitatory and inhibitory synaptic inputs and gate motivational and emotional behavior output.Here we report that the relative intensity of excitatory and inhibitory synaptic inputs to MSNs of the NAc shell was decreased in mice with neuropathic pain induced by spinal nerve ligation(SNL).SNL increased the frequency,but not the amplitude of spontaneous inhibitory postsynaptic currents(sIPSCs),and decreased both the frequency and amplitude of spontaneous excitatory postsynaptic currents(sEPSCs)in the MSNs.SNL also decreased the paired-pulse ratio(PPR)of evoked IPSCs but increased the PPR of evoked EPSCs.Moreover,acute bath application of C–C motif chemokine ligand 2(CCL2)increased the frequency and amplitude of sIPSCs and sEPSCs in the MSNs,and especially strengthened the amplitude of N-methyl-D-aspartate receptor(NMDAR)-mediated miniature EPSCs.Further Ccl2 overexpression in the NAc in vivo decreased the peak amplitude of the sEPSC/sIPSC ratio.Finally,Ccr2 knock-down improved the impaired induction of NMDAR-dependent long-term depression(LTD)in the NAc after SNL.These results suggest that CCL2/CCR2 signaling plays a role in the integration of excitatory/inhibitory synaptic transmission and leads to an increase of the LTD induction threshold at the synapses of MSNs during neuropathic pain.

Clinical observation of physiological and psychological reactions to electric stimulation of the amygdaloid nucleus and the nucleus accumbens in heroin addicts after detoxification

Background Stereotactic surgery has been used to treat heroin abstinence in China since 2000 by ablating the amygdaloid nucleus （AMY） and the nucleus accumbens （NAc）,which also provides opportunity to identify the relationship between these nuclei and addiction.Our study aimed to explore the physiological and psychological effects of electrically stimulating the AMY and the NAc in herein addicts after detoxification by observing changes of heart rate,arterial pressure and occurrence of euphoria similar to heroin induced euphoria.Methods A total of 70 heroin addicts after detoxification were recruited,and 61 of them were eligible to be given stereotactic surgery for heroin abstinence.The operation was carried out after determining the coordinates of all target nucleuses,and stimulation was performed at the AMY and the NAc solely or jointly.Heart rate,arterial pressure and occurrence of euphoria similar to heroin induced euphoria were recorded and analyzed.Results The average heat rate was （66±10） beats/min before electric stimulation,and significantly increased to （84±14） beats/min during stimulation,and changed to （73±12） beats/min 10 minutes after stimulation.There was a significant elevation of the average arterial pressure from 83 mmHg before stimulation to 98 mmHg during the stimulation,and it then decreased to 90 mmHg after stimulation.Forty-three of the 61 patients showed intense euphoria similar to heroin induced euphoria.The largest number （118/186） of euphoric responses occurred when the AMY and the NAc were stimulated at the same time.Odds ratio was 5.4 （95% CI： 2.4-11.9,P 〈0.0001） to quantify the association.Results from a Logistic regression model showed a positive correlation between unilateral stimulation of either the AMY or NAC and induction of euphoria （OR 〉1 ）,especially when the left AMY or left NAc was stimulated （P 〈0.05）.Conclusions Our data are consistent with existing results that the AMY and the NAc are related to addiction.Different roles in drug dependence would be suggested according to the location of the AMY and NAc.

Noninvasive ultrasound deep brain stimulation of nucleus accumbens induces behavioral avoidance

Ultrasound stimulation is an emerging noninvasive option in treating neuropsychiatric disorders. The present study investigates the behavioral alterations resulting from ultrasound stimulation on the nucleus accumbens(NAc) in freely moving mice. Our results show that an acute ultrasound stimulation on the NAc, rather than the visual cortex or auditory cortex, led to a pronounced avoidance behavior, while repeated NAc ultrasound stimulation resulted in an obvious conditioned place aversion with changes in synaptic protein(Glu A1/2 subunit) expression. Notably, NAc ultrasound stimulation suppressed the morphine-induced conditioned place preference. The results provide evidence that NAc ultrasound stimulation can be applied as a potential noninvasive therapeutic option in treating psychiatric disorders.

THE INTERACTION BETWEEN PERIAQUEDUCTAL GRAY AND NUCLEUS ACCUMBENS IN ACCELER-ATING THE RELEASE OF ENKEPHALINS AND β-ENDORPHIN

There is a growing body of evidence showing that periaqueductal gray (PAG) and nucleus accumbens (N. accumbens) play important roles in the modulation of nociception. In our previous study of the mechanisms of morphine analgesia we found that opioid antagonist naloxone injected into either of the two nuclei, PAG or N. accumbens, could

Early-life stress alters sleep structure and the excitatory-inhibitory balance in the nucleus accumbens in aged mice

Background:Exposure to adverse experiences in early life may profoundly reshape the neurodevelopmental trajectories of the brain and lead to long-lasting behavioral and neural alterations.One deleterious effect of early-life stress that manifests in later life is sleep disturbance,but this has not been examined in aged mice and the underlying neural mechanisms remain unknown.Considering the important role of the nucleus accumbens (NAc) in the sleep-wake regulation,this study aimed to assess the effects of early-life stress on the sleep behaviors in aged mice and the potential involvement of the NAc in stress-induced sleep abnormalities.Methods:Twenty aged male C57BL/6 mice (>16 months,n =10 per group) were used in this study.During post-natal days 2 to 9,dams were provided with either sufficient (control) or a limited nesting and bedding materials (stressed).When the mice were 16 to 17 months old,their sleep-wake behaviors were recorded over 24 h using electroencephalogram and electromyelogram.The amount of each sleep-wake stage,mean duration,and stage transition was analyzed.Then,five animals were randomly chosen from each group and were used to measure the expression levels of vesicular glutamate transporter-1 (VGluT1) and vesicular transporters of γ-aminobutyric acid (VGAT) in the NAc using immunohistochemistry.Group comparisons were carried out using Student t test or analysis of variances when appropriate.Results:Compared with the control mice,the early-life stressed aged mice spent less time awake over 24 h (697.97 ± 77.47 min vs.631.33 ± 34.73 min,t17 =2.376,P =0.030),accordingly,non-rapid eye movement sleep time was increased (667.37 ± 62.07 min vs.723.54 ± 39.21 min,t17 =2.326,P =0.033) and mean duration of rapid eye movement sleep was prolonged (73.00 ± 8.98 min vs.89.39 ± 12.69 min,t17 =3.277,P =0.004).Meanwhile,we observed decreased VGluT1/VGAT ratios in the NAc in the stressed group (F(1,16) =81.04,P < 0.001).Conclusion:Early adverse experiences disrupt sleep behaviors in aged mice,which might be associated with the excitatory-inhibitory imbalance in the NAc.

Reduced Firing of Nucleus Accumbens Parvalbumin Interneurons Impairs Risk Avoidance in DISC1 Transgenic Mice

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^(TM))mice to investigate risk avoidance and found that these mice were impaired in risk avoidance on the elevated plus maze(EPM)and showed reduced social preference in a three-chamber social interaction test.Following EPM tests,c-Fos expression levels indicated that the nucleus accumbens(NAc)was associated with risk-avoidance behavior in DISC1-N^(TM)mice.In addition,in vivo electrophysiological recordings following tamoxifen administration showed that the firing rates of fast-spiking neurons(FS)in the NAc were significantly lower in DISC1-N^(TM)mice than in wild-type(WT)mice.In addition,in vitro patch clamp recording revealed that the frequency of action potentials stimulated by current injection was lower in parvalbumin(PV)neurons in the NAc of DISC1-N^(TM)mice than in WT controls.The impairment of risk avoidance in DISC1-N^(TM)mice was rescued using optogenetic tools that activated NAcPV neurons.Finally,inhibition of the activity of NAcPV neurons in PV-Cre mice mimicked the risk-avoidance impairment found in DISC1-N^(TM)mice during tests on the elevated zero maze.Taken together,our findings confirm an impairment in risk avoidance in DISC1-N^(TM)mice and suggest that reduced excitability of NAc^(PV) neurons is responsible.

Inhibition of the reinstatement of morphine-induced place preference in rats by high-frequency stimulation of the bilateral nucleus accumbens

Background Opiate 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. Methods A 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. Results High-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. Conclusion Bilateral high-frequency stimulation of the shell of the NAc may be useful as a novel therapeutic modality for the treatment of severe morphine addiction.

Adolescent social isolation influences cognitive function in adult rats

Adolescence is a critical period for neurodevelopment. Evidence from animal studies suggests that isolated rearing can exert negative effects on behavioral and brain development. The present study aimed to investigate the effects of adolescent social isolation on latent inhibition and brain-derived neurotrophic factor levels in the forebrain of adult rats. Male Wistar rats were randomly divided into adolescent isolation （isolated housing, 38-51 days of age） and social groups. Latent inhibition was tested at adulthood. Brain-derived neurotrophic factor levels were measured in the medial prefrontal cortex and nucleus accumbens by an enzyme-linked immunosorbent assay. Adolescent social isolation impaired latent inhibition and increased brain-derived neurotrophic factor levels in the medial prefrontal cortex of young adult rats. These data suggest that adolescent social isolation has a profound effect on cognitive function and neurotrophin levels in adult rats and may be used as an animal model of neurodevelopmental disorders.

Intravenous morphine self-administration alters accumbal microRNA profiles in the mouse brain

A significant amount of evidence indicates that microRNAs （miRNAs） play an important role in drug addiction. The nucleus accumbens （NAc） is a critical part of the brain’s reward circuit and is involved in a variety of psychiatric disorders, including depression, anxiety, and drug addiction. However, few studies have examined the expression of miRNAs and their functional roles in the NAc under conditions of morphine addiction. In this study, mice were intravenously infused with morphine （0.01, 0.03, 0.3, 1 and 3 mg/kg/infusion） and showed inverted U-shaped response. After morphine self-administration, NAc was used to analyze the functional networks of altered miRNAs and their putative target mRNAs in the NAc following intravenous self-administration of morphine. We utilized several bioinformatics tools, including Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway mapping and CyTargetLinker. We found that 62 miRNAs were altered and exhibited differential expression patterns. The putative targets were related to diverse regulatory functions, such as neurogenesis, neurodegeneration, and synaptic plasticity, as well as the pharmacological effects of morphine （receptor internalization/endocytosis）. The present findings provide novel insights into the regulatory mechanisms of accumbal molecules under conditions of morphine addiction and identify several novel biomarkers associated with morphine addiction.