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.

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.

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.

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.

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

Abstract 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.

Chinese herbal medicine enhances sexual function and c-Fos/nNOS expression in the nucleus accumbens of orchidectomized rats

OBJECTIVE: To determine whether the central nervous system is involved in the effect of Chinese herbal medicine on sexual function recovery in orchidectomized rats.METHODS: Orchidectomized rats were administered intragastrically with a decoction of "kidneynourishing" Chinese herbal medicine once per day for 28 days. Accessory genital organ weight, plasma testosterone, and mating behavior were investigated. The expression of c-Fos and neuronal nitric oxide synthase(n NOS) in neuronal cells in the nucleus accumbens(NAc) was analyzed by immunohistochemistry.RESULTS: There was a decrease in accessory genital organ weight, plasma testosterone, and sexual behavior, as well as a low number of c-Fos-positive cells and a large n NOS-positive cell area in orchidectomized rats. Administration of the herbal medicine increased accessory genital organ weight, testosterone level, mating behavior, and c-Fos-positive cell number, while it decreased the n NOS-positive cell area in orchidectomized rats.CONCLUSION: An increase of plasma testosterone after administration of "kidney-nourishing" herbal medicine might contribute to the elevated sexual function and activity in orchidectomized rats. In addition, a central nervous system mechanism, such as the functional alteration of NAc, might be involved.

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.

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.

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.

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.

Modulation of γ-aminobutyric acid on painful sense in central nervous system of morphine-dependent rats

Objective To observe the effects of y-aminobutyric acid （GABA） on the electric activities of pain-excited neurons （PEN） in nucleus accumbens （NAc） in central nervous system （CNS） of morphine-dependent rats. Methods After GABA or the GABAA-receptor antagonist, bicuculline （Bic）, was injected into cerebral ventricles or NAc, right sciatic nerve was stimulated by electrical pulses, which was considered as traumatic pain stimulation. Extracellular recordings methods were used to record the electric activities of PEN in NAc. Results When GABA was injected into intracerebroventricle （ICV） as well as NAc, it could decrease the pain-evoked discharge frequency and prolong the latency of PEN. Bic could interdict the above effects of GABA on the electric activities of PEN. Conclusion Exogenous GABA might have an inhibitory effect on the central pain adjustment. Furthermore, GABA and GABAA receptor participate and mediate the traumatic information transmission process in CNS.

Microinjection of M_5 muscarinic receptor antisense oligonucleotide into VTA inhibits FosB expression in the NAc and the hippocampus of heroin sensitized rats

Objective To investigate the effect of M5 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. Methods Locomotor 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 M5 muscarinic receptor was transferred with the lipofectin. Results Microinjection of AS-ONs targeting M5 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 hippocam- pus increased in heroin-induced locomotor sensitized rats. The enhancement of FosB-positive neurons in the NAc or DG could be inhibited by microinjection of M5 muscarinic receptor AS-ONs into the VTA before the heroin-induced locomotor sensitization was performed. In contrast, microinjection of M5 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. Conclusion Blocking M5 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. M5 muscarinic receptor may be a useful pharmacological target for the treatment of heroin 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.

Attenuation of opioid addiction in mice lacking aquaporin 4

OBJECTIVE To examine the effects of aquaporin 4(AQP4) on opioid addiction and underlie the mechanism behind it. METHODS(1) In the heroin-induced self-administration(SA) experiment,we explored the role of AQP4 on heroin-induced psychological addiction. After the mice were trained to learn heroin-induced SA under a fixedratio1(FR1) reinforcement program for 7 d,we randomly switched the heroin doses to 0.00625,0.0125,0.025,0.05 or 0.1 mg·kg^(-1)per infusion to counterbalance assignment design. In the end,all mice underwent extinction training and reinstatement testing.(2) In oral sucrose self-administration,5% sucrose solution was used for the mice and the procedures were similar to heroin SA.(3) In morphine-induced hyperactivity test,mice were habituated in the test apparatus for 30 min and then were given saline(10 mL·kg^(-1),sc) or morphine(10 or 20 mg·kg^(-1),sc) to record the locomotion for 1.5 h.(4) For the in vivo microdialysis experiment,mice were surgically implanted with intracranial guide cannula into nucleus accumbens(AP +1.4 mm,ML ±0.9 mm,DV-3.8 mm from bregma). After 5 d of recovery from surgery,the mice were challenged by saline(10 mL·kg^(-1),sc)or morphine(10 mg·kg^(-1),sc),and then samples were collected every 20 min. RESULTS We found that AQP4 deletion had no effects on sucrose-seeking and sucrose-taking,but it significantly attenuated heroin-taking and heroin-seeking behaviors in heroin self-administration. Besides these,AQP4 deletion had no effects on basal level of locomotion,but dramatically decreased morphine-induced hyperactivity.Furthermore,the in vivo microdialysis studies showed that AQP4 deficiency inhibited morphine(10mg · kg^(-1),sc)-induced elevation of extracellular dopamine levels in nucleus accumbens in mice.CONCLUSION Our present findings demonstrate that AQP4 was potentially involved in the properties of opioid rewarding by inhibiting dopamine release in nucleus accumbens(NAc).

Phosphorylation of group I metabotropic glutamate receptors in drug addiction and translational research

Protein phosphorylation is an important posttranslational modification of group I metabotropic glutamate receptors （ mGluR1 and mGluR5 subtypes, mGluR1/5 ） which are widely distributed throughout the mammalian brain. Several common protein kinases are involved in this type of modification, including protein kinase A, protein kinase C, and extracellular signal-regulated kinase. Through constitutive and activity-dependent phosphorylation of mGluR1/5 at specific residues, protein kinases regulate trafficking, subcellular/subsynaptic distribution, and function of modified receptors. Increasing evidence demonstrates that mGluR1/5 phosphorylation in the mesolimbic reward circuitry is sensitive to chronic psychostimulant exposure and undergoes adaptive changes in its abundance and activity. These changes contribute to long-term excitatory synaptic plasticity related to the addictive property of drugs of abuse. The rapid progress in uncovering the neurochemical basis of addiction has fostered bench-to-bed translational research by targeting mGluR1/5 for developing effective pharmacotherapies for treating addiction in humans. This review summarizes recent data from the studies analyzing mGluR1/5 phosphorylation. Phosphorylation-dependent mechanisms in stimulant-in-duced mGluR1/5 and behavioral plasticity are also discussed in association with increasing interest in mGluR1/5 in translational medicine.

Integration of animal behaviors under stresses with different time courses

We used animal models of ＂forced swim stress＂ and ＂chronic unpredictable stress＂, and tried to reveal whether a passive coping style of high flotation behavior in forced swim stress predicts an- hedonia behavior after chronic unpredictable stress, and whether the dopamine system regulates floating and anhedonia behaviors. Our results confirmed that depression-prone rats use ＂floating behavior＂ as a coping strategy in forced swim stress and more readily suffer from anhedonia during chronic unpredictable stress. Intraperitoneal injection or nucleus accumbens microin- jection of the dopamine 2/3 receptor subtype agonist ropinirole reduced floating behaviors in depression-prone animals, but increased sucrose preference in rats showing anhedonia. These data indicate that floating behavior is a defensive mode that is preferred by susceptible individ- uals under conditions of acute stress. Simultaneously, these animals more readily experienced anhedonia under long-term stress; that is, they were more readily affected by depression. Our results suggest that dopamine 2/3 receptor subtypes in the nucleus accumbens play an important role in floating behaviors and anhedonia.

Attenuated inhibition of medium spiny neurons participates in the pathogenesis of childhood depression

Accumulating evidence suggests that the nucleus accumbens, which is involved in mechanisms of reward and addiction, plays a role in the pathogenesis of depression and in the action of anti-depressants. In the current study, intraperitoneal injection of nomifensine, a dopamine reuptake inhibitor, decreased depression-like behaviors in the Wistar Kyoto rat model of depression in the sucrose-preference and forced swim tests. Nomifensine also reduced membrane excitability in medium spiny neurons in the core of the nucleus accumbens in the childhood Wistar Kyoto rats as evaluated by electrophysiological recording. In addition, the expression of dopamine D2-like receptor mRNA was downregulated in the nucleus accumbens, striatum and hippocampus of nomifensine-treated childhood Wistar Kyoto rats. These experimental ifndings indicate that impaired inhibition of medium spiny neurons, mediated by dopamine D2-like receptors, may be involved in the formation of depression-like behavior in childhood Wistar Kyoto rats, and that nomifensine can alleviate depressive behaviors by reducing medium spiny neuron membrane excitability.