NMDA receptors in nucleus accumbens modulate stress-induced dopamine release in nucleus accumbens and ventral tegmental area

Converging evidence suggests that dopamine (DA) transmission in nucleus accumbens (NAcc) is modulated locally by an excitatory amino acid (EAA)-containing input possibly originating in medial prefrontal cortex (PFC). In the present study, we examined the effects of intra-NAcc administration of EAA receptor antagonists on stress-induced increases of NAcc DA levels and of dendritically released DA in the ventral tegmental area (VTA). Local injection of the NMDA receptor antagonist—AP-5 (0.05, 0.5, and 5.0 nmoles)—dose-dependently potentiated increases in NAcc DA levels elicited by 15 min of restraint stress. In contrast, local application of equivalent doses of the kainate/AMPA receptor antagonist—DNQX—failed to alter the NAcc DA stress response reliably. In a separate experiment, we found that intra-NAcc injection of AP-5 also potentiated stress-induced increases in VTA DA levels. These results indicate that EAAs acting at NMDA receptors in NAcc can modulate stress-induced DA release in this region. Our data indicate, however, that this action exerts an inhibitory influence on the NAcc DA stress response, suggesting that the relevant population of NMDA receptors are not located on NAcc DA terminals. The fact that intra-NAcc AP-5 injections also potentiated the DA stress response in VTA suggests instead an action mediated by NMDA receptors located on NAcc neurons that feedback, directly or indirectly, to cell bodies of the mesocorticolimbic DA system. Synapse 26:225–234, 1997. © 1997 Wiley-Liss Inc.     

Hippocampal modulation of locomotor activity induced by focal activation of postsynaptic dopamine receptors in the core of the nucleus accumbens

The locomotor effects of intra-NAcc injection of dopamine receptor agonists following discrete lesion or inhibition of the DH or the VH have been poorly investigated using only the indirect dopamine receptor agonist amphetamine. In the present study, we investigated how lidocaine in the DH or the VH modulated hyperlocomotion induced by focal injection into the NAcc core of the selective D1-like receptor agonist, SKF 38393, or coinjection of SKF 38393, and the selective D2-like receptor agonist, LY 171555; the latter pharmacological condition being required for the full expression of the postsynaptic effects of D2-like receptor agonists, and recognized to produce a locomotor response mainly mediated by D2-like postsynaptic receptors. Rats were given the D1-like receptor agonist SKF 38393 alone or in combination with the D2-like receptor agonist LY 171555 into the NAcc core, and lidocaine into the DH or the VH. Then, locomotor activity was recorded. Focal injection into the NAcc core of SKF 38393 alone or in combination with LY 171555 resulted in an increase of locomotor activity. Administration of lidocaine into the DH further potentiated the increase in locomotor activity induced by activation of D1-like receptors or co-activation of D1-like and D2-like receptors in the NAcc core. Administration of lidocaine into the VH also potentiated the increase in locomotor activity induced by D1-like receptor activation, but decreased that produced by co-activation of D1-like and D2-like receptors in the NAcc core. Taken together, these results suggest that under lidocaine-free conditions the DH may exert a tonic inhibitory modulation on hyperlocomotion mediated by D1-like and D2-like postsynaptic receptors in the NAcc core, while the VH may exert a tonic inhibitory on hyperlocomotion mediated by D1-like receptors and a tonic facilitatory control on hyperlocomotion mediated by D2-like postsynaptic receptors.     

Neurotensin peptides antagonistically regulate postsynaptic dopamine D2 receptors in rat nucleus accumbens: a receptor binding and microdialysis study

Summary An in vitro receptor binding and in vivo microdialysis study was performed to further investigate the modulation of dopamine (DA) D₂ receptors by neurotensin (NT) peptides. Saturation experiments with the D₂ agonist [³H]NPA (N-propylnorapomorphine) showed that 10 nM of NT, 10 nM of neuromedin N (NN) and 1 nM of the C-terminal NT-(8–13) fragment significantly increased the K_D values by 125%, 181%, and 194%, respectively without significantly affecting the B_max value of the [³H]NPA binding sites in coronal sections of rat ventral forebrain mainly containing the nucleus accumbens (Acb) and the olfactory tubercle.In line with the previous findings that NT can increase GABA release in the Acb and that NT receptors are not found on DA terminals in this brain region, the present in vivo microdialysis study demonstrated that local perfusion of NT (1 nM) counteracted the D₂ agonist pergolide (2M) induced inhibition of GABA, but not of DA release in the rat Acb. This result indicates that NT counteracts the D₂ agonist induced inhibition of GABA release in the rat Acb, via an antagonistic postsynaptic NT/D₂ receptor interaction as also suggested by the inhibitory regulation of D₂ receptor affinity in the Acb by the NT peptides demonstrated in the present receptor binding experiments. Thus, the neuroleptic and potential antipsychotic profile of the NT peptides may involve an antagonistic NT/D₂ receptor regulation in the ventral striatum.Abbreviations Acb nucleus accumbens - DA dopamine - NPA N-propylnorapomorphine - NT neurotensin     

Blockade of D-1 dopamine receptors in the medial prefrontal cortex produces delayed effects on pre- and postsynaptic indices of dopamine function in the nucleus accumbens

The actions mediated by limbic system output projections of the basal ganglia were investigated by studying the effects of ventral pallidum (VP) stimulation on the activity of neurons in thalamic target nuclei, including several of the dorsal thalamic nuclei and the nucleus reticularis, using in vivo intracellular recordings in rats. Intracellular injection of Lucifer yellow was used in a subset of experiments to identify the neurons recorded and to confirm their location with respect to the specific thalamic nuclei targeted. Stimulation of the VP evoked ipsps in 79% of the mediodorsal cells recorded. In the reticular nucleus, 73% of the neurons tested responded with evoked ipsps. In contrast, in other dorsal thalamic nuclei VP stimulation evoked depolarizations in 58% of the cells recorded. The latency to onset of the ipsps in the mediodorsal nucleus and in the reticular nucleus were not substantially different (1.7 ± 1.1 msec vs. 2.7 ± 1.1 msec), whereas the depolarizing response evoked in dorsal thalamic nucleus neurons typically occurred at longer and more variable latencies (3.5 ± 2.7 msec).     

Stimulation of dopamine D2 receptors in the nucleus accumbens inhibits inflammatory pain

Previous studies suggest that dopamine in the nucleus accumbens links noxious or mesolimbic stimulation with the feedback inhibition of nociception. To test the hypothesis that pharmacological agonism at dopamine receptors in the nucleus accumbens elicits antinociception, we bilaterally microinjected dopamine D1- and D2-receptor subtype selective drugs, and then evaluated behavioral responses to noxious intraplantar formalin. While the D1-selective agonist SKF 38393 was without effect at a dose of 0.5 nmol/side, the D2-selective agonist quinpirole dose-dependently (0.05-5.0 nmol/side, bilateral) inhibited the persistent phase of formalin-induced nociception. This was blocked by pre-administration of a selective D2-dopaminergic antagonist raclopride (0.3 nmol/side, bilateral). Quinpirole did not produce overt behavioral effects and did not change rotarod latency. Our results indicate that quinpirole acts at dopamine D2 receptors in the nucleus accumbens to inhibit persistent nociception at doses that circumvent confounding non-specific motor deficits, namely, sedation and motor coordination.     

脑深部电刺激对吗啡心理依赖大鼠伏核多巴胺受体的影响

目的探讨脑深部电刺激(DBS)对大鼠双侧伏核多巴胺D1A受体(D1AR)和D2受体(D2R)表达的影响以及多巴胺受体(DAR)在DBS治疗吗啡心理依赖中的作用。方法将60只SD大鼠随机分为假刺激组(ShS组)、电刺激组(DBS组)和生理盐水对照组(NS组),20只/组。用免疫组化法和RT-PCR法检测各组大鼠伏核多巴胺D1AR和D2R表达的变化。结果ShS组伏核D1AR阳性细胞数较NS组、DBS组明显增多(P0.01),而DBS组与NS组比较,差异无统计学意义(P0.05);三组间D1ARmRNA比较,差异无统计学意义(P0.05)。DBS组大鼠D2R阳性细胞数较NS组明显下降(P0.01),但较ShS组明显上升(P0.01);ShS组大鼠伏核D2RmRNA较NS组及DBS组显著上升(P0.01),而DBS组与NS组比较,差异无统计学意义(P0.05)。结论DBS对吗啡心理依赖大鼠伏核D1AR和D2R的表达起反向调节作用。     

Major coexpression of kappa-opioid receptors and the dopamine transporter in nucleus accumbens axonal profiles.

The behavioral effects of psychostimulants, which are produced at least in part through inhibition of the dopamine transporter (DAT), are modulated by kappa-opioid receptors (KOR) in the nucleus accumbens (Acb). Using electron microscopic immunocytochemistry, we reveal that in the Acb KOR labeling is mainly, and DAT immunoreactivity is exclusively, presynaptic. From 400 KOR-labeled presynaptic structures, including axon terminals, intervaricosities, and small axons, 51% expressed DAT and 29% contacted another population of terminals exclusively labeled for DAT. Within axonal profiles that contained both antigens, DAT and KOR were prominently localized to plasma membrane segments that showed overlapping distributions of the respective immunogold-silver and immunoperoxidase markers. KOR labeling was also localized to membranes of small synaptic vesicles in terminals with or without DAT immunoreactivity. In addition, from 24 KOR-immunoreactive dendritic spines 42% received convergent input from DAT-containing varicosities and unlabeled terminals forming asymmetric, excitatory-type synapses. Our results provide the first ultrastructural evidence that in the Acb, KOR is localized to strategic sites for involvement in the direct presynaptic release and/or reuptake of dopamine. These data also suggest a role for KOR in the presynaptic modulation of other neurotransmitters and in the postsynaptic excitatory responses of single spiny neurons in the Acb. Dual actions on dopamine terminals and their targets in the Acb may account for KOR-mediated attenuation of drug reinforcement and sensitization.     

Alcohol promotes dopamine release in the human nucleus accumbens

Microdialysis experiments in rodents indicate that ethanol promotes dopamine release predominantly in the nucleus accumbens, a phenomenon that is implicated in the reinforcing effects of drugs of abuse. The aim of the present study was to test the hypothesis in humans that an oral dose of ethanol would lead to dopamine release in the ventral striatum, including the nucleus accumbens. Six healthy subjects underwent two [(11)C]raclopride PET scans following either alcohol (1 ml/kg) in orange juice or orange juice alone. Subjective mood changes, heart rate, and blood-alcohol levels were monitored throughout the procedure. Personality traits were evaluated using the tridimensional personality questionnaire. PET images were co-registered with MRI and transformed into stereotaxic space. Statistical parametric maps of [(11)C]raclopride binding potential change were generated. There was a significant reduction in [(11)C]raclopride binding potential bilaterally in the ventral striatum/nucleus accumbens in the alcohol condition compared to the orange juice condition, indicative of increased extracellular dopamine. Moreover, the magnitude of the change in [(11)C]raclopride binding correlated with the alcohol-induced increase in heart rate, which is thought to be a marker of the psychostimulant effects of the drug, and with the personality dimension of impulsiveness. The present study is the first report that, in humans, alcohol promotes dopamine release in the brain, with a preferential effect in the ventral striatum. These findings support the hypothesis that mesolimbic dopamine activation is a common property of abused substances, possibly mediating their reinforcing effects.     

Cannabinoid self-administration increases dopamine release in the nucleus accumbens

In the present study, dopamine release was monitored during cannabinoid self-administration in rats to achieve a detailed understanding of the way in which dopamine mediates the reinforcing effects of cannabinoids. Extracellular dopamine levels were measured in the shell of the nucleus accumbens of either Lister Hooded or Long Evans rats trained to self-administer the cannabinoid CB1 receptor agonist WIN 55,212-2. A significant relationship between extracellular dopamine levels and bar-pressing rates was observed in both strains, as the dopamine content appreciably increased in respect to basal values during cannabinoid intake. Importantly, dopamine was not modified when trained rats were shifted to vehicle self-administration suggesting that an enhanced activity of the mesolimbic dopamine pathway underlies cannabinoid-taking behaviour.     

Colocalization of CART peptide with prodynorphin and dopamine D1 receptors in the rat nucleus accumbens

CART peptide is a peptidergic neurotransmitter that is expressed in brain regions involved in critical biological processes such as feeding and stress, and in areas associated with drug reward and abuse including the dopamine-rich nucleus accumbens (NAcc), which can be considered part of the basal ganglia. Because CART has been shown to colocalize with substance P, a marker of the basal ganglia direct pathway, we now test for colocalization with other markers of the direct pathway to determine if CART colocalizes with dynorphin and dopamine D1 receptors. In the NAcc, CART peptide immunoreactivity (IR) was colocalized with prodynorphin-IR in neurons. Approximately 80.1% of CART-IR cells colocalized with prodynorphin-IR, while only 27.6% of prodynorphin-IR neurons contained CART-IR, suggesting that CART cells are a subset of dynorphin cells. In contrast, only about 25% of CART-IR cell bodies demonstrated dopamine D1 receptor-IR. Because dynorphin and D1 receptors are markers for the basal ganglia direct pathway, from the NAcc to the basal ganglia output nuclei, and because CART significantly colocalizes with these markers, some CART neurons are part of the direct pathway or some comparable pathway in the accumbens. The presence of CART in NAcc neurons and the fact that NAcc projection neurons have extensive local collaterals suggest that CART may have effects in both terminal and cell body regions of the accumbens and may therefore affect information processing in the NAcc by modulating accumbal neurons.     

Regional distribution of dopamine D1 and D2 receptors in the nucleus accumbens of the rat

Dopamine (DA) D1 receptor density was found to be significantly lower in the rostral than in the medial and caudal areas of the nucleus accumbens. This roughly followed the distribution of DA terminals. The distribution of DA D2 receptors did not follow the DA terminal distribution. DA D2 receptor number was lower in the ventrorostral and higher in the dorsomedial area than in any other area of the nucleus accumbens.     

Dexmedetomidine decreases extracellular dopamine concentrations in the rat nucleus accumbens

The effects of dexmedetomidine, a highly selective alpha(2)-adrenoceptor agonist, on extracellular dopamine (DA) concentrations in the nucleus accumbens of awake rats were collected via in vivo cerebral microdialysis and measured using HPLC with electrochemical detection. The administration of dexmedetomidine (DEX) at a low dose (2 microg/kg bolus i.v. over 2 min followed by a continuous infusion of 0.1 microg/kg per min) and a high dose (20 microg/kg bolus i.v. over 2 min followed by a continuous infusion of 1 microg/kg per min), significantly decreased extracellular dopamine concentrations in the nucleus accumbens. The observed decrease was dose-dependent, occurring sooner and to a greater magnitude in the rats receiving a high dose of DEX. This inhibitory modulation of accumbal dopamine was receptor-specific, as the decrease in extracellular DA produced by DEX was no longer evident following pre-treatment and co-infusion with the highly selective alpha(2)-adrenoceptor antagonist, atipamezole (ATZ). Thus, these data suggest that adrenoceptor agonists and antagonists may modulate dopaminergic neurotransmission via mechanisms that are specific to the alpha(2)-adrenoceptor.     

Does cholecystokinin potentiate dopamine action in the nucleus accumbens?

Extracellular single unit recording and microiontophoretic techniques were used to determine whether sulfated cholecystokinin octapeptide (CCK-8S) potentiates the inhibitory action of dopamine (DA) on neurons in the nucleus accumbens of rats. The results show that CCK-8S attenuated, rather than enhanced the action of DA. The interaction between CCK-8S and DA does not appear to be specific because similar antagonizing actions between CCK-8S and serotonin were observed. In addition to opposing the inhibitory effects of DA and serotonin, CCK-8S potentiated the activation of glutamate. It is concluded that CCK-8S and DA exerted their actions independently via depolarizing and hyperpolarizing the neuronal membrane of the NAc neurons, respectively.     

Modeling fast dopamine neurotransmission in the nucleus accumbens during behavior

Recent advances in electrophysiology and voltammetry permit monitoring of dopamine (DA) neuronal activity in real time in the brain of awake animals. Studies using these approaches demonstrate that behaviorally relevant events elicit characteristic patterns of electrical activity in midbrain DA neurons as well as large, transient changes in extracellular DA in the nucleus accumbens (NAc). In addition to providing insight into the role of the DA system in the processing of motor, motivational, and sensory information, the new findings also shed light on fast DA neurotransmission in a behavioral context. This report, (1). summarizes the information obtained by electrophysiological and real-time voltammetric approaches and (2). describes a general model of phasic DA signaling in the NAc that links the observed changes in DA electrical activity and extracellular dynamics. The analysis demonstrates that the behaviorally evoked DA transients are governed by similar mechanisms as those produced by short trains of electrical stimulation. Thus, action potential-dependent release and presynaptic uptake are primary determinants of functional DA levels in the brain during behavior. Interestingly, the model predicts that the same burst of electrical activity generated at DA cell bodies produces markedly different DA dynamics in forebrain projection fields. The distinct changes result from heterogeneous release and uptake rates and may underlie region-specific effects of DA. Auto- and heteroreceptors, as well as other sites of presynaptic control, could further modulate the DA transients.     

Testosterone and nucleus accumbens dopamine in the male Syrian hamster

Most drugs of abuse increase dopamine (DA) in nucleus accumbens (Acb). However, the effects of anabolic androgenic steroids (AAS) on Acb DA have not been examined. We determined the effects of subcutaneous (sc) testosterone (T) on Acb DA in male hamsters. The effects of sc amphetamine were also examined for comparison. In addition, Acb DA was evaluated during intracerebroventricular (ICV) T infusion, designed to mimic T intake during ICV T self-administration in drug-na?ve and drug-preexposed animals. Acb DA was measured using in vivo microdialysis and HPLC-EC. T (7.5 or 37.5 mg/kg), amphetamine (1 or 5 mg/kg), or vehicle was injected sc and Acb DA monitored for 4h. In the ICV experiment, T (1 or 2 microg/infusion) or vehicle was infused ICV every 6 min for 4h and Acb DA monitored. ICV T preexposure was accomplished by repeating the same ICV T infusion (1 microg/infusion) daily for 14 days, and T infusion was accompanied by microdialysis on 15th day. Neither sc nor ICV T administration increased Acb DA. At high dose (2 microg/infusion), ICV T decreased Acb DA. Likewise, daily ICV infusion of T for 15 days did not alter Acb DA. In contrast, sc amphetamine significantly increased Acb DA at both doses. Therefore, unlike many drugs of abuse, AAS does not increase Acb DA levels. The reduction in DA at high T doses is likely due to autonomic depressant effects of AAS. We suggest that AAS act via mechanism distinct from those of stimulants, but may share neural substrates with other drugs of abuse.     

Mechanics of self-stimulation and dopamine release in the nucleus accumbens

Robust self-stimulation can be obtained from electrodes implanted in the medial forebrain bundle. We used in-vivo voltammetry to monitor stimulated dopamine release in the mouse nucleus accumbens during implantation of the stimulating electrodes. The higher the level of stimulated dopamine release during electrode implantation, the lower was the threshold for self-stimulation and the shorter the duration of the stimulation train when it was controlled by animal. We suggest that dopamine release is a reliable indicator of the proximity of the stimulating electrode to the brain reward sites. Inclusion of this indicator solves the problem of large interindividual variation in self-stimulation currents and permits a new approach to studies on mechanisms and pathways involved in brain reward.     

GABAB modulation of dopamine release in the nucleus accumbens core

Modulation of the concentration of dopamine (DA) released from dopaminergic terminals in the nucleus accumbens (NAc) influences behaviours such as the motivation to obtain drugs of abuse. γ‐Aminobutyric acid type B (GABA_B) receptors are expressed throughout the mesolimbic circuit, including in the NAc, and baclofen, an agonist of GABA_B receptors, can decrease drug‐seeking behaviours. However, the mechanism by which GABA_B receptors modulate terminal DA release has not been well studied. We explored how baclofen modulates the concentration of DA released from terminals in the NAc core using fast‐scan cyclic voltammetry in brain slices from adult male C57BL/6J mice. We found that baclofen concentration‐dependently decreased single pulse‐evoked DA release. This effect was blocked by the GABA_B antagonist, CGP 52432, but not by a nicotinic acetylcholine receptor antagonist. Suppression of DA release by a saturating concentration of baclofen was sustained for up to 1 h. The effect of baclofen was reduced with electrical stimulations mimicking burst firing of DA neurons. Similar to the D₂ receptor agonist, quinpirole, baclofen reduced the probability of DA release, supporting a mechanistic overlap with D₂ receptors. Baclofen‐mediated suppression of DA release persisted after a locomotor‐sensitizing cocaine treatment, indicating that GABA_B receptors on DA terminals were not altered by cocaine exposure. These data suggest that baclofen‐mediated suppression of terminal DA release is due to GABA_B activation on DA terminals to reduce the probability of DA release. This effect does not readily desensitize, and persists regardless of chronic cocaine treatment.     

The dopamine patchwork of the rat nucleus accumbens core

The dopamine (DA) terminal field in the rat dorsal striatum is organized as a patchwork of domains that show distinct DA kinetics. The rate and short‐term plasticity of evoked DA release, the rate of DA clearance and the actions of several dopaminergic drugs are all domain‐dependent. The patchwork arises in part from local variations in the basal extracellular concentration of DA, which establishes an autoinhibitory tone in slow but not fast domains. The present study addressed the hypothesis that a domain patchwork might also exist in the nucleus accumbens core (NAcc), a DA terminal field that is deeply involved in reward processing and the mechanisms underlying substance abuse. DA recordings in the NAcc by fast‐scan voltammetry during electrical stimulation of the medial forebrain bundle confirmed that the NAcc contains a patchwork of fast and slow domains showing significantly different rates of evoked DA release and DA clearance. Moreover, the NAcc domains are substantially different from those in the dorsal striatum. There were no signs in the NAcc of short‐term plasticity of DA release during multiple consecutive stimuli, and no signs of a domain‐dependent autoinhibitory tone. Thus, the NAcc domains are distinct from each other and from the domains of the dorsal striatum.     

Searching for presynaptic NMDA receptors in the nucleus accumbens

The nucleus accumbens shell (NAc) is a key brain region mediating emotional and motivational learning. In rodent models, dynamic alterations have been observed in synaptic NMDA receptors (NMDARs) within the NAc following incentive stimuli, and some of these alterations are critical for acquiring new emotional/motivational states. NMDARs are prominent molecular devices for controlling neural plasticity and memory formation. Although synaptic NMDARs are predominately located postsynaptically, recent evidence suggests that they may also exist at presynaptic terminals and reshape excitatory synaptic transmission by regulating presynaptic glutamate release. However, it remains unknown whether presynaptic NMDARs exist in the NAc and contribute to emotional and motivational learning. In an attempt to identify presynaptically located NMDARs in the NAc, the present study uses slice electrophysiology combined with pharmacological and genetic tools to examine the physiological role of the putative presynaptic NMDARs in rats. Our results show that application of glycine, the glycine-site agonist of NMDARs, potentiated presynaptic release of glutamate at excitatory synapses on NAc neurons, whereas application of 5,7-dichlorokynurenic acid or 7-chlorokynurenic acid, the glycine-site antagonists of NMDARs, produced the opposite effect. However, these seemingly presynaptic NMDAR-mediated effects could not be prevented by application of d-APV, the glutamate-site NMDAR antagonist, and were still present in the mice in which NMDAR NR1 or NR3 subunits were genetically deleted. Thus, rather than suggesting the existence of presynaptic NMDARs, our results support the idea that an unidentified type of glycine-activated substrate may account for the presynaptic effects appearing to be mediated by NMDARs.     

Selegiline potentiates cocaine-induced increases in rodent nucleus accumbens dopamine

Selegiline has been proposed as a treatment for cocaine addiction and studies in humans suggest that it attenuates cocaine's reinforcing effects. Here we assessed the effects of selegiline treatment on cocaine-induced increases in nucleus accumbens (NAc) dopamine (DA) in freely moving rodents. Chronic treatment with selegiline (L-deprenyl, 0.25/mg/kg, 24 days) potentiated cocaine-induced increases in NAc DA from 350-600%. However, this enhanced response was abolished when animals were treated chronically with both cocaine and selegiline. Inasmuch as increases in NAc DA are associated with the reinforcing effects of cocaine, these results obtained in rodents suggest that MAO-A and -B inhibition may not be a suitable strategy to antagonize cocaine's reinforcing effects during cocaine detoxification. On the other hand, chronic selegiline treatment may improve DA deficits, which are thought to contribute to relapse through a decreased response to natural rewards.