NAcc Medium Spiny Neurons Research Articles

Retinoic acid-mediated homeostatic plasticity drives cell type-specific CP-AMPAR accumulation in nucleus accumbens core and incubation of cocaine craving.

Incubation of cocaine craving, a translationally relevant model for the persistence of drug craving during abstinence, ultimately depends on strengthening of nucleus accumbens core (NAcc) synapses through synaptic insertion of homomeric GluA1 Ca 2+ -permeable AMPA receptors (CP-AMPARs). Here we tested the hypothesis that CP-AMPAR upregulation results from a form of homeostatic plasticity, previously characterized in vitro and in other brain regions, that depends on retinoic acid (RA) signaling in dendrites. Under normal conditions, ongoing synaptic transmission maintains intracellular Ca 2+ at levels sufficient to suppress RA synthesis. Prolonged blockade of neuronal activity results in disinhibition of RA synthesis, leading to increased GluA1 translation and synaptic insertion of homomeric GluA1 CP-AMPARs. Using slice recordings, we found that increasing RA signaling in NAcc medium spiny neurons (MSN) from drug-naïve rats rapidly upregulates CP-AMPARs, and that this pathway is operative only in MSN expressing the D1 dopamine receptor. In MSN recorded from rats that have undergone incubation of craving, this effect of RA is occluded; instead, interruption of RA signaling in the slice normalizes the incubation-associated elevation of synaptic CP-AMPARs. Paralleling this in vitro finding, interruption of RA signaling in the NAcc of 'incubated rats' normalizes the incubation-associated elevation of cue-induced cocaine seeking. These results suggest that RA signaling becomes tonically active in the NAcc during cocaine withdrawal and, by maintaining elevated CP-AMPAR levels, contributes to the incubation of cocaine craving.

Chronic Exposure to High Fat Diet Affects the Synaptic Transmission That Regulates the Dopamine Release in the Nucleus Accumbens of Adolescent Male Rats

Obesity is a pandemic caused by many factors, including a chronic excess in hypercaloric and high-palatable food intake. In addition, the global prevalence of obesity has increased in all age categories, such as children, adolescents, and adults. However, at the neurobiological level, how neural circuits regulate the hedonic consumption of food intake and how the reward circuit is modified under hypercaloric diet consumption are still being unraveled. We aimed to determine the molecular and functional changes of dopaminergic and glutamatergic modulation of nucleus accumbens (NAcc) in male rats exposed to chronic consumption of a high-fat diet (HFD). Male Sprague-Dawley rats were fed a chow diet or HFD from postnatal day (PND) 21 to 62, increasing obesity markers. In addition, in HFD rats, the frequency but not amplitude of the spontaneous excitatory postsynaptic current is increased in NAcc medium spiny neurons (MSNs). Moreover, only MSNs expressing dopamine (DA) receptor type 2 (D2) increase the amplitude and glutamate release in response to amphetamine, downregulating the indirect pathway. Furthermore, NAcc gene expression of inflammasome components is increased by chronic exposure to HFD. At the neurochemical level, DOPAC content and tonic dopamine (DA) release are reduced in NAcc, while phasic DA release is increased in HFD-fed rats. In conclusion, our model of childhood and adolescent obesity functionally affects the NAcc, a brain nucleus involved in the hedonic control of feeding, which might trigger addictive-like behaviors for obesogenic foods and, through positive feedback, maintain the obese phenotype.

HIV Tat excites D1 receptor-like expressing neurons from rat nucleus accumbens

BackgroundHIV-1 infection and drug abuse are frequently co-morbid and their association greatly increases the severity of HIV-1-induced neuropathology. While nucleus accumbens (NAcc) function is severely perturbed by drugs of abuse, little is known about how HIV-1 infection affects NAcc. MethodsWe used calcium and voltage imaging to investigate the effect of HIV-1 trans-activator of transcription (Tat) on rat NAcc. Based on previous neuronal studies, we hypothesized that Tat modulates intracellular Ca2+ homeostasis of NAcc neurons. ResultsWe provide evidence that Tat triggers a Ca2+ signaling cascade in NAcc medium spiny neurons (MSN) expressing D1-like dopamine receptors leading to neuronal depolarization. Firstly, Tat induced inositol 1,4,5-trisphsophate (IP3) receptor-mediated Ca2+ release from endoplasmic reticulum, followed by Ca2+ and Na+ influx via transient receptor potential canonical channels. The influx of cations depolarizes the membrane promoting additional Ca2+ entry through voltage-gated P/Q-type Ca2+ channels and opening of tetrodotoxin-sensitive Na+ channels. By activating this mechanism, Tat elicits a feed-forward depolarization increasing the excitability of D1-phosphatidylinositol-linked NAcc MSN. We previously found that cocaine targets NAcc neurons directly (independent of the inhibition of dopamine transporter) only when IP3-generating mechanisms are concomitantly initiated. When tested here, cocaine produced a dose-dependent potentiation of the effect of Tat on cytosolic Ca2+. ConclusionWe describe for the first time a HIV-1 Tat-triggered Ca2+ signaling in MSN of NAcc involving TRPC and depolarization and a potentiation of the effect of Tat by cocaine, which may be relevant for the reward axis in cocaine-abusing HIV-1-positive patients.

Cocaine effects on mouse incentive-learning and human addiction are linked to α2 subunit-containing GABA A receptors

Because GABA(A) receptors containing alpha2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltage-clamp recordings from NAcc medium spiny neurons of mice with alpha2 gene deletion showed reduced synaptic GABA(A) receptor-mediated responses. Behaviorally, the deletion abolished cocaine's ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization. In mice with a point mutation in the benzodiazepine binding pocket of alpha2-GABA(A) receptors (alpha2H101R), GABAergic neurotransmission in medium spiny neurons was identical to that of WT (i.e., the mutation was silent), but importantly, receptor function was now facilitated by the atypical benzodiazepine Ro 15-4513 (ethyl 8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate). In alpha2H101R, but not WT mice, Ro 15-4513 administered directly into the NAcc-stimulated locomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of alpha2-GABA(A) receptors (most likely in NAcc) is both necessary and sufficient for behavioral sensitization. Consistent with a role of these receptors in addiction, we found specific markers and haplotypes of the GABRA2 gene to be associated with human cocaine addiction.

ATP-induced Ca2+ waves in the nucleus accumbens

Event Abstract Back to Event ATP-induced Ca2+ waves in the nucleus accumbens Tünde Molnár1*, Gabriella Nyitrai1, Péter Barabás1, Julianna Kardos1 and Miklós Palkovits2 1 Chemical Research Center, Hungarian Academy of Sciences, Department of Neurochemistry, Institute of Biomolecular Chemistry, Hungary 2 Semmelweis University and Hungarian Academy of Sciences, Neuromorphological and Neuroendocrine Research Laboratory, Hungary We have previously described a membrane target in subfractions of the nucleus accumbens (NAcc) that binds metabolites succinic acid (SUC) and gamma-hydroxybutyric acid (GHB), as well as the gap-junction blocker carbenoxolone (CBX). In the present study, we investigated the acute effect of SUC, GHB and CBX on propagating Ca2+ waves induced by extracellular ATP (100 μM) in NAcc slices loaded by the fluorescent intracellular Ca2+ indicator Fluo-4 AM. Confocal laser scanning microscopy has been used to detect changes in numbers and the fluorescence intensity of cells participating in the Ca2+ wave. We suggest, that ATP-induced Ca2+ wave propagates in astrocytes located in the NAcc, which can be significantly decreased by gap-junction blockers CBX (0.1 and 1 mM) and flufenamic acid (FFA 1 mM). Conversely, the non-selective P2 purinergic antagonist suramin (0.1 and 1 mM) had no significant blocking effect on the number and the fluorescence intensity of cells of ATP-induced Ca2+ waves in the NAcc, suggesting that such propagation depends mainly on the functional activity of gap-junctions. The effects of SUC and GHB were found as concentration-dependent. In low concentration (0.05 mM) SUC and GHB enhanced both the number and the fluorescence intensity of cells, while their applications in higher concentrations (0.2 and 2 mM) elicited an inhibitory effect of SUC. In addition, whole cell patch clamp recordings of tetrasodium Fluo-4 loaded NAcc medium spiny neurons showed no changes in electrical activity and intracellular Ca2+ level during the propagation of ATP-induced astrocytic Ca2+ wave. Our findings indicate that calcium waves propagate by a mechanism involving gap-junction mediated interactions between astrocytes in the Nacc. The facilitatory role in astrocytic Ca2+ wave propagation suggests that SUC may represent a strong candidate for metabolic signalling, and therefore, a benefit for further studies. Conference: IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010. Presentation Type: Poster Presentation Topic: Cellular neuroscience Citation: Molnár T, Nyitrai G, Barabás P, Kardos J and Palkovits M (2010). ATP-induced Ca2+ waves in the nucleus accumbens. Front. Neurosci. Conference Abstract: IBRO International Workshop 2010. doi: 10.3389/conf.fnins.2010.10.00096 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 22 Apr 2010; Published Online: 22 Apr 2010. * Correspondence: Tünde Molnár, Chemical Research Center, Hungarian Academy of Sciences, Department of Neurochemistry, Institute of Biomolecular Chemistry, Budapest, Hungary, tmolnar@chemres.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Tünde Molnár Gabriella Nyitrai Péter Barabás Julianna Kardos Miklós Palkovits Google Tünde Molnár Gabriella Nyitrai Péter Barabás Julianna Kardos Miklós Palkovits Google Scholar Tünde Molnár Gabriella Nyitrai Péter Barabás Julianna Kardos Miklós Palkovits PubMed Tünde Molnár Gabriella Nyitrai Péter Barabás Julianna Kardos Miklós Palkovits Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Ontogeny of altered dendritic morphology in the rat prefrontal cortex, hippocampus, and nucleus accumbens following Cesarean delivery and birth anoxia

We used a delayed Cesarean birth model and the Golgi-Cox staining method to investigate the effects of perinatal anoxia on prefrontal cortex (PFC) and hippocampal (CA1) pyramidal neurons as well as nucleus accumbens (NAcc) medium spiny neurons. Dendritic morphology in these regions was studied on postnatal days (P) 2, 7, 14, 21, 35, and 70 in male Sprague-Dawley rats born either vaginally (VAG) or by Cesarean section either with (C + anoxia) or without (C-only) anoxia. The most striking birth group differences seen were at the level of dendritic spine densities on P35. During this postnatal period the dendritic spine density of PFC neurons was significantly lower in C + anoxia and C-only animals than in VAG controls; however, by P70 PFC spine densities in all birth groups were comparable. In contrast, hippocampal spine densities on P35 were comparably greater in C + anoxia animals than in VAG controls, whereas in C-only animals spine densities were lower than controls; here again, by P70 all groups had comparable hippocampal spine densities. In NAcc greater spine densities were seen on medium spiny neurons of C + anoxia animals on P35. These findings provide evidence that perinatal insult in the form of Cesarean birth with or without anoxia alters the dendritic development of PFC and hippocampal pyramidal neurons and to some extent also of NAcc medium spiny neurons. They also suggest that perinatal anoxia can alter the neuronal development of key structures thought to be affected in such late-onset dopamine-related disorders as schizophrenia and Attention Deficit Hyperactivity Disorder (ADHD).

Postweaning social isolation enhances morphological changes in the neonatal ventral hippocampal lesion rat model of psychosis

Neonatal ventral hippocampal (nVH) lesions in rats have been widely used as a neurodevelopmental model that mimics schizophrenia-like behaviors. Recently, we reported that nVH-lesions result in significant decreases in both length of dendrites and dendritic density of spines of pyramidal neurons of the prefrontal cortex (PFC) and in the density of dendritic spines of medium spiny neurons of the nucleus accumbens (NAcc). Moreover, postweaning social isolation induces major decreases in dendritic spiny density of PFC neurons. We investigated here the comparative dendritic morphology of PFC pyramidal neurons and NAcc medium spiny neurons in nVH rats, following social isolation after weaning (8 weeks). Morphological characteristics of dendrites were measured using the Golgi-Cox procedure followed by a Sholl analysis. Social isolation (SI) by itself induced decreases in dendritic length and dendritic spine density of the NAcc. In socially isolated nVH-lesion rats decrease in dendritic length in PFC and NAcc neurons were exacerbated whereas an increase in spine density of medium spiny neurons was observed in the NAcc. These results indicate that nVH-lesions alter dendritic morphology of NAcc and PFC neurons. These anatomical modifications in both structures may be relevant to behaviors observed in schizophrenia.

Chronic morphine treatment alters N-methyl-D-aspartate receptors in freshly isolated neurons from nucleus accumbens.

Although there is now evidence of a role for N-methyl-D-aspartate (NMDA) receptors in nucleus accumbens (NAcc) neurons in the effects of chronic opiate treatment, the cellular and molecular mechanisms underlying this phenomenon are still unclear. Therefore, we studied the effects of chronic morphine on the pharmacological and biophysical properties of NMDA receptors in freshly isolated medium spiny neurons from NAcc. We found that chronic morphine treatment did not alter the affinity for NMDA receptor agonists such as glutamate, homoquinolinic acid, and NMDA, but decreased the affinity of glycine, the allosteric NMDA receptor coagonist, from 2.24 +/- 0.15 microM to 5.1 +/- 1.45 microM. Chronic morphine treatment also altered the affinity of two noncompetitive NMDA receptor antagonists, 7-chloro-kynurenic acid and ifenprodil. However, morphine had no effect on a third antagonist, D-(-)-2-amino-5-phosphonopentanoic acid. Single-exponential fits of desensitized NMDA current tails gave tau values ranging from 0.5 to 4 s in neurons from both control and morphine-treated rats. However, a shift to the left of the distribution of tau values after morphine treatment revealed that NMDA current desensitization rate was accelerated in a majority of NAcc neurons. Taken together with our recent molecular studies, our data are consistent with a shift away from NMDA receptor subunit (NR) NR2B and 2C function toward increased NR2A subunit expression or function after chronic morphine, a process that could alter excitability and integrative properties and may represent a neuroadaptation of NAcc medium spiny neurons underlying morphine dependence.

Differential modulation of nucleus accumbens synapses.

The nucleus accumbens (NAcc) is a brain region involved in functions ranging from motivation and reward to feeding and drug addiction. The NAcc is typically divided into two major subdivisions, the shell and the core. The primary output neurons of both of these areas are medium spiny neurons (MSNs), which are quiescent at rest and depend on the relative input of excitatory and inhibitory synapses to determine when they fire action potentials. These synaptic inputs are, in turn, regulated by a number of neurochemical signaling agents that can ultimately influence information processing in the NAcc. The present study characterized the ability of three major signaling pathways to modulate synaptic transmission in NAcc MSNs and compared this modulation across different synapses within the NAcc. The opioid [Met](5)enkephalin (ME) inhibited excitatory postsynaptic currents (EPSCs) in shell MSNs, an effect mediated primarily by micro-opioid receptors. Forskolin, an activator of adenylyl cyclase, potentiated shell EPSCs. An analysis of miniature EPSCs indicated a primarily presynaptic site of action, although a smaller postsynaptic effect may have also contributed to the potentiation. Adenosine and an adenosine A(1)-receptor agonist inhibited shell EPSCs, although no significant tonic inhibition by endogenous adenosine was detected. The effects of these signaling agents were then compared across four different synapses in the NAcc: glutamatergic EPSCs and GABAergic inhibitory postsynaptic currents (IPSCs) in both the core and shell subregions. ME inhibited all four of these synapses but produced a significantly greater inhibition of shell IPSCs than the other synapses. Forskolin produced an increase in transmission at each of the synapses tested. However, analysis of miniature IPSCs in the shell showed no sign of a postsynaptic contribution to this potentiation, in contrast to the shell miniature EPSCs. Tonic inhibition of synaptic currents by endogenous adenosine, which was not observed in shell EPSCs, was clearly present at the other three synapses tested. These results indicate that neuromodulation can vary between the different subregions of the NAcc and between the different synapses within each subregion. This may reflect differences in neuronal interconnections and functional roles between subregions and may contribute to the effects of drugs acting on these systems.