scholarly journals Dopamine receptors mediate strategy abandoning via modulation of a specific prelimbic cortex–nucleus accumbens pathway in mice

2018 ◽  
Vol 115 (21) ◽  
pp. E4890-E4899 ◽  
Author(s):  
Qiaoling Cui ◽  
Qian Li ◽  
Hongyan Geng ◽  
Lei Chen ◽  
Nancy Y. Ip ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Dopamine Receptors ◽  
Cortical Neurons ◽  
Critical Role ◽  
D2 Receptor ◽  
Receptor Activation ◽  
Prelimbic Cortex ◽  
Dopamine Depletion ◽  
Dopaminergic Tone ◽  
Type Receptor

The ability to abandon old strategies and adopt new ones is essential for survival in a constantly changing environment. While previous studies suggest the importance of the prefrontal cortex and some subcortical areas in the generation of strategy-switching flexibility, the fine neural circuitry and receptor mechanisms involved are not fully understood. In this study, we showed that optogenetic excitation and inhibition of the prelimbic cortex–nucleus accumbens (NAc) pathway in the mouse respectively enhances and suppresses strategy-switching ability in a cross-modal spatial-egocentric task. This ability is dependent on an intact dopaminergic tone in the NAc, as local dopamine denervation impaired the performance of the animal in the switching of tasks. In addition, based on a brain-slice preparation obtained from Drd2-EGFP BAC transgenic mice, we demonstrated direct innervation of D2 receptor-expressing medium spiny neurons (D2-MSNs) in the NAc by prelimbic cortical neurons, which is under the regulation by presynaptic dopamine receptors. While presynaptic D1-type receptor activation enhances the glutamatergic transmission from the prelimbic cortex to D2-MSNs, D2-type receptor activation suppresses this synaptic connection. Furthermore, manipulation of this pathway by optogenetic activation or administration of a D1-type agonist or a D2-type antagonist could restore impaired task-switching flexibility in mice with local NAc dopamine depletion; this restoration is consistent with the effects of knocking down the expression of specific dopamine receptors in the pathway. Our results point to a critical role of a specific prelimbic cortex–NAc subpathway in mediating strategy abandoning, allowing the switching from one strategy to another in problem solving.

scholarly journals The Adenosine A2A Receptor Activation in Nucleus Accumbens Suppress Cue-Induced Reinstatement of Propofol Self-administration in Rats

2021 ◽  
Author(s):  
Zhanglei Dong ◽  
Bingwu Huang ◽  
Chenchen Jiang ◽  
Jiangfan Chen ◽  
Han Lin ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
D2 Receptor ◽  
Fixed Ratio ◽  
Receptor Activation ◽  
Addictive Behaviors ◽  
Self Administration ◽  
A2a Receptors ◽  
Mediated Effects ◽  
Seeking Behavior ◽  
Adenosine A2a

AbstractPropofol has shown strong addictive properties in rats and humans. Adenosine A2A receptors (A2AR) in the nucleus accumbens (NAc) modulate dopamine signal and addictive behaviors such as cocaine- and amphetamine-induced self-administration. However, whether A2AR can modulate propofol addiction remains unknown. AAV-shA2AR was intra-NAc injected 3 weeks before the propofol self-administration training to test the impacts of NAc A2AR on establishing the self-administration model with fixed ratio 1 (FR1) schedule. Thereafter, the rats were withdrawal from propofol for 14 days and tested cue-induced reinstatement of propofol seeking behavior on day 15. The propofol withdrawal rats received one of the doses of CGS21680 (A2AR agonist, 2.5–10.0 ng/site), MSX-3 (A2AR antagonist, 5.0–20.0 μg/site) or eticlopride (D2 receptor (D2R) antagonist, 0.75–3.0 μg/site) or vehicle via intra-NAc injection before relapse behavior test. The numbers of active and inactive nose-poke response were recorded. Focal knockdown A2AR by shA2AR did not affect the acquisition of propofol self-administration behavior, but enhance cue-induced reinstatement of propofol self-administration compared with the AAV-shCTRLgroup. Pharmacological activation of the A2AR by CGS21680 (≥ 5.0 ng/site) attenuated cue-induced reinstatement of propofol self-administration behavior. Similarly, pharmacological blockade of D2R by eticlopride (0.75–3.0 μg/site) attenuated propofol seeking behavior. These effects were reversed by the administration of MSX-3 (5.0–20.0 μg/site). The A2AR- and D2R-mediated effects on propofol relapse were not confounded by the learning process, and motor activity as the sucrose self-administration and locomotor activity were not affected by all the treatments. This study provides genetic and pharmacological evidence that NAc A2AR activation suppresses cue-induced propofol relapse in rats, possibly by interacting with D2R.

scholarly journals Role of PKA signaling in D2 receptor-expressing neurons in the core of the nucleus accumbens in aversive learning

2015 ◽  
Vol 112 (36) ◽  
pp. 11383-11388 ◽  
Author(s):  
Takashi Yamaguchi ◽  
Akihiro Goto ◽  
Ichiro Nakahara ◽  
Satoshi Yawata ◽  
Takatoshi Hikida ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Critical Role ◽  
D2 Receptor ◽  
Resonance Energy ◽  
Memory Formation ◽  
Memory Retention ◽  
Aversive Learning ◽  
Indirect Pathway ◽  
Specific Expression ◽  
Direct Pathway

The nucleus accumbens (NAc) serves as a key neural substrate for aversive learning and consists of two distinct subpopulations of medium-sized spiny neurons (MSNs). The MSNs of the direct pathway (dMSNs) and the indirect pathway (iMSNs) predominantly express dopamine (DA) D1 and D2 receptors, respectively, and are positively and negatively modulated by DA transmitters via Gs- and Gi-coupled cAMP-dependent protein kinase A (PKA) signaling cascades, respectively. In this investigation, we addressed how intracellular PKA signaling is involved in aversive learning in a cell type-specific manner. When the transmission of either dMSNs or iMSNs was unilaterally blocked by pathway-specific expression of transmission-blocking tetanus toxin, infusion of PKA inhibitors into the intact side of the NAc core abolished passive avoidance learning toward an electric shock in the indirect pathway-blocked mice, but not in the direct pathway-blocked mice. We then examined temporal changes in PKA activity in dMSNs and iMSNs in behaving mice by monitoring Förster resonance energy transfer responses of the PKA biosensor with the aid of microendoscopy. PKA activity was increased in iMSNs and decreased in dMSNs in both aversive memory formation and retrieval. Importantly, the increased PKA activity in iMSNs disappeared when aversive memory was prevented by keeping mice in the conditioning apparatus. Furthermore, the increase in PKA activity in iMSNs by aversive stimuli reflected facilitation of aversive memory retention. These results indicate that PKA signaling in iMSNs plays a critical role in both aversive memory formation and retention.

Differential effects of dopamine depletion on the binding and mRNA levels of dopamine receptors in the shell and core of the rat nucleus accumbens

1994 ◽  
Vol 25 (3-4) ◽  
pp. 333-343 ◽  
Author(s):  
Ana L. Jongen-Rêlo ◽  
Gerrit J. Docter ◽  
Allert J. Jonker ◽  
Erno Vreugdenhil ◽  
Henk J. Groenewegen ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Dopamine Receptors ◽  
Mrna Levels ◽  
Dopamine Depletion ◽  
Differential Effects ◽  
Rat Nucleus Accumbens

scholarly journals Delta oscillations are a robust biomarker of dopamine depletion severity and motor dysfunction in awake mice

2020 ◽  
Vol 124 (2) ◽  
pp. 312-329
Author(s):  
Timothy C. Whalen ◽  
Amanda M. Willard ◽  
Jonathan E. Rubin ◽  
Aryn H. Gittis
Keyword(s):  
Basal Ganglia ◽  
D2 Receptor ◽  
Receptor Activation ◽  
Motor Dysfunction ◽  
Motor Symptoms ◽  
Strongly Correlated ◽  
Dopamine Depletion ◽  
Neural Noise ◽  
Novel Method ◽  
Delta Oscillations

This work introduces a novel method to detect spike oscillations amidst neural noise. Using this method, we demonstrate that delta oscillations in the basal ganglia are a defining feature of awake, dopamine-depleted mice and are strongly correlated with dopamine loss and parkinsonian motor symptoms. These oscillations arise from a loss of D2-receptor activation and do not require motor cortex. Similar oscillations in human patients may be an underappreciated marker and target for Parkinson’s disease (PD) treatment.

scholarly journals Positive Reinforcement Mediated by Midbrain Dopamine Neurons Requires D1 and D2 Receptor Activation in the Nucleus Accumbens

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e94771 ◽  
Author(s):  
Elizabeth E. Steinberg ◽  
Josiah R. Boivin ◽  
Benjamin T. Saunders ◽  
Ilana B. Witten ◽  
Karl Deisseroth ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Positive Reinforcement ◽  
D2 Receptor ◽  
Receptor Activation ◽  
Dopamine Neurons ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

scholarly journals D2-Like Dopamine Receptors Modulate SKCa Channel Function in Subthalamic Nucleus Neurons Through Inhibition of Cav2.2 Channels

2008 ◽  
Vol 99 (2) ◽  
pp. 442-459 ◽  
Author(s):  
Sankari Ramanathan ◽  
Tatiana Tkatch ◽  
Jeremy F. Atherton ◽  
Charles J. Wilson ◽  
Mark D. Bevan
Keyword(s):  
Action Potential ◽  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Subthalamic Nucleus ◽  
Brain Slices ◽  
Receptor Activation ◽  
Functional Coupling ◽  
Channel Blockers ◽  
Dopamine Depletion ◽  
Patch Clamp Recording

The activity patterns of subthalamic nucleus (STN) neurons are intimately related to motor function/dysfunction and modulated directly by dopaminergic neurons that degenerate in Parkinson's disease (PD). To understand how dopamine and dopamine depletion influence the activity of the STN, the functions/signaling pathways/substrates of D2-like dopamine receptors were studied using patch-clamp recording. In rat brain slices, D2-like dopamine receptor activation depolarized STN neurons, increased the frequency/irregularity of their autonomous activity, and linearized/enhanced their firing in response to current injection. Activation of D2-like receptors in acutely isolated neurons reduced transient outward currents evoked by suprathreshold voltage steps. Modulation was inhibited by a D2-like receptor antagonist and occluded by voltage-dependent Ca2+ (Cav) channel or small-conductance Ca2+-dependent K+ (SKCa) channel blockers or Ca2+-free media. Because Cav channels are targets of Gi/o-linked receptors, actions on step- and action potential waveform-evoked Cav channel currents were studied. D2-like receptor activation reduced the conductance of Cav2.2 but not Cav1 channels. Modulation was mediated, in part, by direct binding of Gβγ subunits because it was attenuated by brief depolarization. D2 and/or D3 dopamine receptors may mediate modulation because a D4-selective agonist was ineffective and mRNA encoding D2 and D3 but not D4 dopamine receptors was detectable. Brain slice recordings confirmed that SKCa channel-mediated action potential afterhyperpolarization was attenuated by D2-like dopamine receptor activation. Together, these data suggest that D2-like dopamine receptors potently modulate the negative feedback control of firing that is mediated by the functional coupling of Cav2.2 and SKCa channels in STN neurons.

scholarly journals Local Application of Dopamine Inhibits Pyramidal Tract Neuron Activity in the Rodent Motor Cortex

2002 ◽  
Vol 88 (6) ◽  
pp. 3439-3451 ◽  
Author(s):  
Patrick W. Awenowicz ◽  
Linda L. Porter
Keyword(s):  
Motor Cortex ◽  
Dopamine Receptors ◽  
Spontaneous Activity ◽  
Cortical Neurons ◽  
Pyramidal Tract ◽  
D2 Receptor ◽  
Simultaneous Recording ◽  
Neuron Activity ◽  
Receptor Subtypes ◽  
Baseline Levels

Cortical neurons respond in a variety of ways to locally applied dopamine, perhaps because of the activation of different receptors within or among subpopulations of cells. This study was conducted to assess the effects of dopamine and the receptor subtypes that mediate the responses of a specific population of neurons, the pyramidal tract neurons (PTNs) in the rodent motor cortex. The specific subfamilies of dopamine receptors expressed by PTNs also were determined. PTNs were identified by antidromic stimulation in intact animals. Extracellular recordings of their spontaneous activity and glutamate-induced excitation were performed with multi-barrel pipettes to allow simultaneous recording and iontophoresis of several drugs. Prolonged (30 s) application of dopamine caused a progressive, nonlinear decrease in spontaneous firing rates for nearly all PTNs, with significant reductions from baseline spontaneous activity (71% of baseline levels) occurring between 20 and 30 s of iontophoresis. The D1 selective (SCH23390) and the D2 selective (eticlopride) antagonists were both effective in blocking dopamine-induced inhibition in nearly all PTNs. Mean firing levels were maintained within 3% of baseline levels during co-application of the D1 antagonist with dopamine and within 11% of baseline levels during co-application of the D2 antagonist and dopamine. SCH23390 was ineffective however, in 2 of 16 PTNs, and eticlopride was ineffective in 3 PTNs. The dopamine blockade by both antagonists in most neurons, along with the selective blockade by one, but not the other antagonist in a few neurons indicate that the overall population of PTNs exhibits a heterogeneous expression of dopamine receptors. The firing rate of PTNs was significantly enhanced by iontophoresis of glutamate (mean = 141% of baseline levels). These increases were attenuated significantly (mean= 98% of baseline) by co-application with dopamine in all PTNs, indicating dopaminergic interactions with glutamate transmission. The expression of dopamine receptors was studied with dual-labeling techniques. PTNs were identified by retrograde labeling with fast blue and the D1a, D2, or D5 receptor proteins were stained immunohistochemically. Some, but not all PTNs, showed labeling for D1a, D2, or D5 receptors. The D1a and D2 receptor immunoreactivity was observed primarily in the somata of PTNs, whereas D5 immunoreactivity extended well into the apical dendrites of PTNs. In accordance with findings of D1 and D2 receptor antagonism of dopamine's actions, the identification of three DA receptor subtypes on PTNs suggests that dopamine can directly modulate PTN activity through one or more receptor subtypes.

scholarly journals Delta Oscillations Are a Robust Biomarker of Dopamine Depletion Severity and Motor Dysfunction in Awake Mice

2020 ◽  
Author(s):  
Timothy C. Whalen ◽  
Amanda M. Willard ◽  
Jonathan E. Rubin ◽  
Aryn H. Gittis
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
D2 Receptor ◽  
Receptor Activation ◽  
Motor Dysfunction ◽  
Dopamine Depletion ◽  
Novel Approach ◽  
Strong Indicator ◽  
Insight Into ◽  
Delta Oscillations

AbstractDelta oscillations (0.5–4 Hz) are a robust but often overlooked feature of basal ganglia pathophysiology in Parkinson’s disease and their relationship to parkinsonian akinesia has not been investigated. Here, we establish a novel approach to detect spike oscillations embedded in noise to provide the first study of delta oscillations in awake, dopamine depleted mice. We find that approximately half of neurons in the substantia nigra reticulata exhibit delta oscillations in dopamine depletion and that these oscillations are a strong indicator of dopamine loss and akinesia, outperforming measures such as changes in firing rate, irregularity, bursting and synchrony. We further establish that these oscillations are caused by the loss of D2 receptor activation and do not require motor cortex, contrary to previous findings in anesthetized animals. These results give insight into how dopamine loss leads to dysfunction and suggest a reappraisal of delta oscillations as a biomarker in Parkinson’s disease.

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