Maternal deprivation-caused behavioral abnormalities in adult rats relate to a non-methylation-regulated D2 receptor levels in the nucleus accumbens

Background: Repeated cocaine administration changes histone acetylation and methylation on Lys residues and Deoxyribonucleic acid (DNA) within the nucleus accumbens (NAc). Recently Nestler’s group explored histone Arg (R) methylation in reward processing models. Damez-Werno et al. (2016) reported that during investigator and selfadministration experiments, the histone mark protein-R-methyltransferase-6 (PRMT6) and asymmetric dimethylation of R2 on histone H3 (H3R2me2a) decreased in the rodent and cocaine-dependent human NAc. Overexpression of PRMT6 in D2-MSNs in all NAc neurons increased cocaine seeking, whereas PRMT6 overexpression in D1-MSNs protects against cocaine-seeking. Hypothesis: Hypothesizing that dopaminylation (H3R2me2a binding) occurs in psychostimulant use disorder (PSU), and the binding inhibitor Srcin1, like the major DRD2 A2 allelic polymorphism, protects against psychostimulant seeking behavior by normalizing nucleus accumbens (NAc) dopamine expression. Discussion: Numerous publications confirmed the association between the DRD2 Taq A1 allele (30-40 lower D2 receptor numbers) and severe cocaine dependence. Lepack et al. (2020) found that acute cocaine increases dopamine in NAc synapses, results in histone H3 glutamine 5 dopaminylation (H3Q5dop), and consequent inhibition of D2 expression. The inhibition increases with chronic cocaine use and accompanies cocaine withdrawal. They also found that the Src kinase sig-naling inhibitor 1 (Srcin1 or p140CAP) during cocaine withdrawal reduced H3R2me2a binding. Consequently, this inhibited dopaminylation induced a “homeostatic brake.” Conclusion: The decrease in Src signaling in NAc D2-MSNs, like the DRD2 Taq A2 allele, a well-known genetic mechanism protective against SUD normalized nucleus accumbens (NAc) dopamine expression and decreased cocaine reward and motivation to self-administer cocaine. The Srcin1 may be an important therapeutic target.

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Early life maternal deprivation attenuates morphine induced inhibition in lateral paragigantocellularis neurons in adult rats

Brain Research Bulletin ◽

10.1016/j.brainresbull.2021.01.011 ◽

2021 ◽

Vol 169 ◽

pp. 128-135

Author(s):

Hossein Masrouri ◽

Maryam Azadi ◽

Saeed Semnanian ◽

Hossein Azizi

Keyword(s):

Early Life ◽

Maternal Deprivation ◽

Adult Rats

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

Neurochemical Research ◽

10.1007/s11064-021-03238-9 ◽

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.

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Widespread but regionally specific effects of experimenter- versus self-administered morphine on dendritic spines in the nucleus accumbens, hippocampus, and neocortex of adult rats

Synapse ◽

10.1002/syn.10146 ◽

2002 ◽

Vol 46 (4) ◽

pp. 271-279 ◽

Cited By ~ 139

Author(s):

Terry E. Robinson ◽

Grazyna Gorny ◽

Virginia R. Savage ◽

Bryan Kolb

Keyword(s):

Nucleus Accumbens ◽

Dendritic Spines ◽

Adult Rats ◽

Specific Effects

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Diazepam attenuates the effects of cocaine on locomotion, 50-kHz ultrasonic vocalizations and phasic dopamine release in the nucleus accumbens of rats

10.1101/2020.10.13.338343 ◽

2020 ◽

Author(s):

William N. Sanchez ◽

Jose A. Pochapski ◽

Leticia F. Jessen ◽

Marek Ellenberger ◽

Rainer K. Schwarting ◽

...

Keyword(s):

Locomotor Activity ◽

Nucleus Accumbens ◽

Dopamine Release ◽

Ultrasonic Vocalizations ◽

Control Group ◽

List Type ◽

Adult Rats ◽

Fast Scan Cyclic Voltammetry ◽

Entire Duration ◽

Male Wistar Rats

AbstractBackground and PurposeCurrently, no effective drug exists to treat cocaine use disorders, which affect millions of people worldwide. Benzodiazepines are potential therapeutic candidates, as microdialysis and voltammetry studies have shown that they can decrease dopamine release in the nucleus accumbens of rodents. In addition, we have recently shown that diazepam blocks the increase in dopamine release and the affective marker 50-kHz ultrasonic vocalizations (USV) induced by DL-amphetamine in rats.Experimental ApproachHere we tested whether administration of 2.5 mg·kg−1 diazepam (i.p.) in adult male Wistar rats could block the effects of 20 mg·kg−1 cocaine (i.p.) on electrically evoked phasic dopamine release in the nucleus accumbens measured by fast-scan cyclic voltammetry, as well as 50-kHz USV and locomotor activity.Key ResultsCocaine injection increased evoked dopamine release up to 3-fold within 5 min and the increase was significantly higher than baseline for at least 90 min. The injection of diazepam 15 min later attenuated the cocaine effect by nearly 50% and this attenuation was maintained for at least 30 min. Stimulant drugs, natural rewards and reward predictive cues are known to evoke 50-kHz USV in adult rats. In the present study, cocaine increased the number of 50-kHz USV of the flat, step, trill, and mixed kinds by 12-fold. This effect was at maximum 5 min after cocaine injection, decreased with time and lasted at least 40 min. Diazepam significantly blocked this effect for the entire duration of the session. The distance travelled by control rats during a 40-min session of exploration in an open field was at maximum in the first 5 min and decayed progressively until the end of the session. Cocaine-treated rats travelled significantly longer distances when compared to the control group, while diazepam significantly attenuated cocaine-induced locomotion by up to 50%.Conclusions and implicationThese results suggest that the neurochemical, affective, and stimulant effects of cocaine can be mitigated by diazepam.What is already knownDiazepam decreases dopamine release in the rodent nucleus accumbens (NAc) and reduces some effects produced by DL-amphetamine.What this study addsDiazepam attenuated the increase in phasic dopamine release caused by cocaine.Diazepam blocked the effect of cocaine on 50-kHz USV and locomotor activity.Clinical significanceThis study demonstrates that diazepam can block specific effects of cocaine that likely contribute to addiction.

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Ultrastructural immunocytochemical localization of neurotensin and the dopamine D2 receptor in the rat nucleus accumbens

The Journal of Comparative Neurology ◽

10.1002/(sici)1096-9861(19960805)371:4<552::aid-cne5>3.0.co;2-3 ◽

1996 ◽

Vol 371 (4) ◽

pp. 552-566 ◽

Cited By ~ 25

Author(s):

Karen T. Delle Donne ◽

Susan R. Sesack ◽

Virginia M. Pickel

Keyword(s):

Nucleus Accumbens ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Immunocytochemical Localization ◽

Dopamine D2 ◽

Rat Nucleus Accumbens

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Intranasal oxytocin administration improves depression-like behaviors in adult rats that experienced neonatal maternal deprivation

Behavioural Pharmacology ◽

10.1097/fbp.0000000000000248 ◽

2016 ◽

Vol 27 (8) ◽

pp. 689-696 ◽

Cited By ~ 16

Author(s):

Haoyi Ji ◽

Wenlong Su ◽

Ruchen Zhou ◽

Jing Feng ◽

Yue Lin ◽

...

Keyword(s):

Maternal Deprivation ◽

Adult Rats

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1717106115 ◽

2018 ◽

Vol 115 (21) ◽

pp. E4890-E4899 ◽

Cited By ~ 9

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.

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