scholarly journals Accumbens D2-MSN hyperactivity drives antipsychotic-induced behavioral supersensitivity

2021 ◽  
Author(s):  
Anna Kruyer ◽  
Jeffrey Parrilla-Carrero ◽  
Courtney Powell ◽  
Lasse Brandt ◽  
Stefan Gutwinski ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
D2 Receptor ◽  
Treatment Resistance ◽  
Antipsychotic Treatment ◽  
Locomotor Sensitization ◽  
Nucleus Accumbens Core ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Underlying Mechanisms ◽  
Motor Abnormalities

AbstractAntipsychotic-induced dopamine supersensitivity, or behavioral supersensitivity, is a problematic consequence of long-term antipsychotic treatment characterized by the emergence of motor abnormalities, refractory symptoms, and rebound psychosis. The underlying mechanisms are unclear and no approaches exist to prevent or reverse these unwanted effects of antipsychotic treatment. Here we demonstrate that behavioral supersensitivity stems from long-lasting pre, post and perisynaptic plasticity, including insertion of Ca2+-permeable AMPA receptors and loss of D2 receptor-dependent inhibitory postsynaptic currents (IPSCs) in D2 receptor-expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens core (NAcore). The resulting hyperexcitability, prominent in a subpopulation of D2-MSNs (21%), caused locomotor sensitization to cocaine and was associated with behavioral endophenotypes of antipsychotic treatment resistance and substance use disorder, including disrupted extinction learning and augmented cue-induced cocaine-seeking behavior. Chemogenetic restoration of IPSCs in D2-MSNs in the NAcore was sufficient to prevent antipsychotic-induced supersensitivity, pointing to an entirely novel therapeutic direction for overcoming this condition.

scholarly journals Accumbens D2-MSN hyperactivity drives behavioral supersensitivity

2020 ◽  
Author(s):  
Anna Kruyer ◽  
Jeffrey Parilla-Carerro ◽  
Courtney Powell ◽  
Lasse Brandt ◽  
Stefan Gutwinski ◽  
...  
Keyword(s):  
D2 Receptor ◽  
Treatment Resistance ◽  
Term Treatment ◽  
Antipsychotic Treatment ◽  
Medium Spiny Neurons ◽  
Therapeutic Approaches ◽  
Spiny Neurons ◽  
Long Term Treatment ◽  
Underlying Mechanisms

ABSTRACTAntipsychotic-induced behavioral supersensitivity is a problematic consequence of long-term treatment with antipsychotic drugs and is characterized by emergence of refractory symptoms and dyskinesias. The underlying mechanisms are unknown, and no rational approaches exist to prevent or reverse antipsychotic-induced supersensitivity. Here we describe major adaptations impacting populations of striatal medium spiny neurons (MSNs) during the development of behavioral supersensitivity and reveal a prominent role played by D2 receptor expressing MSNs. We show that enhanced D2-MSN activity underlies several symptoms spanning from psychostimulant sensitization, to antipsychotic treatment resistance and drug addiction. Our data warn against severe adverse events following antipsychotic treatment discontinuation and offer insight that may inform therapeutic approaches to overcome antipsychotic-induced supersensitivity.

Dopaminylation in Psychostimulant use Disorder Protects Against Psychostimulant Seeking Behavior by Normalizing Nucleus Accumbens (NAc) Dopamine Expression

2021 ◽  
Vol 09 ◽  
Author(s):  
Kenneth Blum ◽  
Mark S Gold ◽  
Jean L. Cadet ◽  
David Baron ◽  
Abdalla Bowirrat ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Histone H3 ◽  
D2 Receptor ◽  
Reward Processing ◽  
Allelic Polymorphism ◽  
Cocaine Withdrawal ◽  
Src Signaling ◽  
Chronic Cocaine ◽  
Cocaine Seeking ◽  
Seeking Behavior

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.

scholarly journals Cocaine Dependence and D2 Receptor Availability in the Functional Subdivisions of the Striatum: Relationship with Cocaine-Seeking Behavior

2004 ◽  
Vol 29 (6) ◽  
pp. 1190-1202 ◽  
Author(s):  
Diana Martinez ◽  
Allegra Broft ◽  
Richard W Foltin ◽  
Mark Slifstein ◽  
Dah-Ren Hwang ◽  
...  
Keyword(s):  
D2 Receptor ◽  
Cocaine Dependence ◽  
Cocaine Seeking ◽  
Seeking Behavior

scholarly journals CREST in the Nucleus Accumbens Core Regulates Cocaine Conditioned Place Preference, Cocaine-Seeking Behavior, and Synaptic Plasticity

2018 ◽  
Vol 38 (44) ◽  
pp. 9514-9526 ◽  
Author(s):  
Yasaman Alaghband ◽  
Enikö Kramár ◽  
Janine L. Kwapis ◽  
Earnest S. Kim ◽  
Thekla J. Hemstedt ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Nucleus Accumbens ◽  
Conditioned Place Preference ◽  
Place Preference ◽  
Nucleus Accumbens Core ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Accumbens Core

scholarly journals Erratum: Cocaine Dependence and D2 Receptor Availability in Functional Subdivisions of the Striatum: Relationship with Cocaine-Seeking Behavior

2004 ◽  
Vol 29 (9) ◽  
pp. 1763-1763 ◽  
Author(s):  
Diana Martinez ◽  
Allegra Broft ◽  
Richard W Foltin ◽  
Mark Slifstein ◽  
Dah-Ren Hwang ◽  
...  
Keyword(s):  
D2 Receptor ◽  
Cocaine Dependence ◽  
Cocaine Seeking ◽  
Seeking Behavior

scholarly journals Zinc potentiates dopamine neurotransmission and cocaine seeking

2020 ◽  
Author(s):  
Juan L. Gomez ◽  
Jordi Bonaventura ◽  
Jacqueline Keighron ◽  
Kelsey M. Wright ◽  
Dondre L. Marable ◽  
...  
Keyword(s):  
Conditioned Place Preference ◽  
Mechanism Of Action ◽  
Cocaine Abuse ◽  
Cocaine Addiction ◽  
Locomotor Sensitization ◽  
Self Administration ◽  
Pharmacological Mechanism ◽  
Cocaine Seeking ◽  
Seeking Behavior

AbstractCocaine binds to the dopamine transporter (DAT) in the striatum to regulate cocaine reward and seeking behavior. Zinc (Zn2+) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that cocaine abuse in humans correlated with low postmortem striatal Zn2+ content. In mice, cocaine decreased striatal vesicular Zn2+ and increased striatal synaptic Zn2+ concentrations and Zn2+ uptake. Striatal synaptic Zn2+ increased cocaine’s in vivo potency at the DAT and was required for cocaine-induced DAT upregulation. Finally, genetic or dietary Zn2+ manipulations modulated cocaine locomotor sensitization, conditioned place preference, self-administration, and reinstatement. These findings reveal new insights into cocaine’s pharmacological mechanism of action and indicate that Zn2+ can serve as a critical environmentally derived regulator of human cocaine addiction.

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