The Role of DARPP-32 In Addiction, Schizophrenia & Parkinson's Disease

DARPP-32's Role On Dopamine, Glutamate, And Adenosine

 
darpp-32 schizophrenia
 

In this post, we will discuss how protein phosphatase 1 regulatory subunit 1B (PPP1R1B), also known as dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) plays a large role addiction, Parkinson's Disease, schizophrenia, cognition, and cancer. 

Contents:

  1. Basics
  2. DARPP-32 And Disease
  3. What Increases DARPP-32?
  4. What Decreases DARPP-32?
  5. Mechanism Of Action
  6. Genetics
  7. More Research

Basics

Dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) has a pivotal role in dopamine, glutamate, and adenosine neurotransmission, especially in the caudate, putamen, nucleus accumbens, cerebral and cerebellar cortex. R R

DARPP-32 dysregulation plays a role in:

  • Addiction R
  • Alzheimer's Disease R
  • Anhedonia R
  • Anxiety R
  • Bipolar Disorder R
  • Cancer R
  • Huntington's Disease R
  • Infections R
  • Insulin (pancreatic) Regulation R
  • Parkinson's Disease R
  • Schizophrenia R

It is expressed in low levels during development and gradually increases after birth. R

DARPP-32 And Disease

1. Addiction And Reinforcement

 
addiction darpp-32
 

DARPP-32 activity changes with repeated/chronic exposure to specific dopaminergics and addictive substances. R

When first exposed to a substance, DARPP-32 enhances D1-like receptor (D1R) activity, whereas chronic exposure to substances can cause suppression of D1R activity. R

This means repeated exposure to addictive substances suppresses DARPP-32's actions on D1Rs (to be more specific see advanced section). R

Here are some common examples of DARPP-32 playing a big role in addictions:

  • Alcohol R
  • Amphetamines R
  • Caffeine R
  • Cocaine R
  • Methamphetamine R
  • Morphine R 
  • Nicotine R
  • LSD R
  • PCP R

This can be seen in Parkinson's Disease patients with L-DOPA-induced dyskinesia (LID). R

2. Parkinson's Disease

For Parkinson's Disease, in the striatum increasing DARPP-32 in D1Rs is better, while inhibiting DARPP-32 in D2Rs are better. R R

So for example, activating medium spiny neurons (MSN) D1Rs can improve locomotion, whereas D2R activation does the opposite. R

This is because D1Rs activate adenylyl cyclase and cAMP synthesis, whereas D2Rs inhibit them. R

3. Cognition, Memory, And Excitotoxicity

 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581150/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581150/

 

DARPP-32 plays a role in creating new brain cells (via neurogenesis and neuroplasticity) as Brain Derived Neurotrophic Factor (BDNF) can increase levels of DARPP-32. R R

DARPP-32 (along with adductins) is necessary for the induction of striatal LTD and LTP, which is important for memory acquisition and consolidation, as well as neuronal plasticity. R R R

It also plays a role on episodic memory (see genetics below). R

DARPP-32 acts as a regulator of homeostasis in the brain and may help prevent excitotoxicity (too much neuronal activity causing cell death). R

For example, glutamate is able to decrease the action of DARPP-32 (see advanced for more) and inhibiting glutamate receptors (NMDA or AMPA) may prevent glutamate-induced exictoxicity via DARPP-32 regulation. R

4. Hypoxia And Brain Injury

By regulating dopamine and glutamate, DARPP-32 expression may protect the brain during hypoxia and help with traumatic brain injuries (TBI). R

For example, DARPP-32 expression may be lowered after TBI, causing problems with dopamine-induced synaptic plasticity. R

5. Schizophrenia

In schizophrenia, antipsychotic drugs like haloperidol act on the striatum by inhibiting action of D2Rs (aslo leading to increase cAMP). R

This inhibition likely also plays a role on DARPP-32, as some drugs that work on DARPP-32 have also implicated in inducing schizophrenia: (see advanced for explanation)

  • Amphetamines
  • LSD
  • PCP

DARPP-32 protein expression is usually reduced in the dorsolateral prefrontal cortex (PFC) of schizophrenic patients, as well as bipolar patients. R R R 

6. Cancer

DARPP-32 may promote angiogenesis and tumorgenesis. R

DARPP-32 (as well as t-Darpp, the truncated form of DARPP-32) is overexpressed in some cancers:

  • Breast Cancer R
  • Colon Cancer R R
  • Esophageal Cancer R
  • Gastric Cancer (may be overexpression from H. Pylori) R R
  • Prostate Cancer R

This overexpression may cause chemoresistance (such as Herceptin), as it shuts down the Her-2 signaling pathway. R R R

7. Antimicrobial

DARPP-32 may have antimicrobial or anti-inflammatory against H. Pylori. R

8. Motivation And Anhedonia

 
motivation anhedonia darpp-32
 

Low levels of DARPP-32 have been implicated with low motivation and anhedonia. R

Increasing DARPP-32 may help with these problems. R

For example, long-term use of aripiprazole was able restore DARPP-32 and improve anhedonia in a stress-induced model. R

9. Thyroid Function

DARPP-32 is necessary for IGF-1 and TSH (together) to induce thyroid cells to develop. R

What Increases DARPP-32?

 
 

Lifestyle/Diet:

  • Caloric Restriction R
  • Enriched Environment  (increases adducin phosphorylation) R
  • Fasting R
  • High Fat Diet R
  • Pain R

Supplements:

  • Caffeine (increases adducin phosphorylation as well) R R
  • Curcumin R
  • Forskolin - increases DARPP-32 Thr34 phosphorylation by 8-fold, while decreasing Thr75 and Ser97 phosphorylation R
  • Manganese (may be toxic) R

Hormones:

Drugs/Chemicals:

  • Aripiprazole R
  • Baclofen R
  • Chlorbipram R
  • Cyclosporine R
  • Haloperidol - in D2R R
  • L-DOPA - activate D1R R
  • Purmorphamine R
  • Rolipram R

Pathways:

  • Activin A R
  • BDNF - through PI3K/Akt/mTOR signaling pathway R R R
  • cAMP R
  • Dopamine R
  • HDAC inhibition R
  • mAChRs - Thr75 in MSN R
  • NCS-1 R
  • PDE4 inhibition - improves D1R DARPP-32 signalling in frontal cortex (improving cognition) R
  • PKA R

What Decreases DARPP-32?

Lifestyle:

Pathways:

  • AMPA R
  • Glutamate R
  • Nab2 R
  • NMDA R

Mechanism Of Action

 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581150/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581150/

 

Simple:

  • Increases AKT R
  • Increases cAMP R
  • Increases EGFR R
  • Reduces PDE1 R

Advanced:

  • DARPP-32 may have to balance with ARPP-21 (cAMP-Regulated Phosphoprotein 21kDa) for calcium-and dopamine- dependent activation in the striatum. R
  • In the striatum, activation of D1Rs in the direct MSNs leads to Golf-mediated stimulation of adenylyl cyclase, the enzyme responsible for the synthesis of cAMP, which then promotes transmission at AMPA NMDA glutamate receptors -> elevates the ability of sustained release of glutamate to produce depolarized up-states close to spike threshold, thereby promoting the excitability of striatonigral MSNs. R
  • Activation of D2Rs in the indirect MSNs is coupled to Gi/o-mediated inhibition of adenylyl cyclase, which decreases cAMP synthesis, which decreases cell excitability via G-protein-mediated activation of inwardly rectifying K+ channels. R
  • Several D2R antagonists, including antipsychotic drugs, to promote histone H3 phosphorylation at Ser10 depends exclusively on activation of the cAMP/DARPP-32 cascade. R
  • DARPP-32 is phosphorylated at Thr34 by PKA -> inhibits protein phosphatase 1 (PP1), so when PKA is activated in striatal neurons, PP1 inhibition increases the phosphorylation for PKA and PP1. R
  • In addiction, DARPP-32 plays a bidirectional role in drug addiction depending on its phase - P-Thr34 (acted on acutely - activating D1R/PKA signaling) or P-Thr75 (acted on chronically - opposite effect of P-Thr34) as part of homeostasis. R
    • Dopamine -> DARPP-32 at Thr34 -> D1R -> activation of PKA or Dopamine -> DARPP-32 at Thr75 -> cyclin-dependent kinase 5 (CDK5) -> inhibitor of PKA R
  • In schizophrenia drugs, the ones listed above increas P-Thr34 and P-Ser130 and decrease in P-Thr75. R
  • Glutamate decreases the phosphorylation states of DARPP-32 at Ser-97 as well as Thr-34, Thr-75, and Ser-130 by activating NMDA or AMPA receptors in both direct and indirect pathway striatal neurons, thus the effect of glutamate in decreasing Ser-97 phosphorylation was mediated by activation of PP2A. R
  • The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) /mammalian target of rapamycin (mTOR) and the CDK5/p35 signaling pathways are involved in the regulation of DARPP-32 protein levels by BDNF in MSNs. R

Genetics

PPP1R1B

rs879606 (I'm GG)

  • G Allele - higher cortical expression of DARPP-32, higher dopamine receptor efficacy, and greater bias toward positive cues, had increased functional connectivity in cortical-subcortical circuits in response to happy faces, engaging the dorsal prefrontal cortex (DLPFC), fusiform gyrus (FG) and the midbrain (MB). R
  • G allele - dorsolateral prefrontal cortex (DLPFC) volumes were larger compared to A alleles R
  • G allele - performed better on a free recall test of EM compared to A-carriers R
  • Unknown allele - strongly associated with schizophrenia and bipolar disorder R
  • G alleles - alleles displayed increased intrinsic connectivity between the IFG and PHG, as well as increased excitability of the PHG for negative emotional stimuli R

rs907094 

  • T Allele - higher cortical expression of DARPP-32, higher dopamine receptor efficacy, and greater bias toward positive cues, had increased functional connectivity in cortical-subcortical circuits in response to happy faces, engaging the dorsal prefrontal cortex (DLPFC), fusiform gyrus (FG) and the midbrain (MB). R
  • G allele - performed better on a free recall test of EM compared to A-carriers R
  • T alleles - displayed increased intrinsic connectivity between the IFG and PHG, as well as increased excitability of the PHG for negative emotional stimuli R

rs3764352

  • A Allele- higher cortical expression of DARPP-32, higher dopamine receptor efficacy, and greater bias toward positive cues, had increased functional connectivity in cortical-subcortical circuits in response to happy faces, engaging the dorsal prefrontal cortex (DLPFC), fusiform gyrus (FG) and the midbrain (MB). R
  • Unknown allele - strongly associated with schizophrenia and bipolar disorder R
  • A alleles - displayed increased intrinsic connectivity between the IFG and PHG, as well as increased excitability of the PHG for negative emotional stimuli R

rs90974

  • Unknown allele - strongly associated with schizophrenia and bipolar disorder R

Associations Between PPP1R1B Gene Polymorphisms and Anxiety Levels in the Chinese Population (2018) R

More Research

  • Brown fat may contain levels of DARPP-32. R