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

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. 

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

1. Addiction And Reinforcement

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

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

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

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:

• Progesterone R

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

Lifestyle:

• Alcohol Consumption (chronic) R
• Inflammation (such as LPS/endotoxemia) R

Pathways:

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

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

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

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