Investigation into effects of antipsychotics on ectonucleotidase and adenosine deaminase in zebrafish brain

Abstract

Antipsychotic agents are used for the treatment of psychotic symptoms in patients with several brain disorders, such as schizophrenia. Atypical and typical antipsychotics differ regarding their clinical and side-effects profile. Haloperidol is a representative typical antipsychotic drug and has potent dopamine receptor antagonistic functions; however, atypical antipsychotics have been developed and characterized an important advance in the treatment of schizophrenia and other psychotic disorders. Purine nucleotides and nucleosides, such as ATP and adenosine, constitute a ubiquitous class of extracellular signaling molecules crucial for normal functioning of the nervous system. Indirect findings suggest that changes in the purinergic system, more specifically in adenosinergic activity, could be involved in the pathophysiology of schizophrenia. We investigated the effects of typical and atypical antipsychotics on ectonucleotidase and adenosine deaminase (ADA) activities, followed by an analysis of gene expression patterns in zebrafish brain. Haloperidol treatment (9 µM) was able to decrease ATP hydrolysis (35%), whereas there were no changes in hydrolysis of ADP and AMP in brain membranes after antipsychotic exposure. Adenosine deamination in membrane fractions was inhibited (38%) after haloperidol treatment when compared to the control; however, no changes were observed in ADA soluble fractions after haloperidol exposure. Sulpiride (250 µM) and olanzapine (100 µM) did not alter ectonucleotidase and ADA activities. Haloperidol also led to a decrease in entpd2_mq, entpd3 and adal mRNA transcripts. These findings demonstrate that haloperidol is an inhibitor of NTPDase and ADA activities in zebrafish brain, suggesting that purinergic signaling may also be a target of pharmacological effects promoted by this drug.

Cell-subtype-specific changes in adenosine pathways in schizophrenia

“…However, ENTPD2 and A 1 R levels were significantly decreased. Haloperidol also reduced ATP hydrolysis and ENTPD2 gene expression in zebrafish brain [45,46]. A decrease in A 1 R expression may indicate reduced inhibition of glutamate release, leading to increased excitatory signaling in response to hypoglutamatergic function associated with schizophrenia [9].…”

Comprehensive functional annotation of susceptibility SNPs prioritized 10 genes for schizophrenia

“…There were 12 approved drugs from biotech targeted to functional genes, while Pegademase bovine is used for the treatment of adenosine deaminase, which is involved in the pathophysiology of schizophrenia 49 . Botulinum Toxin Type B is used for dystonia, which is one of the symptoms of schizophrenia.…”

Zebrafish models in neuropsychopharmacology and CNS drug discovery

“…The purinergic system has been recently implicated in schizophrenia (Lara and Souza, ), especially since adenosine, the final product in the ectonucleotidase cascade, modulates dopamine and glutamate (Lara and Souza, ). In zebrafish, haloperidol reduces ATP hydrolysis and adenosine deamination, thereby reducing synaptic adenosine levels (Seibt et al, ). The sensitivity of zebrafish ATP hydrolysis to haloperidol suggests an extracellular mechanism of action, potentially relevant to pharmacological targets (Seibt et al, ).…”

“…In zebrafish, haloperidol reduces ATP hydrolysis and adenosine deamination, thereby reducing synaptic adenosine levels (Seibt et al, ). The sensitivity of zebrafish ATP hydrolysis to haloperidol suggests an extracellular mechanism of action, potentially relevant to pharmacological targets (Seibt et al, ).…”