Open AccessAll Roads to Schizophrenia Lead to Dopamine Supersensitivity and Elevated Dopamine D2 High Receptors
Author(s) -
Seeman Philip
Publication year - 2011
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/j.1755-5949.2010.00162.x
Subject(s) - dopamine receptor d2 , aripiprazole , dopamine , dopamine receptor d3 , dopamine hypothesis of schizophrenia , antipsychotic , phencyclidine , clozapine , dopamine receptor , psychosis , agonist , pharmacology , medicine , psychology , schizophrenia (object oriented programming) , neuroscience , receptor , psychiatry , nmda receptor
SUMMARY Background: The dopamine D2 receptor is the common target for antipsychotics, and the antipsychotic clinical doses correlate with their affinities for this receptor. Antipsychotics quickly enter the brain to occupy 60–80% of brain D2 receptors in patients (the agonist aripiprazole occupies up to 90%), with most clinical improvement occurring within a few days. The D2 receptor can exist in a state of high‐affinity (D2 High ) or in a state of low‐affinity for dopamine (D2Low). Aim: The present aim is to review why individuals with schizophrenia are generally supersensitive to dopamine‐like drugs such as amphetamine or methyphenidate, and whether the D2 High state is a common basis for dopamine supersensitivity in the animal models of schizophrenia. Results: All animal models of schizophrenia reveal elevations in D2 High receptors. These models include brain lesions, sensitization by drugs (amphetamine, phencyclidine, cocaine, corticosterone), birth injury, social isolation, and gene deletions in pathways for NMDA, dopamine, GABA, acetylcholine, and norepinephrine. Conclusions: These multiple abnormal pathways converge to a final common pathway of dopamine supersensitivity and elevated D2 High receptors, presumably responsible for psychotic symptoms. Although antipsychotics alleviate psychosis and reverse the elevation of D2 High receptors, long‐term antipsychotics can further enhance dopamine supersensitivity in patients. Therefore, switching from a traditional antipsychotic to an agonist antipsychotic (aripiprazole) can result in psychotic signs and symptoms. Clozapine and quetiapine do not elicit parkinsonism or tardive dyskinesia because they are released from D2 within 12 to 24 h. Traditional antipsychotics remain attached to D2 receptors for days, preventing relapse, but allowing accumulation that can lead to tardive dyskinesia. Future goals include imaging D2 High receptors and desensitizing them in early‐stage psychosis.