title: Is regionally selective D2/D3 dopamine occupancy sufficient for atypical antipsychotic effect? an in vivo quantitative [123I]epidepride SPET study of amisulpride-treated patients.
abstract: OBJECTIVE
  Atypical antipsychotic drug treatment is clinically effective with a low risk of extrapyramidal symptoms. Explanations for the mechanism underlying this beneficial therapeutic profile of atypical over typical antipsychotic agents include 1) simultaneous antagonism of dopamine D(2) and serotonin 5-HT(2A) receptors or 2) selective action at limbic cortical dopamine D(2)-like receptors with modest striatal D(2) receptor occupancy. Amisulpride is an atypical antipsychotic drug with selective affinity for D(2)/D(3) dopamine receptors and provides a useful pharmacological model for examining these hypotheses. The authors' goal was to evaluate whether treatment with amisulpride results in "limbic selective" D(2)/D(3) receptor blockade in vivo.
  
  
  METHODS
  Five hours of dynamic single photon emission tomography data were acquired after injection of [(123)I]epidepride (approximately 150 MBq). Kinetic modeling was performed by using the simplified reference region model to obtain binding potential values. Estimates of receptor occupancy were made relative to a healthy volunteer comparison group (N=6).
  
  
  RESULTS
  Eight amisulpride-treated patients (mean dose=406 mg/day) showed moderate levels of D(2)/D(3) receptor occupancy in the striatum (56%), and significantly higher levels were seen in the thalamus (78%) and temporal cortex (82%).
  
  
  CONCLUSIONS
  Treatment with amisulpride results in a similar pattern of limbic cortical over striatal D(2)/D(3) receptor blockade to that of other atypical antipsychotic drugs. This finding suggests that modest striatal D(2) receptor occupancy and preferential occupancy of limbic cortical dopamine D(2)/D(3) receptors may be sufficient to explain the therapeutic efficacy and low extrapyramidal symptom profile of atypical antipsychotic drugs, without the need for 5-HT(2A) receptor antagonism.
authors.affiliation: British Association of Psychopharmacology, Harrogate, UK. r.bressan@iop.kcl.ac.uk
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Bressan
authors.forename: Kjell
authors.initials: K
authors.lastname: Erlandsson
authors.forename: Hugh M
authors.initials: HM
authors.lastname: Jones
authors.forename: Rachel
authors.initials: R
authors.lastname: Mulligan
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Flanagan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ell
authors.forename: Lyn S
authors.initials: LS
authors.lastname: Pilowsky
mesh_terms: D000328:Adult; D000077582:Amisulpride; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism; D008032:Limbic System / Q000000981:diagnostic imaging* / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D013702:Temporal Lobe / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D013788:Thalamus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D014150:Antipsychotic Agents; D001549:Benzamides; C493593:DRD3 protein, human; D065127:Dopamine D2 Receptor Antagonists; D007457:Iodine Radioisotopes; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C063525:epidepride; D013469:Sulpiride; D000077582:Amisulpride