D2 but not D3 receptors are elevated after 9 or 11 months chronic haloperidol treatment: influence of withdrawal period.
Previous postmortem studies have identified divergent alterations in D2 and D3 receptors in schizophrenia but those results cannot be interpreted without further understanding of whether antipsychotic regulation of the D3 receptor is different from that of the D2 receptor. Depot parenteral administration of haloperidol decanoate was utilized to achieve consistent high levels in rat brain for 9 months with 2-month withdrawal or 11 months with 48-h withdrawal and compared to vehicle control and acute haloperidol (48-h) treatment groups. Autoradiographic means for measuring levels of D2 ([(3)H]-spiperone) and D3 receptors ([(125)I]trans 7-OH-PIPAT) and of D3 mRNA by in situ hybridization histochemistry in rat caudate-putamen, nucleus accumbens, islands of Calleja, and olfactory tubercle determined that there were significant group differences for regulation of D2 receptor. Chronic haloperidol for 9 or 11 months elevated D2 but not D3 receptors or D3 mRNA in all regions measured. Acute haloperidol treatment had no significant effects for any measure. Treatment for 9 months with a 2-month withdrawal resulted in a persistent increase in D2 receptors that was greater than that observed in the 11 months with 48-h withdrawal. This effect was most noticeable in the olfactory tubercle. These data confirm previous findings that short- or long-term haloperidol treatment leads to elevations in D2 but not D3 receptors or D3 mRNA, and long-term withdrawal from chronic haloperidol does not lead to elevations in D3 receptors or D3 mRNA. This suggests that an elevation in D3 receptors identified at postmortem in schizophrenics withdrawn from antipsychotics is not the result of the previous drug history [Gurevich et al. (1997) Arch Gen Psychiatry 54:225-232].
Thomas H. Christopher Center for Parkinson's Disease Research, Sun Health Research Institute, Sun City, AZ 85351, USA. Jeff.Joyce@sunhealth.org
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D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004334:Drug Administration Schedule; D006220:Haloperidol / Q000494:pharmacology*; D007457:Iodine Radioisotopes / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D050637:Receptors, Dopamine D3; D013134:Spiperone / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000503:physiopathology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013997:Time Factors; D014316:Tritium / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes; D014316:Tritium; C081289:7-hydroxy-2-(N-n-propyl-N-(3-iodo-2'-propenyl)-amino)tetralin; D013134:Spiperone; D006220:Haloperidol