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 D-2 and D-3 receptors in schizophrenia but those results cannot be interpreted without further understanding of whether antipsychotic regulation of the D-3 receptor is different from that of the D-2 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 D-2 ([H-3]-spiperone) and D-3 receptors ([I-125]trans 7-OH-PIPAT) and of D-3 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 D-2 receptor. Chronic haloperidol for 9 or 11 months elevated D-2 but not D-3 receptors or D-3 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 D-2 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 D-2 but not D-3 receptors or D-3 mRNA, and long-term withdrawal from chronic haloperidol does not lead to elevations in D-3 receptors or D-3 mRNA. This suggests that an elevation in D-3 receptors identified at postmortem in schizophrenics withdrawn from antipsychotics is not the result of the previous drug history [Gurevich et al.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]. Synapse 40: 137-144, 2001. (C) 2001 Wiley-Liss, Inc.