D-2 but not D-3 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 an d D-3 receptors in schizophrenia but those results cannot be interpreted wi thout further understanding of whether antipsychotic regulation of the D-3 receptor is different from that of the D-2 receptor. Depot parenteral admin istration 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 b y in situ hybridization histochemistry in rat caudate-putamen, nucleus accu mbens, islands of Calleja, and olfactory tubercle determined that there wer e significant group differences for regulation of D-2 receptor. Chronic hal operidol 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 eff ects for any measure. Treatment for 9 months with a 2-month withdrawal resu lted in a persistent increase in D-2 receptors that was greater than that o bserved in the 11 months with 48-h withdrawal. This effect was most noticea ble in the olfactory tubercle. These data confirm previous findings that sh ort- 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 haloperido l does not lead to elevations in D-3 receptors or D-3 mRNA. This suggests t hat an elevation in D-3 receptors identified at postmortem in schizophrenic s withdrawn from antipsychotics is not the result of the previous drug hist ory [Gurevich et al. (1997) Arch Gen Psychiatry 54:225-232]. Synapse 40: 13 7-144, 2001. (C) 2001 Wiley-Liss, Inc.