D₂ but not D₃ receptors are elevated after 9 or 11 months chronic haloperidol treatment: Influence of withdrawal period

Abstract

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 This suggests that an elevation in D3 receptors identified at postmortem in schizophrenics withdrawn from antipsychotics is not the result of the previous drug history [Gurevich et al.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].

“Breakthrough” Dopamine Supersensitivity during Ongoing Antipsychotic Treatment Leads to Treatment Failure over Time

“…Changes in dopamine signaling must therefore be involved. It has been proposed that withdrawal from antipsychotic treatment induces dopamine supersensitivity by increasing striatal D 2 receptor number (Burt et al, 1977;Muller and Seeman, 1977;Clow et al, 1980;Seeman, 1980;Fleminger et al, 1983;Joyce, 2001). Both haloperidol doses we tested led to a supersensitive locomotor response to amphetamine, but only the higher dose increased striatal D 2 receptor number.…”

The Striatal and Extrastriatal D2/D3 Receptor-Binding Profile of Clozapine in Patients with Schizophrenia

“…These differences in competition of clozapine against endogenous dopamine could contribute to the abovementioned regional differences of concentration/occupancy curves. Additionally, upregulation of D 2 but not D 3 receptors under antipsychotic treatment together with different spatial distributions of D 2 and D 3 receptors may contribute to the described observations (Joyce, 2001).…”

“…Calculation of receptor occupancy for a brain region with reduced receptor numbers from a comparison with normal volunteers should lead to overestimation of the occupancy, not underestimation. However, if D 2 and D 3 receptors are differentially regulated by clozapine in selected brain regions, or if D 2 and D 3 receptors are differentially regulated in patients with schizophrenia and normal controls, then the estimation of occupancy values in patients from comparison with normative values obtained in healthy subjects might be misleading (Gurevich et al, 1997;Joyce, 2001).…”

D2-Receptor Upregulation is Dependent upon Temporal Course of D2-Occupancy: A Longitudinal [11C]-Raclopride PET Study in Cats

“…(Malmberg et al, 1993), it is unlikely that the increased [ 11 C]raclopride binding seen after haloperidol reflects increased D 3 -receptor densities. Indeed, previous studies have shown that whereas chronic haloperidol increases D 2 -receptor density, it does not affect D 3 -receptor density in the rat striatum (Levesque et al, 1995;Florijn et al, 1997;Joyce, 2001).…”