Alpha2-adrenergic drugs modulate the binding of [18F]fallypride to dopamine D2/3 receptors in striatum of living mouse

Objectives To reveal modulation of dopaminergic tansmission in brain of living mice by alpha2-ardrenergic agents, through microPET recording with the high-affinity dopamine D2/3 receptor radioligand [18F]fallypride (BPND) following pharmacological challenges with adrenergic drugs.

Methods Groups of anesthetized mice (n=8) were pretreated with either saline, or RX821002 (1 mg/kg; a selective alpha2-antagonist), yohimbine (1mg/kg; non-selective alpha2-antagonist) or clonidine (1 mg/kg; alpha2-agonist). These treatments were followed one half hour later by i.v. injection of FP (9 MBq). 120 minute dynamic emission recordings were acquired with the Inveon microPET. After spatial normalization of individual PET recordings to a common coordinate system of mouse brain, parametric maps of binding potentials (BPND) were calculated using the Logan method with cerebellum as reference region.

Results In the saline group, BPND was 10.8 in striatum. The mean striatal BPND was reduced by 25% reduction in the yohimbine group (p = 0.014), and by 18% in the RX821002 group (p < 0.05). Pretreatment with clonidine evoked no significant change in the striatal binding. Extrastriatal binding is not discernible in mice.

Conclusions These findings are consistent with a tonic inhibition of dopamine release by alpha2 adrenergic receptors, such that alpha2 blockade increased the competition from endogenous dopamine at D2 receptors, thus reducing the FP BPND by about 20%. Absent effects of clonidine suggest a ceiling effect in the tonic inhibition of dopamine release. This is the first in vivo PET evidence of alpha2/dopaminergic interaction, which may be relevant to putative actions of antipsychotic medications via adrenergic receptors