Relationship between receptor occupancy and response at striatal dopamine autoreceptors.

The irreversible dopamine (DA) receptor antagonist N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was used to determine the extent of receptor reserve at DA autoreceptors regulating in vivo tyrosine hydroxylase activity. Rats were treated with vehicle or EEDQ (1 X 0.5-2 X 6 mg/kg, subcutaneously) and, 24 hr later, dose response curves were generated for DA agonist reversal of gamma-butyrolactone-induced striatal L-3,4-dihydroxyphenylalanine (L-DOPA) accumulation. Double reciprocal plots were obtained of equieffective doses of agonist required to elicit response at several levels of effect before and after partial irreversible receptor inactivation. A pseudo-dissociation constant (pseudo-KA, in units of dose) and the fraction of receptors remaining active (q) were determined; these values were then used to calculate the relationship between receptor occupancy and response. The ED50 (1 microgram/kg) for the full DA receptor agonist N-propylnorapomorphine (NPA) was shifted 2.8, 4.8-, and 11.3-fold to the right after partial irreversible receptor blockade which left the fraction of receptors remaining active (q) at 0.37, 0.17 and 0.058, respectively. Corresponding maximal reversal of L-DOPA accumulation was 100, 77, and 58%, indicating a nonlinear relationship between receptor occupancy and response for NPA and the presence of a large receptor reserve; maximal and half-maximal responses were calculated to require occupancy of 30 and 3.8% of the total receptor pool, respectively. Dose response curves were also obtained for the DA autoreceptor-selective agents EMD 23,448 and (+)- and (-)-3-PPP before and after EEDQ treatment. In controls, EMD 23,448 and (+)-3-PPP, like NPA, completely reversed striatal gamma-butyrolactone-induced L-DOPA accumulation, whereas the maximal effect of (-)-3-PPP was 52% reversal. After EEDQ treatment (6 mg/kg), EMD 23,448 and (+)-3-PPP showed relatively small shifts in ED50 values. Furchgott analysis demonstrated that all three atypical agents are partial agonists at the DA autoreceptor with efficacies of 0.19 (EMD 23,448), 0.12 [(+)-3-PPP], and 0.05 [(-)-3-PPP] relative to NPA. The presence of a larger receptor reserve at pre-versus postsynaptic D2 DA receptors and the partial agonist character of drugs such as EMD 23,448 and the enantiomers of 3-PPP may account for their autoreceptor selectivity.