Dopamine agonist-induced elevation of striatal acetylcholine: relationship between receptor occupancy and response in...

Unilateral denervation of the nigrostriatal dopamine (DA) pathway with 6-hydroxydopamine resulted in a supersensitive response for elevation of striatal acetylcholine concentrations by the full DA agonist (R)-(-)-N-n-propylnorapomorphine (NPA), reflected in a parallel 4-fold leftward shift in the dose-response curve (ED50, intact, 8.8 micrograms/kg; denervated, 2.2 micrograms/kg). The maximal response, however, was not changed. In the intact striatum, irreversible DA receptor inactivation with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (6 mg/kg) produced a depression in the maximal acetylcholine increase elicited by NPA (control, 52.4%; EEDQ, 25.0%), without altering the ED50 for the agonist. In contrast, in the denervated striatum, EEDQ treatment produced a much smaller reduction in the maximal response (to 39.6%), as well as a small rightward shift in the ED50 (from 2.2 to 3.5 micrograms/kg). Double-reciprocal analysis of equieffective doses of NPA necessary to elicit response yielded similar values for the pseudo-dissociation constant (pseudo-KA, in units of dose) in intact and denervated striatum (8.3 and 7.0 micrograms/kg, respectively). A plot of receptor occupancy versus response was linear for the intact striatum, indicating the absence of a receptor reserve. In contrast, a nonlinear relationship was obtained for the denervated side, and a small apparent receptor reserve for NPA of 25-30% was estimated to be present. The results suggest that 6-hydroxydopamine-induced supersensitivity reflects the generation of a postsynaptic D2 DA receptor reserve, which may account for the observation that weak partial agonist elicit measurable response in supersensitive animals (and at presynaptic DA receptors, which normally exhibit a receptor reserve for agonists) but not at normosensitive receptors devoid of spare receptors.