INVIVO DISSOCIATION KINETICS OF [H-3] QUINUCLIDINYL BENZILATE - RELATIONSHIP TO MUSCARINIC RECEPTOR CONCENTRATION AND INVITRO KINETICS

The in vivo washout kinetics of ([H-3]quinuclidinyl benzilate ([H-3]QNB) varies significantly in various structures in the rat brain. The slowest washout rates are from the hippocampus, corpus striatum, and cortex, intermediate rates are exhibited from the thalamus and colliculi, while the fastest washout rate is from the cerebellum. We have also demonstrated a difference in the in vitro dissociation rates (k-1) of [H-3]QNB from various structures. The k-1 for the hippocampus, corpus striatum and cortex, is two-fold slower than that observed in the thalamus, colliculi, and cerebellum. The differences in the in vitro dissociation kinetics are not, however, sufficient to explain the differences in the in vivo washout kinetics. We have developed a theoretical formulation which describes conditions under which the washout kinetics are a function of the concentration of receptor in a structure. Furthermore, we present a graphical method in which a plot of the reciprocal of the observed washout rate constant, 1/k(obs), vs receptor concentration is linear. Analysis of the washout kinetics of [H-3]QNB from various structures of the CNS of rat were well described by this theory when the differences in in vitro k-1 are included.