REGIONAL PREFERENCES OF AMPA RECEPTOR MODULATORS DETERMINED THROUGH AGONIST BINDING AUTORADIOGRAPHY

Autoradiographic techniques were used to test if positive modulators o f AMPA-type glutamate receptors have regionally differentiated effects on ligand binding. Cyclothiazide, a drug with ten fold greater effect s on 'flip' than 'flop' splice variants of the receptors, had unequal effects across the subdivisions of hippocampus; i.e., it reduced [H-3] AMPA binding in field CA3 with an EC50 of 24 mu M and in field CA1 and dentate gyrus with EC(50)s between 60 and 100 mu M. The EC50 for the drug's influence on binding was also significantly lower in the superf icial than in the deeper layers of the neocortex, though these differe nces were not as pronounced as those in the hippocampus. The ampakine CX614, a compound with a modest preference for flop variants, had a sl ightly lower EC50 for its effects on [H-3]AMPA binding in CA1 than in CA3. This result was confirmed with [H-3]fluorowillardiine binding. Th e effects of the ampakine in neocortex tended to be greater in the dee per than superficial layers but this did not reach statistical signifi cance. These results indicate that differential effects of modulators on AMPA receptor subunits are reflected in their relative potency acro ss brain subdivisions. This raises the possibility that subclasses of positive modulators will exhibit a measurable degree of selectivity in their physiological and behavioral influences. (C) 1998 Elsevier Scie nce B.V.