COMPARISON OF THE AUTORADIOGRAPHIC BINDING DISTRIBUTION OF [H-3] GABAPENTIN WITH EXCITATORY AMINO-ACID RECEPTOR AND AMINO-ACID-UPTAKE SITE DISTRIBUTIONS IN RAT-BRAIN

1 Gabapentin is a novel anticonvulsant with an unknown mechanism of ac tion. Recent homogenate binding studies with [H-3]-gabapentin have sug gested a structure-activity relationship similar to that shown for the amino acid transport system responsible for the uptake of large neutr al amino acids (LNAA). 2 The autoradiographic binding distribution of [H-3]-gabapentin in rat brain was compared with the distributions for excitatory amino acid receptor subtypes and the uptake sites for excit atory and large neutral amino acids in consecutive rat brain sections. 3 Densitometric measurement of the autoradiographic images followed b y normalisation with respect to the hippocampus CAl stratum radiatum, was carried out before comparison of each binding distribution with th at of [H-3]-gabapentin by linear regression analysis. The correlation coefficients observed showed no absolute correlation was observed betw een the binding distributions of [H-3]-gabapentin and those of the exc itatory amino acid receptor subtypes. The acidic and large neutral ami no acid uptake site distributions demonstrated a much closer correlati on to the [H-3]-gabapentin binding site distribution. The correlation coefficients for D-[H-3]-aspartate, L-[H-3]-leucine and L-[H-3]-isoleu cine binding site distributions were 0.76, 0.90 and 0.88 respectively. 4 Concentration-dependent inhibition by unlabelled gabapentin of auto radiographic binding of L-[H-3]leucine and L-[H-3]-isoleucine was obse rved, with non-specific binding levels being reached at concentrations between 10 and 100 mu M.5 Excitotoxic quinolinic acid lesion studies in rat brain caudate putamen and autoradiography were carried out for the amino acid uptake sites mentioned above. The resulting glial infil tration of the lesioned areas was visualized by autoradiography using the peripheral benzodiazepine receptor specific ligand [H-3]-PK11195. A significant decrease in binding density in the lesioned area compare d with sham-operated animals was observed for D-[H-3]-aspartate, L-[H- 3] leucine, L-[H-3]-isoleucine and [H-3]gabapentin, whilst [H-3]-PK111 95 showed a significant increase in binding density indicative of glia l infiltration into the lesioned area. These results suggest that the gabapentin binding site and the acidic and LNAA uptake site may be pre sent on cell bodies of a neuronal population of cells. 6 From these st udies it appears that [H-3]-gabapentin, L-[H-3]-leucine and L-[H-3]-is oleucine bind to the same site in rat brain. The inhibition of [H-3]-g abapentin binding by the LNAA uptake system-specific ligand, BCH, sugg ests that [H-3]-gabapentin may label this uptake site, termed system-L . Conversely these ligands could be labelling a novel site that coinci dentally has a similar structure-activity relationship to this uptake site. These results suggest a novel mechanistically relevant site of a ction for gabapentin and may enable further anti-epileptic agents of t his type to be developed.