THE EFFECTS OF CHRONIC HALOPERIDOL ADMINISTRATION ON GABA-IMMUNOREACTIVE AXON TERMINALS IN RAT MEDIAL PREFRONTAL CORTEX

Several reports have suggested that chronic haloperidol (HAL) treatmen t induces ultrastructural changes in synapses of substantia nigra, cor pus striatum, and medial prefrontal cortex (mPFC) of rat brain. The ef fects of HAL on specific cortical transmitter systems, however, are no t well characterized. Recent studies have indicated that there may be a loss of gamma-aminobutyric acid (GABA)ergic cells in anterior cingul ate cortex of schizophrenic subjects and this hypothesis has prompted interest in the question of whether dopamine receptor antagonists, suc h as HAL, may influence the activity of this transmitter system. This current report describes a quantitative light microscopic analysis of GABA-immunolabeled axosomatic terminals in mPFC of rats treated with H AL decanoate (0.5 mg/kg/day, i.m.) for a period of 4 months. GABA-cont aining terminals were visualized with an avidin-biotin immunoperoxidas e method for localizing anti-GABA antibodies. Computer-assisted image processing was employed to determine the total number of pixels repres enting GABA-immunoreaction product in axon terminals that were in dire ct apposition to pyramidal cell bodies. Drug-treated animals showed a significant increase in the number of pixels representing GABA-immunor eaction product in axosomatic terminals of layers II, III, V, and VI ( 93%, 63%, 31%, and 43%, respectively). These data are consistent with the idea that chronic HAL administration may be associated with a sign ificant increase in the amount of GABA present in terminals surroundin g pyramidal neurons of rat mPFC. The fact that GABA-containing termina ls showed the greatest increase in layer II is not consistent with the known distribution of dopamine afferents to this region which is lowe st in superficial laminae. Based on the laminar distribution of non-do paminergic receptor types that have a high affinity for HAL, the effec t of this drug on GABAergic transmission could potentially involve cha nges that are mediated through mechanisms in which 5-HT2 or sigma opia te receptors play a role. (C) 1994 Wiley-Liss, Inc.