Brain Research, 348 (1985) 15-20 15 Elsevier BRE 11135 Synaptic Rearrangements in Medial Prefrontal Cortex of Haloperidol-Treated Rats FRANCINE M. BENES 1, PETER A. PASKEVICH, JESSICA DAVIDSON and VALERIE B. DOMESICK 2 Departments of lPsychiatry and 2Anatomy, Harvard Medical School, Mailman Research Center, McLean Hospital, Belmont, MA 02178 (U.S.A.) (Accepted February 5th, 1985) Key words: dendritic synapse - - synaptic rearrangement - - haloperidol - - prefrontal cortex The effects of daily administration of haloperidol for 16 weeks on the structure of layer VI in medial prefrontal cortex of rat was per- formed at the light and electron microscopic levels. At the light microscopic level, no difference in either the size or the density of neu- rons was observed. At the electron microscopic level, the mean dendritic calibre of haloperidol-treated rats was twice that observed in control animals, but this was due to a selective loss of small-calibre dendritic profiles. Rats treated with neuroleptic also showed a re- duction in axon terminals with asymmetric postsynaptic membrane specializations, which, in control animals, were preferentially as- sociated with small-calibre dendritic profiles. These small-calibre dendritic profiles were found to be spines rather than small terminal dendritic shafts. An increase in axon terminals showing no membrane specialization on larger dendritic profiles also occurred in rats treated daily with the neuroleptic. The data suggest the possibility that haloperidol may have induced a relocation of asymmetric ter- minals from resorbed spinous processes to larger dendritic branches with the concomitant loss of their postsynaptic membrane special- ization. INTRODUCTION MATERIALS AND METHODS Clinical observations have encouraged specu- lations that neuroleptic agents such as haloperidol may induce structural alterations in cortical synapses in response to the blockade of dopamine receptors. For example, neuroleptic agents when administered in the treatment of psychosis typically require a few weeks to attain their full antipsychotic action and even months to reverse this effect after cessation of treatment. Our recent studies revealed that haloperi- dol, when given to rats for 16 weeks, was associated with structural changes in synapses of both substantia nigra6 and corpus striatum 7, two important compo- nents of the dopamine system. To test the hypothesis that the antipsychotic action of haloperidol may also involve structural alterations of cortical synapses, an electron microscopic (EM) morphometric analysis was performed on rat medial prefrontal cortex in lay- er VI (MPF-VI), where ventral tegmental dopa- minergic neurons terminate10,12,13,15. Male Sprague-Dawley rats (200 + 5 g) were used in this study. Experimental, drug-treated rats (n = 4) were injected daily with haloperidol (donated by McNeil Labs. ; 3 mg/kg, based on the daily b. wt.) dis- solved in 0.02 mM lactic acid for 16 weeks. Control animals (n = 4) were injected with appropriate vol- umes of lactic acid alone. A detailed description of handling, treatment and behavioral changes has been presented elsewhere 8. At the end of the 16-week in- terval, all animals were anesthetized with pentobar- bital (Chloropent; 1.0 ml/300 g b. wt.), and perfused intracardially9. The MPF samples, excised using a Zeiss OpMi-1 surgical microscope, were postfixed with 1.5% osmium tetroxide in 0.1 M cacodylate buf- fer, pH 7.4, stained en bloc with 2% uranyl acetate, dehydrated with a graded series of ethanol and pro- pylene oxide and embedded in Spurr's epoxy resin. Thin sections (1/~m) were stained with toluidine blue to confirm the presence of the MPF-VI. In addition, Correspondence: Francine M. Benes, McLean Hospital, 115 Mill Street, Belmont, MA 02178, U.S.A. 0006-8993/85/$03.30 © 1985 Elsevier Science Publishers B.V. (Biomedical Division)