~ Pergamon 0306-4522(95)00275-8 Neuroscience Vol. 69, No. 3, pp. 881-891, 1995 Elsevier ScienceLtd Copyright © 1995 IBRO Printed in Great Britain. All rights reserved 0306-4522/95 $9.50 + 0.00 EFFECTS OF HALOPERIDOL, CLOZAPINE AND CITALOPRAM ON MESSENGER RNA LEVELS OF CHROMOGRANINS A AND B AND SECRETOGRANIN II IN VARIOUS REGIONS OF RAT BRAIN S. KROESEN,* J. MARKSTEINER,~" S. K. MAHATA,*J; M. MAHATA,*:~ R. FISCHER-COLBRIE,* A. SARIA,t I. KAPELLER* and H. WlNKLER*§ *Department of Pharmacology and tNeurochemistry Unit of the Department of Psychiatry, University of Innsbruck, A-6020 Innsbruck, Austria Abstract--We have measured the messenger RNA levels of chromogranins A and B and secretogranin II in various brain regions of rats subchronically treated with various antipsychotic drugs. Since, as shown previously, the messenger RNA levels of these peptides are increased when neurons are stimulated, we hoped to identify by this approach those nuclei which are subchronically influenced by these drugs. The drugs chosen were the neuroleptic halperidol, a blocker of dopamine receptors, the atypical antipsychotic clozapine, which in addition to blocking dopamine receptors also blocks those for serotonin, and citalopram, a specific serotonin reuptake inhibitor. In agreement with previous data on neuropeptide messenger RNAs, we found in the dorsolateral striatum an increase of the secretogranin II messenger RNA levels after haloperidol and a much smaller one after clozapine. In the nucleus accumbens and in the bed nucleus of the stria terminalis, both compounds had a comparable positive effect. These differential effects can be attributed to a different action of these drugs on dopamine receptor subtypes. In the zona incerta, clozapine decreased the secretogranin II and chromogranin A message, whereas in the dorsal raphe it led to an increase. On the other hand, citalopram induced exactly the opposite effects in these two brain regions. This phenomenon can be explained by the differential interaction of these drugs with serotonergic mechanisms. Additional, relatively small changes of the mRNAs were seen in several other brain regions. These results establish that changes in the mRNA levels of the chromogranins are good indicators for the effect of drugs on certain brain nuclei. The concomitant action of haloperidol and clozapine on the limbic regions, i.e. the nucleus accumbens and the bed nucleus of the stria terminalis, points to these brain regions for the antipsychotic action of these two neuroleptics. Key words: neuroleptics, antipsychotics, striatum, nucleus accumbens. The chromogranins 5 are acidic proteins which were originally isolated from adrenal chromaffin granules (for reviews see Refs 12, 16, 42 and 58). They comprise chromogranin A: ° chromogranin B, 1~ secretogranin I143 and 7B2. 27 It is by now well established that they are present in large dense-core vesicles throughout the neuroendocrine system. In the brain, immunoreactivity for chromogranin A and its mRNA have a widespread distri- bution, 3'~36'53'56 it has even been claimed that all neurons synthesize this peptide, 48 although to a quite varying degree. Secretogranin II and a peptide derived from it, i.e. secretoneurin, have also been localized throughout the brain and the spinal cord. 8'19'28'56 For chromogranin B, data are still more limited, but at least peptides derived from it and its mRNA are detectable in many neurons of ~Present address: Hypertension Research, Department of Medicine, University of California, San Diego, U.S.A. §To whom correspondence should be addressed. the b r a i n . 13'24'46'56 It seems likely that the chro- mogranins are proproteins for functional peptides. Thus, chromogranin A is processed to pancreastatin, parastatin and vasostatin which have functions in peripheral tissues; ~6 it has also been reported that chromogranin A (or peptides derived from it) can inhibit dopamine release in the retina and possibly also brain. 6'~5 Secretoneurin, a peptide formed from secretogranin II, releases dopamine from central striatal neurons 2'47 and is a chemotactic agent. 38 Finally, a peptide derived from chromogranin B, i.e. secretolytin, was shown to be bactericidal) 4 We have recently described that the mRNAs of the chromogranins are up-regulated in brain when neurons are stimulated by various treatments such as salt loading, 25 lactation and adrenalectomy, 23 kainate 26 or reserpine injection. 22 These results for the steady state levels of the chromogranin mRNAs are analogous to those of various neuropeptide mRNAs. Since the chromogranin messages have a more wide- spread distribution, we proposed 2~ that studying the levels of these messages in various brain nuclei might 881