PII S0031-9384(97)00200-X Manipulation of Behavioral Disorders in Autoimmune Mice via Prolactin NICHOLAS S. WATERS, 1 * LORI L. BADURA,† S. ANSAR AHMED,‡ ROBERT M. GOGAL, JR.‡ AND VICTOR H. DENENBERG* *Biobehavioral Sciences Graduate Degree Program, University of Connecticut, Storrs, CT, USA †Department of Psychology, State University of New York at Buffalo, Buffalo, NY, USA and ‡Department of Biomedical Sciences and Pathobiology, Center for Molecular Medicine and Infectious Diseases, Virginia Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA Received 1 May 1996; Accepted 1 April 1997. WATERS, N. S., L. L. BADURA, S. A. AHMED, R. M. GOGAL, JR. and V. H. Denenberg. Manipulation of behavioral disorders in autoimmune mice via prolactin. PHYSIOL BEHAV 62(5) 983–988, 1997.—Autoimmune mice perform poorly in two-way active avoidance tasks, and the extent of this performance deficit appears to be related to the extent of autoimmunity following developmental manipulations. In the current study, the pituitary hormone prolactin, which has immune-enhancing effects, was used to manipulate this behavioral disorder in adulthood. Prolatinergic manipulation may be achieved by the use of dopaminergic drugs. In two experiments, autoimmune NZB X NZW F1 (BW) mice received either pimozide (PIM; a D 2 antagonist) or bromocriptine (CB154; a dopamine agonist) in their drinking water. Control subjects received plain water. Following treatment, subjects were tested in an activity monitor, and active avoidance learning. Circulating PRL levels, as measured by RIA, were significantly increased by PIM and significantly decreased by CB154. Neither drug affected circulating levels of autoantibodies to DNA or cardiolipin, a phospholipid. In Experiment 1, in which mice were tested at 12 weeks of age, after 6 weeks of drug treatment, PIM treated animals of both sexes showed significantly more failures to escape the shock in avoidance conditioning, while CB154 did not have significant effects. In Experiment 2, in which mice were tested at 16 weeks of age, after 12 weeks of drug treatment, CB154 treated females (males were not tested) showed significantly fewer failures to escape, while PIM did not have significant effects. The effects of PRL on behavior, and its relation to immune system function, are discussed. © 1997 Elsevier Science Inc. Autoimmunity Avoidance learning BW mice Prolactin GENETICALLY autoimmune mice have extreme difficulty learn- ing avoidance tasks (13,14,18,22,24). In two-way active avoid- ance, autoimmune animals characteristically freeze in response to the conditioned and unconditioned stimuli, and, under most con- ditions, do not learn to avoid the shock, even after 250 trials (13,14,18). This behavioral deficit seems to be specific to avoid- ance learning, as autoimmune animals perform well on a number of other learning tests, including simple water escape (12), dis- crimination learning (12), and the Morris spatial maze (28). While previous studies have demonstrated a relationship between the level of autoimmunity and the degree of behavioral disorder fol- lowing developmental manipulations (13,14,22), mice have not previously been tested following postnatal manipulation of auto- immunity. One approach to immunological manipulations is the use of endocrinological factors. The pituitary hormone prolactin (PRL) acts to enhance immune system function, increasing T-cell excitability, and reversing im- munosuppression. Prolactin appears to be necessary for a complete immune response to challenge; blocking PRL increases the lethal- ity of infection, and suppresses T-cell proliferation (for reviews see references 7,16,20, and 25). The regulation of basal prolactin release is largely achieved by changes in the activity of the hypothalamic tuberoinfundibular dopaminergic (DA) neurons (6,21). The DA inhibitory modulation of lactotrope function can be mimicked by administration of DA agonists, such as bromocriptine (CB154), leading to decreased PRL release, whereas administra- tion of specific dopamine receptor-2 (D 2 ) antagonists, such as pimozide (PIM), increases PRL secretion (see [21] for a review). Thus, pharmacological manipulations of DA action lead to changes in basal PRL levels that may alter immune system func- tion, and subsequently alter the behavioral deficits of autoimmune mice. Prolactin levels are important regulators of maternal behav- ior in rodents (9), though the effects of PRL on learning behaviors have not been widely investigated. EXPERIMENT 1 In the current report, two experiments attempted to influence avoidance behavior in adult mice by altering autoimmunity in congenitally autoimmune NZB  NZW F1 (BW) mice via ma- nipulation of circulating PRL. Administration of CB154 and PIM 1 To whom requests for reprints should be addressed (current address): Department of Psychology, 102 Gilmer Hall, University of Virginia, Charlottesville, VA 22903, E-mail: nsw8t@virginia.edu Physiology & Behavior, Vol. 62, No. 5, pp. 983–988, 1997 © 1997 Elsevier Science Inc. All rights reserved. Printed in the U.S.A. 0031-9384/97 $17.00 + .00 983