Neuroscience Vol. 45,No. 3,pp.625429, 1991 Printed in Great zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Britain 0306.4522/91 $3.00 +O.OO PergamonPress plc 0 1991 IBRO NEUROENDOCRINE AND BEHAVIOURAL RESPONSES TO HYPEROSMOLALITY IN RATS WITH LESIONS OF THE LATERAL HYPOTHALAMUS MADE BY N-METHYL-D-ASPARTATE J. M. CLARK,* A. J. M. CLARK,*? D. WARNE,~ E. L. RUGG,* S. L. LIGHTMAN~ and P. WINN*§ *Department of Psychology, University of St Andrews, St Andrews, Fife KY 16 9JU, U.K. SNeuroendocrinology Unit, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, U.K. Abstract-Excitotoxic lesions of rat lateral hypothalamus produce impairments in eating and drinking, but not motor deficits. However, it has not been established what causes these eating and drinking impairments. In the present experiments, drinking, plasma osmolality and arginine-vasopressin concen- tration were measured in lateral hypothalamic-lesioned and control rats following systemic injection of hypertonic saline. In response to hyperosmolality, N-methyl-D-aspartate-lesioned rats drank significantly less than controls but showed normal increases in plasma osmolality and arginine-vasopressin concen- tration. This dissociation of neuroendocrine and behavioural responses suggests that the impairment of rats with excitotoxic lesions of the lateral hypothalamus is unrelated to physiological (as opposed to behavioural) mechanisms of homeostasis. Bilateral electrolytic lesions of the lateral hypothala- mus (LH) produce aphagia, adipsia and motor deficits.‘0~“~20 In contrast, excitotoxic lesions which spare ascending mesotelencephalic dopamine neurons and remain restricted to the LH and zona incerta produce deficits in the production of eating and drinking but not motor impairments.5~24~25 Micro- injections of ibotenate or N-methyl-D-aspartate (NMDA),*~.4,%*4.*5 or microiontophoretic application6 (but not microinjection’5) of kainate, into the rat LH are associated with hypophagia, hypodipsia and a loss of body weight. Despite these difficulties, responses to 24 h food or water deprivation are unimpaired,* there is no change in reactions to adul- teration of the diet or water supply with quinine or saccharin2s24 and responses to the anorectic drugs amphetamine and fenfluramine are identical to those of controls.’ One deficit always present in rats bearing excitotoxic lesions of the LH, however, is an inability to respond properly over 1 or 3 h to dipsogenic, dehydrating or glucoprivic challenges, regardless of the extent to which eating and drinking in the home cage have recovered.’ 4,6.9.24.25 The precise cause of these eating and drinking impairments in response to physiological challenges remains uncertain. One explanation suggests that the LH is normally involved in the maintenance of peripheral physiological state in concert with medial tPresent address: Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, U.K. $To whom correspondence should be addressed. Abbreviations: AVP, arginine-vasopressin; LH, lateral hypo- thalamus(-ic); NMDA, N-methyl-D-aspartate. hypothalamic nuclei, and that it receives information from the periphery and in response makes adjust- ments to the state of the periphery by regulating neural and neuroendocrinological processes.lY An alternative explanation suggests that the LH (unlike medial hypothalamic structures such as the paraven- tricular nucleus’*) is not concerned primarily with the direct maintenance of peripheral physiological state but that it is concerned with those higher- order integrative processes which help control behaviour,I.“,I6.21~** We have examined whether or not the failure of rats bearing excitotoxic lesions of the LH to drink following systemic administration of hypertonic saline is related to an inability to make appropriate neuroendocrine responses to that challenge. In- creased plasma osmolality activates osmoreceptors in the hypothalamus which in turn activate both the behavioural response of drinking and the neuroendo- crine release of the antidiuretic hormone arginine- vasopressin (AVP). Drinking in response to plasma hyperosmolality elicited by hypertonic saline is re- duced following excitotoxic lesions of the LH* 4,h.9.24.‘5 but the physiological responses to dehydration made by rats bearing excitotoxic lesions of the LH have not been examined. For this experiment, we chose to measure the levels of AVP in the general circulation after injections of hypertonic and isotonic saline. In response to dehydration, AVP, synthesized in the hypothalamic, supraoptic and paraventricular nuclei, is released from axon terminals in the posterior pituitary’* and acts on V2 receptors in the renal medulla to promote water re-absorption. Changes in plasma AVP concentration reflect the ability of the 625