Physiology & Behavior, Vol. 15, pp. 377-379. Pergamon Press and Brain Research Publ., 1975. Printed in the U.S.A.
BRIEF COMMUNICATION Water Intoxication Death Following Hypothalamic Lesions in the Rat I THOMAS B. WlSHART AND ELWOOD K. WALLS
Department o f Psychology, University o f Saskatchewan, Saskatoon, Saskatchewan, Canada
(Received 10 November 1974) WlSHART, T. B. AND E. K. WALLS. Water intoxication death following hypothalamic lesions in the rat. PHYSIOL. BEHAV. 15(4) 377-379, 1975. - Rats received large, bilateral lesions of the ventromedial hypothalamus. Water or saline intakes, urine outputs and body temperatures were observed for up to 24 hr after surgery. Fifty percent of the operated animals drank excessively and died within 4 - 6 hr when permitted access to water. Urine outputs were low and symptoms of water intoxication were evident. When allowed access to saline, outputs rose and the number of animals which survived increased as the saline concentration increased. Body temperatures approached 40°C during drinking, but did not differ from operated animals which refused to drink. It was concluded that the deposition of metallic ions strongly stimulates a hypothalamic drinking system which results in overhydration and water intoxication death. Ventromedial hypothalamic lesions
METHOD WHILE lesions placed in the hypothalamus typically result in adipsia [7, 13, 14] or at most, polydipsia secondary to polyuria , recent reports indicate a primary, though transient, polydipsia may be initiated by medial hypothalamic destruction [ 10, 11, 15]. The increase in drinking has been identified as the result of an irritative focus initiated by the deposition of metallic ions around the lesion [ 10]. Presumably, the focus activates or excites a drinking system in which the lateral hypothalamus is considered to be of primary importance [ 12]. Rolls [ 10] reported that three animals sustaining irritatire lesions of the hypothalamus died after having consumed 2 to 3 times their normal daily intake. All 3 rats were however, bilaterally nephrectomized and thus unable to eliminate any portion of their increased intake. Wishart and Walls  observed that 6 of 16 animals with lesions in the ventro-medial hypothalamic area overdrank to the point of death during the immediate postoperative period despite intact renal systems. In this report some additional observations are made on this phenomenon. In particular, body temperatures and consumption of various concentrations of saline were investigated following lesioninduced polydipsia.
Forty-five male, albino rats weighing 2 5 0 - 3 0 0 g at the time of surgery were employed in the study. Each rat was anaesthetized with sodium pentobarbital (45 mg/kg), and placed in a stereotaxic apparatus. Electrolytic lesions were produced bilaterally in the region of the ventromedial hypothalamus by passing 1.0 mA anodal direct current for 2 5 - 3 0 sec through a stainless steel electrode insulated except for 0.5 mm at the tip. A rectal cathode completed the circuit. Following surgery, the rat was placed in a metabolic cage from which urine output could be collected and measured. Water but not food was made available in a graduated drinking tube. In 10 animals rectal temperatures were measured every 15 min for 6 hr after surgery, using a Yellow Springs thermometer and probe. Total water intakes and urine outputs were measured at the end of the 6 hr period. Of the remaining 35 animals, 24 drank after surgery (called drinkers) and were included in the study. These 24 rats were divided into 6 groups with the animals in each group allowed access to a saline solution of concentration 0.0, 0.2, 0.3, 0.4, 0.5 or 1.0 percent. The volumes of saline
1Supported by a grant from the National Research Council of Canada. 377
WlSHART AND WALLS
intake and urine output were recorded every 1/2 hour for 6 hr and after 24 hr when the animal survived. Histological examination of the brains of all animals was carried out using the frozen section technique and thionin staining procedures. RESULTS Five of the 10 rats in which body temperatures were recorded drank water and died within 4 - 6 hr after surgery. Water intake averaged 76.9 ml in these animals. Urine output began only after the onset of drinking and averaged 10.6 ml. An initial hypothermia occurred during the surgical procedure and was followed by a hyperthermic response in all animals. The body temperatures of 2 rats (one drinker and one non-drinker) are presented in Fig. 1. Temperatures in some cases exceeded 40°C before slowly declining to near normal values over a period of several hours.
concentration rose. Animals which were permitted access to 0.0 or 0.2 percent saline drank large volumes of the fluids, excreted little and died within 6 hr. At 0.3 and 0.4 percent concentrations 2 and 3 animals respectively excreted sufficient fluid to survive. At the highest concentrations employed all animals survived. The excreted fluids of the survivors were not recognizable as urine. Rather, the fluid appeared to be a liquid, dilute feces. The volumes of fluid collected in these cases were underestimates since the undersides of the animals were coated with the liquid, fecal material. The lesions in all cases destroyed the medial hypothalamus, extending to the medial border of the lateral hypothalamus. Rostrally the lesion invaded the preoptic region while the caudal limit of damage was usually the posterior border of the ventromedial nucleus. The main difference between the drinkers and nondrinkers was in the size and lateral extent of the lesions, being larger and extending further lateral in the former. DISCUSSION
-~ Non-Drinker = Drinker
E i.~ 38m
t~ o ~) 37IZ:
FIG. 1. Body temperature responses in "one drinker and one non-drinker rat following ventro-medial hypothalamic lesions. Arrows indicate onset and termination of drinking. Drinking, when it occurred, invariably began during the hyperthermic phase. The average body temperature at the onset of drinking was 39.6°C. Hyperactivity was noticeable in animals which consumed water as well as in those which did not. In the drinkers the consummatory behavior was frequently interrupted by walking and rearing. Hyperactivity and drinking disappeared simultaneously and left the animal in a comatose-like state. Massive convulsions, accompanied by repeated ejaculations and respiratory depression, preceded death. At autopsy, the stomachs and intestines of the animals which drank after surgery were markedly distended with fluid, and evidence of pulmonary edema was present in 9 of the 10 rats. Table 1 presents the results of the second part of the experiment in which rats which drank after surgery were permitted access to saline. The most noticeable effect was an increase in fluid excretion and survival rate as the saline
Rolls  has shown that electrolytic lesions which deposit irritative ions in the hypothalamus stimulate a drinking system. In the present study, the stimulation was of sufficient intensity to result in overhydration and water intoxication death. In subsequent experiments, rats have been identified as drinkers by providing only momentary access to water. Among these animals, which were not allowed to consume water, the mortality rate was only 10 percent, thereby indicating that the deaths observed in this study were primarily due to water intoxication. Pulmonary edema following large hypothalamic lesions which invade the preoptic region has been previously noted  and has also been attributed to an irritative action of deposited ions  upon sympathetic fibers descending from or through the hypothalamus. Local infusions of aconitine  or carbachol  into the preoptic region may also effect pulmonary edema. The degree of edema observed in the present series of animals was not so severe as to be lethal itself. It may have been a contributing factor in the deaths observed. The enhanced consumption of water following ventromedial hypothalamic damage appears to be a primary effect of the lesion as urine output was not greatly increased. Also, although hyperthermia may be a contributing factor to the hyperdipsia, it does not seem to initiate drinking since even the non-drinkers showed the hyperthermic response. The addition of sodium chloride to the drinking water prevented, at high concentrations, water intoxication. While the volumes of saline consumed were comparable to, or even larger than, those of water drunk, fluid elimination was greatly augmented by saline ingestion. A large portion of the increased output was in the form of a dilute, liquid feces similar to that observed in diarrhea, suggesting decreased absorption of liquid from the gut. Elimination of sodium and water by the kidney may also have increased; however the relative contributions of the two elimination routes to the total output could not be determined. Despite rather large consumptions of water following lesions of the ventromedial hypothalamus, urine outputs remained low. This response is exactly that expected of an animal in a state of negative water balance, although in exaggerated form. Irritative lesions in this region of the
W A T E R I N T O X I C A T I O N A N D LH L E S I O N S
379 TABLE 1
CONSUMPTION OF SALINE FOLLOWING HYPOTHALAMIC LESIONS: WATER INTOXICATION DEATH OR SURVIVAL* Volume Consumed (ml) Saline Concentration Percent
0.0 0.2 0.3
69.8±11.0 135.8 ± 7.9 102.5 ± 12.1
0.4 0.5 1.0
75.8 ± 16.7 211.0 ± 24.1 217.0+-82.3
Volume Excreted (ml)
105.5 ± 16.5
11.0± 3.7 21.3 +- 8.6 28.5 ± 10.5
84.0 ± 1.0
0 0 50
92.0-+ 15.3 230.8 ± 31.0 360.0-+ 116.0
24.3 -+ 8.2 160.8-+ 17.5 191.0-+ 82.7
57.7± 9.6 198.5-+ 25.2 358.0 ±118.0
75 100 100
*Values reported are means -+ standard deviations.
b r a i n t h u s a p p e a r to a c t i v a t e a n e u r a l s y s t e m i n v o l v e d in t h e c o n t r o l o f w a t e r b a l a n c e [ 1 2 ] . Initially this s y s t e m appeared to be cholinergically m e d i a t e d as c h o l i n e r g i c agents like c a r b a c h o l elicit d r i n k i n g following i n t r a c r a n i a l application [ 2 ] , b u t m o r e r e c e n t e v i d e n c e p o i n t s t o a n involvem e n t o f adrenergic n e u r o n s . L e i b o w i t z [ 5 ] , elicited drinking b y a p p l y i n g i s o p r o t e r e n o l , a/~-adrenergic agonist, t o t h e lateral h y p o t h a l a m i c a n d p r e o p t i c areas. A n o b s e r v a t i o n r e m a r k a b l y similar to t h a t described in t h e results s e c t i o n of this p a p e r was m a d e b y L e h r e t al.  f o l l o w i n g periph-
eral a d m i n i s t r a t i o n o f i s o p r o t e r e n o l . C o p i o u s d r i n k i n g a n d s i m u l t a n e o u s i n h i b i t i o n o f u r i n e e x c r e t i o n lasted for u p t o 3 h r a f t e r t h e i n j e c t i o n . T h e e f f e c t c o u l d be b l o c k e d b y p r i o r a d m i n i s t r a t i o n o f p r o p a n o l o l , a /~-adrenergic antagonist [ 1 ] . It m a y well be this s y s t e m w h i c h is a f f e c t e d b y irritative lesions placed in t h e region o f the v e n t r o m e d i a l h y p o t h a l a m u s . W a t e r i n t o x i c a t i o n d e a t h m a y e n s u e unless p r e v e n t a t i v e measures, such as r e m o v i n g access to w a t e r or p r o v i d i n g a saline s o l u t i o n , are taken.
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