Lack of tolerance development to the dipsogenic actions of barbital

Pharmacology Biochemistry and Behavior, Vol. 2, pp. 431-434. ANKHO International Inc., 1974. Printed in the U.S.A.

BRIEF COMMUNICATION Lack of Tolerance Development to the Dipsogenic Actions of Barbital I ROGER P. MAICKEL AND GREG J. MALONEY ~

Department o f Pharmacology, Medical Sciences Program, Indiana University, Bloomington, IN 47401

(Received 19 February 1974)

I~IAICKEL, R. P. AND G. J. MALONEY. Lack of tolerance development to the dipsogenic actions of barbital. PHARMAC. BIOCHEM. BEHAV. 2(3) 431-434, 1974.- Chronic dosage of rats with barbital produced a dipsogenie state with overhydration. No tolerance could be seen to this effect in fourteen days; on withdrawal of drugs, the water intake of the rats fell to below normal levels, on a weight basis. When daily intake of fluid was restricted during the period of barbital dosage, overhydration did not occur and drinking during the withdrawal phase was increased. Barbital

Drug induced drinking

Tolerance

and Purina Rat Chow ad lib for at least 1 week after arrival in the laboratory. All solutions for injection were made in glass distilled water such that a dose volume of 0.1 ml per 100 g body weight contained the desired dose; all injections were given intraperitoneally, 15 min prior to placing the animals in the drinking cages. The procedures used to measure deprivation-induced water consumption were. basically those of Gerald and Maickel [5]. Rats were placed in cages, 7 x 7 x 14 in., identical to the home cages of the animals. The cages were suspended in individual compartments of a sound-proofed box with uniform fluorescent lighting. Constant circulation of air by blowers maintained uniform temperature in the compartments; the noise level of blowers served as a white noise. Each cage contained a drinking tube connected to an external 50 ml buret filled with distilled water at the start of each test run and stoppered. As the animal consumed water, the change in volume was measured visually to the nearest 0.1 ml. The front door of each compartment was equipped with an eye-piece lens to permit visual observation of the rats without disturbing their behavioral performance. For at least 1 week prior to testing drug effects, rats were deprived of water daily for 23 hr prior to testing, then placed in the drinking cages and allowed to drink for 1 hr. Food was available ad lib in the home cages but was not available in the drinking cages. In the restricted intake studies, rats were given only a fixed volume of water, 14.0 ml. Drug trials were started only after the animals demonstrated stable baselines (less than 5% daily variation) of

SCHMIDT and co-workers [ 1 1 - 1 9 ] have studied the effects of a variety of barbiturates on water consumption induced in rats by various means. In general, the compounds had a dipsogenic action, a finding corroborated by us for a variety of depressant drugs [7]. In addition, this laboratory recently reported an exhaustive study of factors involved in the dipsogenic actions of barbital [6]. Schmidt, et al. [16,18] administered phenobarbital to deprived rats daily for 30 days 'and measured water intake; no indication of tolerance to the dipsogenic effect of the drug was observed. Upon withdrawal of the drug from these animals, and also upon withdrawal of a group given drug for 14 days, the rats consumed less water than a saline control group for several days. This was later interpreted as the development of a hypersensitivity to the dipsogenic effect after a 15 day phenobarbital treatment and a 10 day withdrawal [19]. As evidence of hypersensitivity the authors cited the fact that the response to the second phenobarbital treatment, that is, after 15 days treatment and 10 days withdrawal, was greater than the initial response to the same dose. The present paper reports on the effects of chronic daily dosage of barbital on the fluid intake of rats with restricted or unlimited access to water. MATERIALS AND METHOD Adult ( 2 8 0 - 2 9 0 g) male, Sprague-Dawley rats (Murphy Breeding Laboratories, Plainfield, Indiana) were used in all experiments. The animals were maintained on tap water

1Supported in part by USPHS Grants MH-18852 and KO2-MH-41083 and by NASA Grant NGL 15-003-117. 2Taken in part from a thesis submitted by Greg J. Maloney for the M.S. degree in Pharmacology, Indiana University, 1972. 431

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FIG. 1. Effects of barbital on fluid consumption-unrestricted intake. Each symbol is the mean of values obtained from 8 rats as described in Materials and Method. Vertical bars indicate 1 S.D. Solid circles indicate days of dosage with barbital (80 mg/kg, i.p.); open circles are placebo dosage.

water intake. The schedule for drug studies was arranged so that the rats were run daily. Water intake was recorded at 15, 30, and 60 rain of the consummatory sessions, the greatest proportion of drinking occurred in the first 15 min in all cases. Barbital sodium was used in all experiments, dosages are reported as weight of barbital administered in mg/kg body weight. Groups of 8 rats were run in each test system; data are reported as mean -+ S.D. RESULTS

Effect of Chronic Daily Dosage of Barbital on Fluid Consumption of Rats with Unlimited Volume Available As shown in Fig. l, chronic barbital (80 mg/kg, i.p.) increased daily fluid consumption above baseline for the duration of drug administration. There is a trend suggesting development of tolerance to the dipsogenic effect over the

14 days of drug t.reatment, seen when consummatory volume was plotted as ml/100 g body weight. The animals gained an average of 100 g of body weight during the course of this experiment. Substitution of saline for barbital resulted in a decrease in fluid consumption on the second day after drug withdrawal with a return to normal on the third and subsequent days. A weight loss of 18 g was also observed during this withdrawal period. Of particular interest is the fact that administration of a single dose of barbital on the ninth day after drug withdrawal (Day 33) gave a normal dipsogenic response (Table 1).

Effect of Chronic Daily Dosage of Barbital on Fluid Consumption of Rats with Limited Volume Available Figure 2 shows the effect of limiting fluid intake during the drug treatment period of 14 ml/rat/day. Here, overdrinking and the weight gain during the drug period are

DIPSOGENIC ACTIONS OF BARBITAL

433

TABLE 1

p r e v e n t e d w i t h t h e r e s u l t t h a t n o w t h e r e is n o w i t h d r a w a l d e c r e a s e in fluid i n t a k e n o r w e i g h t loss. T h e p e r i o d o f w i t h d r a w a l s h o w s a s i g n i f i c a n t l y g r e a t e r fluid i n t a k e b y t h e animals.

DIPSOGENIC EFFECTS OF BARBITAL BEFORE AND AFTER CHRONIC TREATMENT

DISCUSSION

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F r o m a c o n s i d e r a t i o n o f t h e d a t a p r e s e n t e d in t h i s p a p e r , it s e e m s likely t h a t t h e earlier w o r k o f S c h m i d t a n d cow o r k e r s [ 1 6 , 18, 19] s u f f e r s f r o m several d e f e c t s . First, n o r e c o g n i t i o n was m a d e o f t h e large w e i g h t g a i n d u r i n g t h e p e r i o d o f t h e s t u d y . It is p o s s i b l e t h a t t h e i n c r e a s e d i n t a k e a t t r i b u t e d t o h y p e r s e n s i t i v i t y a f t e r a p e r i o d o f d r u g trials [ 1 9 ] m a y m e r e l y reflect t h e fact t h a t h e a v i e r a n i m a l s c o n s u m e m o r e fluid. W h e n fluid c o n s u m p t i o n b y o u r a n i m a l s is e x p r e s s e d in m l c o n s u m e d / 1 0 0 g b o d y w e i g h t , t h e daily i n t a k e d e c r e a s e s slightly o v e r t h e d r u g p e r i o d o f 14 d a y s . A t r a n s i e n t w e i g h t loss a n d d e c r e a s e in fluid c o n s u m p t i o n are p r e s e n t d u r i n g t h e w i t h d r a w a l p e r i o d as p r e v i o u s l y r e p o r t e d by others [14,15]. S c h m i d t e t al. [ 12,15] also c o n s i d e r e d t h e c h r o n i c overh y d r a t i o n o f t h e a n i m a l s d u r i n g t h e d r u g p e r i o d as i n c o n s e -

Data are presented as volume consumed by 8 animals. Barbital (80 mg/kg, i.p.) was given as described in Materials and Methods. *mean -+ S.D. of 8 animals per day for number of days indicated t m e a n ± S.D. of 8 animals on a single day

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quential to the characteristics of the withdrawal state. In the present study, w h e n o v e r h y d r a t i o n was prevented, the decrease in fluid c o n s u m p t i o n and b o d y weight during withdrawal did not occur. The increase in fluid intake over baseline on the first day of withdrawal m a y reflect the presence of barbital in the animal since the drug is not appreciably m e t a b o l i z e d and is e x c r e t e d slowly [ 6 ] . It is unlikely, however, that this drug carryover w o u l d explain the increased c o n s u m p t i o n on subsequent days. It is reasonable, in light of the changes in n e u r o s e c r e t o r y material in the n e u r o h y p o p h y s e a l system during overhydration [ 1 ], that prolonged o v e r h y d r a t i o n in itself could lead to a decrease in fluid c o n s u m p t i o n u p o n removal of the stimulus for overdrinking. The animal is in a state of positive water balance and will restore his fluid balance by consuming less fluid. The post-drug weight loss appears directly related to the decrease in fluid c o n s u m p t i o n since the animals did not lose weight if t h e y were prevented from overdrinking prior to withdrawal. The dipsogenic response during the post-drug t r e a t m e n t period by the limitedv o l u m e animals m a y reflect an alteration in fluid balance systems induced by the drug t r e a t m e n t . A direct central action u p o n neurons involved in the regulation of water balance m a y cause the dipsogenic effect by depression of inhibiting centers. Animals with lesions in the septal area and in the anterior h y p o t h a l a m u s show an increased fluid c o n s u m p t i o n [ 2 , 1 0 ] . These drug effects

could be due to chemical lesions via a depression of the septal area or h y p o t h a l a m u s . Interference with the hypothalamus n e u r o h y p o p h y s e a l system may also be involved in the dipsogenic action. Barbiturates are k n o w n to release A D H from the posterior pituitary [ 3 ] . The depression of o s m o r e c e p t o r cells in the CNS, possibly those near the A D H secreting neurons, may alter an animals p r e c e p t i o n of his actual state of h y d r a t i o n and cause him to c o n t i n u e drinking longer than usual. The c o n s u m m a t o r y act itself may b e c o m e pleasurable if the drug has depressed inhibitory brain areas. In the rat satiation precedes restoration of the osmotic imbalance and comes about via impulses from nerves in the oral cavity traveling along cranial nerves to brain regions involved in fluid c o n s u m p t i o n [ 4 ] . If drugs were to interfere with the transmission of i n f o r m a t i o n as to the nature and a m o u n t of the fluid the rat is consuming, the animal might ingest larger a m o u n t s or cease earlier depending on the nature of the interference. Evidence for the involvem e n t of the peripheral nervous system [5] suggests that depression of these neurons may interfere with the regulation of fluid intake. A n o t h e r peripheral action could be drug interaction with the renin-angiotensin system. The release of ADH by barbiturates could also be a manifestation of the mediation of angiotensin since angiotensin itself releases A D H [8].

REFERENCES

1. Andersson, B. The effect of long term periods of continuous hydration on the neurosecretory material in the hypothalamus of the dog. Endocrinology 15: 332-338, 1957. 2. Blass, E. M. and D. Hanson. Primary hyperdipsia in the rat following septal lesions. J. comp. physiol. Psychol. 70: 87-93, 1970. 3. Bodo, R. L. and K. F. Prescott. The antidiuretic action of barbiturates and the mechanism involved in this action. Pharrnac. exp. Ther. 229: 223-233, 1945. 4. Deutsch, J. A. Hunger and thirst. In: Physiological Psychology, edited by J. A. Deutsch and D. Deutsch. Homewood, II1.: Dorsey Press, 1966. 5. Gerald, M. C. and R. P. Maickel. Evidence for peripheral cholinergic components in thirst-induced water consumption. Int. J. Neuropharm. 8: 337-346, 1969. 6. Maickel, R. P. and G. J. Maloney. Effect of barbital on deprivation-induced water consumption by rats. Physiol. Behav. 8: 1175-1178, 1972. 7. Maickel, R. P. and G. J. Maloney. Effects of various depressant drugs on deprivation-induced water consumption. Neuropharmac. 12: 777-782, 1973. 8. Malvin, R. Possible role of the renin angiotensin system in regulation of antidiuretic hormone secretion. Fedn Proc. 30: 1387-1394, 1971. 9. Maynert, E. W. and H. B. van Dyke. The metabolism of barbiturates. Pharmac. Rev. 1:217-242, 1949.

10. Richter, C. F. and J. F. Eckert. Further evidence for the primary of polydipsia in diabetes insipidus. Am. J. Physiol. 113" 578-581, t935. 11. Schmidt, H., Jr. Pentobarbital facilitation of water ingestion in the albino rat. J. cornp, physiol. Psychol. 51: 26-28, 1958. 12. Schmidt, H., Jr. Variations of water ingestion: The response to barbiturates. Prog. Brain Res. 16: 263-284, 1965. 13. Schmidt, H., Jr. Alterations of central thirst mechanisms by drugs. Ann. N. Y. Acad. Sci. 157" 962-976, 1969. 14. Schmidt, H., Jr. and L. Dry. Comparison of phenobarbital and pentobarbital actions upon water ingestion. J. comp. physiol. Psychol. 56: 179-182, 1963. 15. Schmidt, H., Jr. and L. Dry. Dose and time as variables in barbiturate action upon water ingestion. Am. J. Physiol. 204: 817-820, 1963. 16. Schmidt, H. and K. Kleinman. Effects of chronic administration and withdrawal of barbiturates upon drinking in the rat. Archs int. Pharmacodyn. Ther. 151: 142-149, 1964. 17. Schmidt, H., Jr. and S. J. Moak. Some drug effects influencing barbiturate facilitation of water ingestion. Am. J. Physiol. 196: 307-310, 1959. 18. Schmidt, H., K. Kleinman and T. Douthitt. Enhancement of the drinking response to phenobarbital after a previous course of barbiturates. Physiol. Behav. 2: 265-271, 1967. 19. Schmidt, H., K. Skinner and K. Kleinman. Phenobarbital withdrawal weight loss is in part independent of ingestion. Archs int. Pharmacodyn. Ther. 160: 241-247, 1966.