Psychopharmacology
Psychopharmacology 58, 317-322 (1978)
.9 by Springer-Verlag 1978
Lithium Effects on Rat Brain Glucose Metabolism in Long-Term Lithium-Treated Rats Studied in vivo Per Plenge Psykokemisk Institut, KCbenhavns Universitet, Rigshospitalet, Blesdamsvej 9, DK-2100 K0benhavn O. Denmark
Abstract. The time course o f lithium effects on several b r a i n energy m e t a b o l i t e s has been investigated in rats. The rats were injected once daily with lithium chloride a n d killed by freezing in liquid nitrogen 1 - 8 h after the last injection. T h e effect o f lithium was m o s t m a r k e d in the p e r i o d in which the b r a i n lithium c o n c e n t r a t i o n was increasing, whereas the effect was wearing off when the brain lithium c o n c e n t r a t i o n h a d stabilized, even t h o u g h the lithium c o n c e n t r a t i o n was higher. These results led to the h y p o t h e s i s t h a t the effect o f lithium o n several p a r a m e t e r s d e p e n d s on the increase in lithium c o n c e n t r a t i o n following the a d m i n i s t r a t i o n o f lithium, r a t h e r t h a n on the a b s o l u t e c o n c e n t r a t i o n o f lithium.
Key words: Brain - L i t h i u m - G l u c o s e - Glycolysis -
K r e b s cycle -
Metabolism
In the present study l o n g - t e r m l i t h i u m - t r e a t e d rats were used. The lithium was a d m i n i s t e r e d in one daily i n t r a p e r i t o n e a l injection. The brain c o n c e n t r a t i o n s o f glucose, glucose-6-phosphate, f r u c t o s e - l , 6 - d i p h o s phate, lactate, glycogen, 6 - p h o s p h o g l u c o n a t e , malate, citrate, c~-ketoglutarate, a n d g l u t a m a t e were m e a s u r e d at different times after the last injection o f lithium. F u r t h e r was the labelling o f glycogen, lactate, and g l u t a m a t e together with the u p t a k e o f 14C in whole b r a i n m e a s u r e d after a d m i n i s t r a t i o n o f r a d i o a c t i v e glucose. Investigation o f the p a r a m e t e r s at different times after the a d m i n i s t r a t i o n o f lithium indicated t h a t most o f t h e effects o f lithium on the a b o v e - m e n t i o n e d p a r a m e t e r s d e p e n d e d on the changes r a t h e r than on the a b s o l u t e c o n c e n t r a t i o n o f the b r a i n - l i t h i u m concentration.
Materials and Methods In r e p o r t s on v a r i o u s aspects o f the p h a r m a c o l o g i c a l effects o f lithium in rats, i.e., on kidney water a b s o r p tion, b r a i n d o p a m i n e , a n d b r a i n serotonin metabolism (Olesen et al., 1976; Stefanini et al., 1976; K n a p p a n d M a n d e l l , 1975), it can be seen that the effect o f lithium is d e p e n d e n t on or e n c h a n c e d by p e a k values in the b o d y lithium c o n c e n t r a t i o n p r o d u c e d by injection o f lithium in c o n t r a s t to a d m i n i s t r a t i o n o f lithium with food. Also, in manic-depressive patients u n d e r g o i n g lithium t r e a t m e n t , some p h a r m a c o l o g i c a l effects seem to be c o n n e c t e d with the increase in serumlithium c o n c e n t r a t i o n following i n t a k e o f the daily dose o f lithium (Bech et al., 1976). This holds true for the decrease in serum p h o s p h a t e c o n c e n t r a t i o n ( M e l l e r u p et al., 1976) a n d for the increase in glucose tolerance (Vendsborg, u n p u b l i s h e d d a t a ) following i n t a k e o f a n o r m a l dose o f lithium in patients on p r o p h y l a c t i c lithium treatment.
Female Wistar rats, weighing about 100g at the start of the experiment, were used. The rats were injected i.p. once daily in the morning for 15 days with 400 ~tmoles (2 ml of a 0.2 M solution) of either NaC1 or LiCI. The rats had free access to food (rat pellets, K.F.K., Copenhagen) and 50 mM NaC1. The latter was given instead of tap water to ensure that the rats were not sodium deficient, as this is known to increase the toxicity of lithium (Thomsen, 1973). After polyuria had developed, 3 - 4 days after the start of injections, gratings were placed in the cages, and the bedding was changed every day (Plenge et al., 1973), thus keeping the rats from getting wet from the urine. Using this procedure, the lithium-treated rats increased their weight more than the control rats. Control rats averaged 3.76 g/day, lithium-treated rats 4.37 g/day (P < 0.001, paired t-test). At time intervals of 1 - 8 h after the last injection of NaCl or LiC1 the rats were killed by immersion in liquid nitrogen. Four, 8, or 12rain before freezing the rats were injected i.p. with 1 ml of a solution containing 10~Ci U-14C r~-glucose (NEN) in 154mM NaCI, 1 mM D-glucose. As previously described (Plenge, 1976), the i.p. administration of radioactive glucose in a volume of 1 ml physiological saline containing 1 mM glucose will give a rather constant specific activity of blood glucose over the first 12 min after
0033-3158/78/005.8/0317/$1.20
318
Psychopharmacology 58 (1978)
Lithium(mmot/kg)
BRAINMETABOLITES
2st
% of control 140-T
,2~t
Psychopharmacology 58, 317-322 (1978)
.9 by Springer-Verlag 1978
Lithium Effects on Rat Brain Glucose Metabolism in Long-Term Lithium-Treated Rats Studied in vivo Per Plenge Psykokemisk Institut, KCbenhavns Universitet, Rigshospitalet, Blesdamsvej 9, DK-2100 K0benhavn O. Denmark
Abstract. The time course o f lithium effects on several b r a i n energy m e t a b o l i t e s has been investigated in rats. The rats were injected once daily with lithium chloride a n d killed by freezing in liquid nitrogen 1 - 8 h after the last injection. T h e effect o f lithium was m o s t m a r k e d in the p e r i o d in which the b r a i n lithium c o n c e n t r a t i o n was increasing, whereas the effect was wearing off when the brain lithium c o n c e n t r a t i o n h a d stabilized, even t h o u g h the lithium c o n c e n t r a t i o n was higher. These results led to the h y p o t h e s i s t h a t the effect o f lithium o n several p a r a m e t e r s d e p e n d s on the increase in lithium c o n c e n t r a t i o n following the a d m i n i s t r a t i o n o f lithium, r a t h e r t h a n on the a b s o l u t e c o n c e n t r a t i o n o f lithium.
Key words: Brain - L i t h i u m - G l u c o s e - Glycolysis -
K r e b s cycle -
Metabolism
In the present study l o n g - t e r m l i t h i u m - t r e a t e d rats were used. The lithium was a d m i n i s t e r e d in one daily i n t r a p e r i t o n e a l injection. The brain c o n c e n t r a t i o n s o f glucose, glucose-6-phosphate, f r u c t o s e - l , 6 - d i p h o s phate, lactate, glycogen, 6 - p h o s p h o g l u c o n a t e , malate, citrate, c~-ketoglutarate, a n d g l u t a m a t e were m e a s u r e d at different times after the last injection o f lithium. F u r t h e r was the labelling o f glycogen, lactate, and g l u t a m a t e together with the u p t a k e o f 14C in whole b r a i n m e a s u r e d after a d m i n i s t r a t i o n o f r a d i o a c t i v e glucose. Investigation o f the p a r a m e t e r s at different times after the a d m i n i s t r a t i o n o f lithium indicated t h a t most o f t h e effects o f lithium on the a b o v e - m e n t i o n e d p a r a m e t e r s d e p e n d e d on the changes r a t h e r than on the a b s o l u t e c o n c e n t r a t i o n o f the b r a i n - l i t h i u m concentration.
Materials and Methods In r e p o r t s on v a r i o u s aspects o f the p h a r m a c o l o g i c a l effects o f lithium in rats, i.e., on kidney water a b s o r p tion, b r a i n d o p a m i n e , a n d b r a i n serotonin metabolism (Olesen et al., 1976; Stefanini et al., 1976; K n a p p a n d M a n d e l l , 1975), it can be seen that the effect o f lithium is d e p e n d e n t on or e n c h a n c e d by p e a k values in the b o d y lithium c o n c e n t r a t i o n p r o d u c e d by injection o f lithium in c o n t r a s t to a d m i n i s t r a t i o n o f lithium with food. Also, in manic-depressive patients u n d e r g o i n g lithium t r e a t m e n t , some p h a r m a c o l o g i c a l effects seem to be c o n n e c t e d with the increase in serumlithium c o n c e n t r a t i o n following i n t a k e o f the daily dose o f lithium (Bech et al., 1976). This holds true for the decrease in serum p h o s p h a t e c o n c e n t r a t i o n ( M e l l e r u p et al., 1976) a n d for the increase in glucose tolerance (Vendsborg, u n p u b l i s h e d d a t a ) following i n t a k e o f a n o r m a l dose o f lithium in patients on p r o p h y l a c t i c lithium treatment.
Female Wistar rats, weighing about 100g at the start of the experiment, were used. The rats were injected i.p. once daily in the morning for 15 days with 400 ~tmoles (2 ml of a 0.2 M solution) of either NaC1 or LiCI. The rats had free access to food (rat pellets, K.F.K., Copenhagen) and 50 mM NaC1. The latter was given instead of tap water to ensure that the rats were not sodium deficient, as this is known to increase the toxicity of lithium (Thomsen, 1973). After polyuria had developed, 3 - 4 days after the start of injections, gratings were placed in the cages, and the bedding was changed every day (Plenge et al., 1973), thus keeping the rats from getting wet from the urine. Using this procedure, the lithium-treated rats increased their weight more than the control rats. Control rats averaged 3.76 g/day, lithium-treated rats 4.37 g/day (P < 0.001, paired t-test). At time intervals of 1 - 8 h after the last injection of NaCl or LiC1 the rats were killed by immersion in liquid nitrogen. Four, 8, or 12rain before freezing the rats were injected i.p. with 1 ml of a solution containing 10~Ci U-14C r~-glucose (NEN) in 154mM NaCI, 1 mM D-glucose. As previously described (Plenge, 1976), the i.p. administration of radioactive glucose in a volume of 1 ml physiological saline containing 1 mM glucose will give a rather constant specific activity of blood glucose over the first 12 min after
0033-3158/78/005.8/0317/$1.20
318
Psychopharmacology 58 (1978)
Lithium(mmot/kg)
BRAINMETABOLITES
2st
% of control 140-T
,2~t
