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Neurochemical correlate of body weight in rats
Brain Research, 96 (1975) 153-155 © Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
153
Neurochemical correlate of body weight in rats
STANLEY D. GLICK AND MICHAEL E. STANLEY Department of Pharmacology, Mount Sinai School of Medicine, City University of New York, New York, N.Y. 10029 (U.S.A.)
(Accepted May 27th, 1975)
In recent years, there has been a great deal of interest and research in the neural and neurochemical determinants of feeding behavior and body weight regulation. Many studies have been concerned with correlating the effects of brain lesions (e.g. refs. 4, 8 and 10) or drug treatments (e.g. refs. 2, 15 and 16) on feeding behavior with their effects on brain levels of one or more putative neurotransmitters. Surprisingly, there has been little attempt to find correlations between feeding behavior and brain chemistry in normal animals. The present study began as such an attempt: a relationship between feeding behavior and brain levels of catecholamines in normal rats was sought. Although no simple relationship between chemical and behavioral measurements was found, a more complex but strikingly consistent correlation between body weight and an index of catecholamine balance was observed. The subjects were 22 naive female Sprague-Dawley rats. At the time rats were killed for the neurochemical determinations, 11 rats were approximately 100 days old and weighing ( i S.D.) 256.5 ± 17.6 g and the other 11 rats were approximately 135 days old and weighing ( ± S.D.) 323.5 ± 26.0 g. Prior to being killed, rats were housed individually and allowed to eat powdered food from jars 6 and drink water from graduated drinking tubes. A d libitum consumption of food and water as well as body weight were measured daily for each rat for at least 10 days before being killed. Rats were killed by decapitation, their brains were removed and the hypothalamus and corpus striatum were dissected. Each rat's striata were assayed for dopamine whereas the hypothalamus and the tel-diencephalon (excluding striata and hypothalamus) were assayed separately for norepinephrine by fluorometric methods 14. For the whole group of rats, mean values ( ± S.D.) for striatal dopamine, hypothalamic norepinephrine and tel-diencephalic norepinephrine were 7.49 :L 0.98 #g/g, 2.14 ± 0.37/zg/g and 0.349 ± 0.046 #g/g, respectively. Mean ( ± S.D.) food and water intakes for the 24 h prior to being killed were 23.5 ± 3.49 g and 40.0 ± 8.82 ml, respectively. Because the two subgroups of 11 rats differed in age and body weight, they were treated separately for the purpose of analyzing relationships between the chemical and behavioral measures. Regression correlation coefficients were computed for all combinations of each chemical and behavioral measure. The only significant (P < 0.05, t-test) correlation coefficient in both subgroups of rats was the relationship
154 between food and water intake (r -- +0.72 and +0.61 for the younger and older rats, respectively). Correlation coefficients were then computed for each of 3 indices of catecholamine balance (i.e. the quotient of one chemical level divided by another) versus each behavioral measure. The only significant (P < 0.05, t-test) correlation coefficient in both subgroups of rats was a relationship between body weight and the ratio of striatal dopamine to hypothalamic norepinephrine (r :: -~ 0.73 and + 0.63 for the younger and older rats, respectively). When both subgroups were considered together, this latter correlation coefficient was +0.84, significant well beyond a P value of 0.001 (t-test). The function relating body weight and the striatal-hypothalamic ratio does not appear to change with age: the slopes of the regression lines for the two subgroups of rats are not significantly different (P ~- 0.2, t-test). The serendipitous discovery that a balance between striatal dopamine and hypothalamic norepinephrine might be related to body weight prompted us to look for other available data which had not been previously analyzed in this fashion. Neurochemical and body weight data from 29 rats that had received only saline were found and analyzed (these rats were approximately 95 days old, weighing 246 ~_ 15.8 g and served as controls in other unrelated drug experiments). The only significant (P < 0.05, t test) correlation (r =- -50.64) was again the relationship between body weight and the same neurochemical balance (i.e. the ratio of striatal dopamine to hypothalamic norepinephrine). With the additional 29 rats added to the previous group of 22, the correlation coefficient for all 51 rats was +0.74, again significant well beyond a P value of 0.001 (t-test). The striatal-hypothalamic ratio appears to be a unique correlate of body weight which cannot be attributed to age and which is unrelated to acute consummatory activities. Although the present data are not definitive in this respect, it is likely that the ratio is an index of the set-point for body weight regulation. The importance of a striatal-hypothalamic balance for weight regulation is consistent with several other findings. Most notably, it is consistent with the observations that lesions which selectively damage noradrenergic pathways coursing through the hypothalamus result in obesity 1,3,a,7 whereas lesions which damage the dopaminergic nigro-striatal pathway result in subnormal body weight maintenanceg, la,t3. The present findings may help explain why decreases in body weight can sometimes not be related simply to depletion of striatal dopamine when the particular experimental treatment also produces even a small depletion of brain norepinephrinO 2. In view of the lack of a correlation between striatal dopamine and hypothalamic norepinephrine (r -- +0.21 for all 51 rats, P ~ 0.1), it would appear that the striatal-hypothalamic balance represents the operation of two antagonistic but separate systems. The present neurochemical correlate should facilitate study of the interactions of these systems. This research was supported by N I M H Grant MH25644 and N I M H Research Scientist Development Award (Type 2) DA70082 to S.D.G. We thank L. Manzino for his help in conducting the neurochemical assays.
155 1 AHLSKOG, D. J., AND I"IOEBEL,B. G., Overeating and obesity from damage to a noradrenergic system in the brain, Science, 182 (1973) 166-169. 2 FIaIGER, H. C., ZIS, A. P., AND MCGEER, E. G., Feeding and drinking deficits after 6-hydroxydopamine administration in the rat: similarities to the lateral hypothalamic syndrome, Brain Research, 55 (1973) 135-148. 3 GLICK,S. D., GREENSTEIN,S., AND WATERS, D. H., Ventromedial hypothalamic lesions and brain catecholamines, PharmacoL Biochem. Behav., 1 (1973) 591-592. 4 GLICK, S.D., GREENSTEIN,S., AND WATERS, D. H., Lateral hypothalamic lesions and striatal dopamine levels, Life Sci., 14 (1974) 747-750. 5 GOLD, R. M., Hypothalamic obesity: the myth of the ventromedial nucleus, Science, 182 (1973) 488-490. 6 JoY, R. T., EMMA, C. P., AND MAYER,J., New rat feeding jar: use in study of relationships of food intake and body weight, J. appl. PhysioL, 23 (1967 289-290. 7 KAPATOS,G., ANDGOLD, R. M., Evidence for ascending noradrenergic mediation of hypothalamic hyperphagia, Pharmacol. Biochem. Behav., 1 (1973) 81-87. 8 MARSHALL,J. F., RICHARDSON,J. S., AND TEITELBAUM,P., Nigro-striatal bundle damage and the lateral hypothalamic syndrome, J. comp. physiol., Psychol., 87 (1974)) 808-830. 9 MYERS, R. D., AND MARTIN,G. E., 6-OHDA lesions of the hypothalamus: interaction of aphagia, food palatability, set-point for weight regulation and recovery of feeding, Pharmacol. Biochem. Behav., 1 (1973) 329-345. 10 OLTMANS, G.A., AND HARVEY, J.A., LH syndromes and brain catecholamine levels after lesions of the nigro-striatal bundle, Physiol. Behav., 8 (1972) 69-78. l l POWLEY, T. L., AND KEESEY, R.E., Relationship of body weight to the lateral hypothalamic feeding syndrome, J. comp. physiol. Psychok 70 (1970) 25-36. 12 STR1CKER, E., AND ZIGMOND, M.J., Effects on homeostasis of intraventricular injections of 6hydroxydopamine in rats, J. comp. physiol. PsychoL, 86 (1974) 973-994. 13 UNGERSTEDT, U., Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system, Acta physiol, scand., Suppl. 367 (1971) 95-122. 14 WEIL-MALHERBE, H., The estimation of total (free + conjugated) catecholamines and some catecholamine metabolites in human urine, Meth. biochem. Anal., 16 (1968) 293-326. 15 ZIGMOND,M. J., AND STRICKER,E. M., Deficits in feeding behavior after intraventricular injection of 6-hydroxydopamine in rats, Science, 177 0972) 1211-1213. 16 ZIGMOND, M.J., AND STRICKER, E. M., Recovery of feeding and drinking by rats after intraventricular 6-hydroxydopamine or lateral hypothalamic lesions, Science, 182 (1973) 717-720.
153
Neurochemical correlate of body weight in rats
STANLEY D. GLICK AND MICHAEL E. STANLEY Department of Pharmacology, Mount Sinai School of Medicine, City University of New York, New York, N.Y. 10029 (U.S.A.)
(Accepted May 27th, 1975)
In recent years, there has been a great deal of interest and research in the neural and neurochemical determinants of feeding behavior and body weight regulation. Many studies have been concerned with correlating the effects of brain lesions (e.g. refs. 4, 8 and 10) or drug treatments (e.g. refs. 2, 15 and 16) on feeding behavior with their effects on brain levels of one or more putative neurotransmitters. Surprisingly, there has been little attempt to find correlations between feeding behavior and brain chemistry in normal animals. The present study began as such an attempt: a relationship between feeding behavior and brain levels of catecholamines in normal rats was sought. Although no simple relationship between chemical and behavioral measurements was found, a more complex but strikingly consistent correlation between body weight and an index of catecholamine balance was observed. The subjects were 22 naive female Sprague-Dawley rats. At the time rats were killed for the neurochemical determinations, 11 rats were approximately 100 days old and weighing ( i S.D.) 256.5 ± 17.6 g and the other 11 rats were approximately 135 days old and weighing ( ± S.D.) 323.5 ± 26.0 g. Prior to being killed, rats were housed individually and allowed to eat powdered food from jars 6 and drink water from graduated drinking tubes. A d libitum consumption of food and water as well as body weight were measured daily for each rat for at least 10 days before being killed. Rats were killed by decapitation, their brains were removed and the hypothalamus and corpus striatum were dissected. Each rat's striata were assayed for dopamine whereas the hypothalamus and the tel-diencephalon (excluding striata and hypothalamus) were assayed separately for norepinephrine by fluorometric methods 14. For the whole group of rats, mean values ( ± S.D.) for striatal dopamine, hypothalamic norepinephrine and tel-diencephalic norepinephrine were 7.49 :L 0.98 #g/g, 2.14 ± 0.37/zg/g and 0.349 ± 0.046 #g/g, respectively. Mean ( ± S.D.) food and water intakes for the 24 h prior to being killed were 23.5 ± 3.49 g and 40.0 ± 8.82 ml, respectively. Because the two subgroups of 11 rats differed in age and body weight, they were treated separately for the purpose of analyzing relationships between the chemical and behavioral measures. Regression correlation coefficients were computed for all combinations of each chemical and behavioral measure. The only significant (P < 0.05, t-test) correlation coefficient in both subgroups of rats was the relationship
154 between food and water intake (r -- +0.72 and +0.61 for the younger and older rats, respectively). Correlation coefficients were then computed for each of 3 indices of catecholamine balance (i.e. the quotient of one chemical level divided by another) versus each behavioral measure. The only significant (P < 0.05, t-test) correlation coefficient in both subgroups of rats was a relationship between body weight and the ratio of striatal dopamine to hypothalamic norepinephrine (r :: -~ 0.73 and + 0.63 for the younger and older rats, respectively). When both subgroups were considered together, this latter correlation coefficient was +0.84, significant well beyond a P value of 0.001 (t-test). The function relating body weight and the striatal-hypothalamic ratio does not appear to change with age: the slopes of the regression lines for the two subgroups of rats are not significantly different (P ~- 0.2, t-test). The serendipitous discovery that a balance between striatal dopamine and hypothalamic norepinephrine might be related to body weight prompted us to look for other available data which had not been previously analyzed in this fashion. Neurochemical and body weight data from 29 rats that had received only saline were found and analyzed (these rats were approximately 95 days old, weighing 246 ~_ 15.8 g and served as controls in other unrelated drug experiments). The only significant (P < 0.05, t test) correlation (r =- -50.64) was again the relationship between body weight and the same neurochemical balance (i.e. the ratio of striatal dopamine to hypothalamic norepinephrine). With the additional 29 rats added to the previous group of 22, the correlation coefficient for all 51 rats was +0.74, again significant well beyond a P value of 0.001 (t-test). The striatal-hypothalamic ratio appears to be a unique correlate of body weight which cannot be attributed to age and which is unrelated to acute consummatory activities. Although the present data are not definitive in this respect, it is likely that the ratio is an index of the set-point for body weight regulation. The importance of a striatal-hypothalamic balance for weight regulation is consistent with several other findings. Most notably, it is consistent with the observations that lesions which selectively damage noradrenergic pathways coursing through the hypothalamus result in obesity 1,3,a,7 whereas lesions which damage the dopaminergic nigro-striatal pathway result in subnormal body weight maintenanceg, la,t3. The present findings may help explain why decreases in body weight can sometimes not be related simply to depletion of striatal dopamine when the particular experimental treatment also produces even a small depletion of brain norepinephrinO 2. In view of the lack of a correlation between striatal dopamine and hypothalamic norepinephrine (r -- +0.21 for all 51 rats, P ~ 0.1), it would appear that the striatal-hypothalamic balance represents the operation of two antagonistic but separate systems. The present neurochemical correlate should facilitate study of the interactions of these systems. This research was supported by N I M H Grant MH25644 and N I M H Research Scientist Development Award (Type 2) DA70082 to S.D.G. We thank L. Manzino for his help in conducting the neurochemical assays.
155 1 AHLSKOG, D. J., AND I"IOEBEL,B. G., Overeating and obesity from damage to a noradrenergic system in the brain, Science, 182 (1973) 166-169. 2 FIaIGER, H. C., ZIS, A. P., AND MCGEER, E. G., Feeding and drinking deficits after 6-hydroxydopamine administration in the rat: similarities to the lateral hypothalamic syndrome, Brain Research, 55 (1973) 135-148. 3 GLICK,S. D., GREENSTEIN,S., AND WATERS, D. H., Ventromedial hypothalamic lesions and brain catecholamines, PharmacoL Biochem. Behav., 1 (1973) 591-592. 4 GLICK, S.D., GREENSTEIN,S., AND WATERS, D. H., Lateral hypothalamic lesions and striatal dopamine levels, Life Sci., 14 (1974) 747-750. 5 GOLD, R. M., Hypothalamic obesity: the myth of the ventromedial nucleus, Science, 182 (1973) 488-490. 6 JoY, R. T., EMMA, C. P., AND MAYER,J., New rat feeding jar: use in study of relationships of food intake and body weight, J. appl. PhysioL, 23 (1967 289-290. 7 KAPATOS,G., ANDGOLD, R. M., Evidence for ascending noradrenergic mediation of hypothalamic hyperphagia, Pharmacol. Biochem. Behav., 1 (1973) 81-87. 8 MARSHALL,J. F., RICHARDSON,J. S., AND TEITELBAUM,P., Nigro-striatal bundle damage and the lateral hypothalamic syndrome, J. comp. physiol., Psychol., 87 (1974)) 808-830. 9 MYERS, R. D., AND MARTIN,G. E., 6-OHDA lesions of the hypothalamus: interaction of aphagia, food palatability, set-point for weight regulation and recovery of feeding, Pharmacol. Biochem. Behav., 1 (1973) 329-345. 10 OLTMANS, G.A., AND HARVEY, J.A., LH syndromes and brain catecholamine levels after lesions of the nigro-striatal bundle, Physiol. Behav., 8 (1972) 69-78. l l POWLEY, T. L., AND KEESEY, R.E., Relationship of body weight to the lateral hypothalamic feeding syndrome, J. comp. physiol. Psychok 70 (1970) 25-36. 12 STR1CKER, E., AND ZIGMOND, M.J., Effects on homeostasis of intraventricular injections of 6hydroxydopamine in rats, J. comp. physiol. PsychoL, 86 (1974) 973-994. 13 UNGERSTEDT, U., Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system, Acta physiol, scand., Suppl. 367 (1971) 95-122. 14 WEIL-MALHERBE, H., The estimation of total (free + conjugated) catecholamines and some catecholamine metabolites in human urine, Meth. biochem. Anal., 16 (1968) 293-326. 15 ZIGMOND,M. J., AND STRICKER,E. M., Deficits in feeding behavior after intraventricular injection of 6-hydroxydopamine in rats, Science, 177 0972) 1211-1213. 16 ZIGMOND, M.J., AND STRICKER, E. M., Recovery of feeding and drinking by rats after intraventricular 6-hydroxydopamine or lateral hypothalamic lesions, Science, 182 (1973) 717-720.