Ah'ohol. Vol 8. pp. 137-141. e PergamonPresspk:, 1991. Printed in the U.S.A.
0741-8329/91 $3.00 + .00
Hypothalamic Monoamines and Food Intake in Alcohol-Preferring AA and Alcohol-Avoiding ANA Rats E. R. KORPI,* P. P,~IV,~RINTA,* B. S J O H O L M ' t A N D M. K O U L U ' t
*Research Laboratories, Alko Ltd., P.O.B. 350, SF-O0101, Helsinki, Finland ~'Department o f Pharmacology, Unit,ersita' o f Turku, SF-20520 Turku, Finland R e c e i v e d 30 July 1990; A c c e p t e d 22 O c t o b e r 1990
KORPI, E. R., P. PAIV,~RINTA. B. sJOHOLM AND M. KOULU. Hypothalamic numoamines and food intake in alcohol-preferring AA and alcohol-avoiding ANA rats. ALCOHOL 8(21 137-141, 1991.--The concentrations and synthesis of monoamines in various hypothalamic nuclei and the influence of monoaminergic drugs on food intake were studied in two rat lines produced by selective outbreeding for voluntary high and low alcohol drinking. The hypothalamic nuclei of the alcohol-preferring AA rats contained slightly more serotonin than those of the alcohol-avoiding ANA rats. but the accumulation of 5-hydroxytryptophan after inhibition of aromatic amino acid decarboxylase was the same in both lines. There was no significant difference in the basal concentrations of catecholamines between the lines, but the accumulation of L-DOPA was significantly greater in the ANA than the AA rats, suggesting differences in catecholamine turnover. This difference was significant in the paraventricular nucleus, which is involved in the regulation of food intake. Clonidine (an c~2-agonist) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HTIA agonist) induced hyperphagia and 1-13-trifluoromethylphenyl)piperazine (TFMPP, a 5-HTIB agonist) induced hypophagia dose-dependently in both rat lines. Clonidine tended to be more potent in the ANA than the AA rats. Food intake lbllowing a 20-h fast was significantly lower in the ANA than AA rats. These results suggest that the alcohol-avoiding ANA and alcohol-preferring AA rats have different hypothalamic monoamine mechanisms controlling food intake, which could also partially account for their differential alcohol acceptance. Selected rat lines Hypothalamus Alcohol preference 8-OH-DPAT Tk-'MPP Hypophagia Hyperphagia
Serotonin
Dopamine
Norepinephrine
Clonidine
enhancement of the dopaminergic system by alcohol may be associated with the psychomotor-stimulating effects of alcohol (7). At least under some conditions, acute alcohol administration can decrease serotonergic activity (291 and enhance the activity of noradrenergic mechanisms (311. Voluntary alcohol consumption in rats can be influenced by drugs that act on these monoaminergic mechanisms (4, 26, 32). Thus, monoaminergic mechanisms seem to be of importance in both alcohol drinking and food intake. Mechanisms of alcohol drinking can be studied in several rodent line pairs developed for differences in alcohol acceptance (10, 24, 25). Our studies on the alcohol-preferring AA and alcohol-avoiding ANA rats, developed by selective breeding (10), have suggested that, while the AA rats consume alcohol for its reinforcing effects (30), the ANA rats do not because of their aversiveness to the acetaldehyde accumulation after alcohol intake (8). These explanations, however, just begin to reveal the regulatory factors involved in voluntary alcohol drinking. We do. not know to what extent alcohol is consumed by AA rats for its
ALCOHOL abuse and eating disorders have been considered to be very similar syndromes or "'two sides of the same coin" (5,33) and, therefore, they might be based on some common abnormalities in central nervous system function. Normal eating behavior seems to be under complex hypothalamic control, involving, among other neurotransmitters and neuromodulators, the monoamines. There exists an interaction between noradrenergic and serotonergic systems, especially in the paraventricular nucleus (PVN), wherein these systems act antagonistically on the regulation of food intake [see (23)]. Local injection of norepinephrine into the PVN elicits a feeding response via et,,-adrenoceptors (221, while the introduction of serotonin decreases food intake (28). Agonists of postsynaptic 5-HTIB receptors duplicate this decrease, while 5-HTIA autoreceptor agonists cause an increase in food intake, probably by blocking serotonergic neurotransmission (14,15). Central regulation of voluntary alcohol drinking is poorly understood, but monoamines have been implicated in many of the behavioral effects of alcohol [see (6,18)]. For example, functional
137
138
KORPI ET AL.
~" ..c
6
>., "o45 o ..o
concentrations of hypothalamic monoamines between alcohol-naive AA and ANA rats (2, 3, 20). The concentrations of serotonin and norepinephrine are higher and that of dopanfine lower in whole hypothalami from alcohol-preferring AA rats than from alcoholavoiding ANA rats (201. The food intake of the AA and ANA rats has not been studied pharmacologically. Our present efforts were aimed at characterizing our rat lines more profoundly by studying the concentrations and synthesis of monoamines in various hypothalamic nuclei, and by studying the effects of some highly selective monoaminergic drugs, administered systemically. on food intake.
~ ] ANA
.-~ 5.5 5
I-:-I AA
i_
4
i
I
~3.5
~_ 3 c~ 2.5 c
~ 2 N 1.5 8 ii
05
METHOD
0
Saline
15
30
60
Animals
Dose of clonidine 0.tg/kg, IP)
~ r-
6
•03 ~ 5.5 ~: 5
Altogether 28 adult male AA and 28 adult male ANA rats, alcohol- and drug-naive at the beginning of the experiments, were used. The rats were maintained on a 12/12 h light/dark cycle (lights on at 6:00 a.m.) in an ambient temperature of 2 2 ± 2 ° C and a relative humidity of 50--- 5%. They had free access to powdered R3 rodent food (Ewos AB, S6derttilje. Sweden) and tap water. All experimental procedures were conducted between 10:00 a.m. and 1:00 p.m.
[] ANA r~AA
"~ 4 5 4
¢~
3
Measurement of Monoamines in Hypothalamic Nuclei
o4 2 5
~
2 ~.5
'-i
1
1:3 o 0.5 LI0
Saline
IO0
200
500
Dose of 8 - O H - D P A T (lag/kg, IP) []
c-
ANA
[ ] AA ~'24
.='J.
_8 B~ ~16 tr-12 QI f"10 0 0 I.L
4 0
**°
Saline 1 2 Dose of T F M P P (mg/kg, IP)
.--/5 5
FIG. 1. Clonidine- and 8-OH-DPAT-induced hyperphagia and TFMPPinduced hypophagia in AA and ANA rats. Columns are means, with bars depicting the SEMs, of 12 animals from both rat lines. The significance of the difference from saline treatment (Fisher LSD-test): *p
0741-8329/91 $3.00 + .00
Hypothalamic Monoamines and Food Intake in Alcohol-Preferring AA and Alcohol-Avoiding ANA Rats E. R. KORPI,* P. P,~IV,~RINTA,* B. S J O H O L M ' t A N D M. K O U L U ' t
*Research Laboratories, Alko Ltd., P.O.B. 350, SF-O0101, Helsinki, Finland ~'Department o f Pharmacology, Unit,ersita' o f Turku, SF-20520 Turku, Finland R e c e i v e d 30 July 1990; A c c e p t e d 22 O c t o b e r 1990
KORPI, E. R., P. PAIV,~RINTA. B. sJOHOLM AND M. KOULU. Hypothalamic numoamines and food intake in alcohol-preferring AA and alcohol-avoiding ANA rats. ALCOHOL 8(21 137-141, 1991.--The concentrations and synthesis of monoamines in various hypothalamic nuclei and the influence of monoaminergic drugs on food intake were studied in two rat lines produced by selective outbreeding for voluntary high and low alcohol drinking. The hypothalamic nuclei of the alcohol-preferring AA rats contained slightly more serotonin than those of the alcohol-avoiding ANA rats. but the accumulation of 5-hydroxytryptophan after inhibition of aromatic amino acid decarboxylase was the same in both lines. There was no significant difference in the basal concentrations of catecholamines between the lines, but the accumulation of L-DOPA was significantly greater in the ANA than the AA rats, suggesting differences in catecholamine turnover. This difference was significant in the paraventricular nucleus, which is involved in the regulation of food intake. Clonidine (an c~2-agonist) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HTIA agonist) induced hyperphagia and 1-13-trifluoromethylphenyl)piperazine (TFMPP, a 5-HTIB agonist) induced hypophagia dose-dependently in both rat lines. Clonidine tended to be more potent in the ANA than the AA rats. Food intake lbllowing a 20-h fast was significantly lower in the ANA than AA rats. These results suggest that the alcohol-avoiding ANA and alcohol-preferring AA rats have different hypothalamic monoamine mechanisms controlling food intake, which could also partially account for their differential alcohol acceptance. Selected rat lines Hypothalamus Alcohol preference 8-OH-DPAT Tk-'MPP Hypophagia Hyperphagia
Serotonin
Dopamine
Norepinephrine
Clonidine
enhancement of the dopaminergic system by alcohol may be associated with the psychomotor-stimulating effects of alcohol (7). At least under some conditions, acute alcohol administration can decrease serotonergic activity (291 and enhance the activity of noradrenergic mechanisms (311. Voluntary alcohol consumption in rats can be influenced by drugs that act on these monoaminergic mechanisms (4, 26, 32). Thus, monoaminergic mechanisms seem to be of importance in both alcohol drinking and food intake. Mechanisms of alcohol drinking can be studied in several rodent line pairs developed for differences in alcohol acceptance (10, 24, 25). Our studies on the alcohol-preferring AA and alcohol-avoiding ANA rats, developed by selective breeding (10), have suggested that, while the AA rats consume alcohol for its reinforcing effects (30), the ANA rats do not because of their aversiveness to the acetaldehyde accumulation after alcohol intake (8). These explanations, however, just begin to reveal the regulatory factors involved in voluntary alcohol drinking. We do. not know to what extent alcohol is consumed by AA rats for its
ALCOHOL abuse and eating disorders have been considered to be very similar syndromes or "'two sides of the same coin" (5,33) and, therefore, they might be based on some common abnormalities in central nervous system function. Normal eating behavior seems to be under complex hypothalamic control, involving, among other neurotransmitters and neuromodulators, the monoamines. There exists an interaction between noradrenergic and serotonergic systems, especially in the paraventricular nucleus (PVN), wherein these systems act antagonistically on the regulation of food intake [see (23)]. Local injection of norepinephrine into the PVN elicits a feeding response via et,,-adrenoceptors (221, while the introduction of serotonin decreases food intake (28). Agonists of postsynaptic 5-HTIB receptors duplicate this decrease, while 5-HTIA autoreceptor agonists cause an increase in food intake, probably by blocking serotonergic neurotransmission (14,15). Central regulation of voluntary alcohol drinking is poorly understood, but monoamines have been implicated in many of the behavioral effects of alcohol [see (6,18)]. For example, functional
137
138
KORPI ET AL.
~" ..c
6
>., "o45 o ..o
concentrations of hypothalamic monoamines between alcohol-naive AA and ANA rats (2, 3, 20). The concentrations of serotonin and norepinephrine are higher and that of dopanfine lower in whole hypothalami from alcohol-preferring AA rats than from alcoholavoiding ANA rats (201. The food intake of the AA and ANA rats has not been studied pharmacologically. Our present efforts were aimed at characterizing our rat lines more profoundly by studying the concentrations and synthesis of monoamines in various hypothalamic nuclei, and by studying the effects of some highly selective monoaminergic drugs, administered systemically. on food intake.
~ ] ANA
.-~ 5.5 5
I-:-I AA
i_
4
i
I
~3.5
~_ 3 c~ 2.5 c
~ 2 N 1.5 8 ii
05
METHOD
0
Saline
15
30
60
Animals
Dose of clonidine 0.tg/kg, IP)
~ r-
6
•03 ~ 5.5 ~: 5
Altogether 28 adult male AA and 28 adult male ANA rats, alcohol- and drug-naive at the beginning of the experiments, were used. The rats were maintained on a 12/12 h light/dark cycle (lights on at 6:00 a.m.) in an ambient temperature of 2 2 ± 2 ° C and a relative humidity of 50--- 5%. They had free access to powdered R3 rodent food (Ewos AB, S6derttilje. Sweden) and tap water. All experimental procedures were conducted between 10:00 a.m. and 1:00 p.m.
[] ANA r~AA
"~ 4 5 4
¢~
3
Measurement of Monoamines in Hypothalamic Nuclei
o4 2 5
~
2 ~.5
'-i
1
1:3 o 0.5 LI0
Saline
IO0
200
500
Dose of 8 - O H - D P A T (lag/kg, IP) []
c-
ANA
[ ] AA ~'24
.='J.
_8 B~ ~16 tr-12 QI f"10 0 0 I.L
4 0
**°
Saline 1 2 Dose of T F M P P (mg/kg, IP)
.--/5 5
FIG. 1. Clonidine- and 8-OH-DPAT-induced hyperphagia and TFMPPinduced hypophagia in AA and ANA rats. Columns are means, with bars depicting the SEMs, of 12 animals from both rat lines. The significance of the difference from saline treatment (Fisher LSD-test): *p
