Alcohol, Vol. 9, pp. 559-561, 1992
0741-8329/92 $5.00 + .00 Copyright©1992PergamonPress Ltd.
Printed in the U.S.A. All rights reserved.
Effect of Dexfenfluramine on Alcohol Intake in Alcohol-Preferring "P" Rats N E l L E. R O W L A N D I A N D K E N N E T H
R. M O R I A N
Department o f Psychology, University o f Florida, Gainesville, FL 32611 Received 18 F e b r u a r y 1992; A c c e p t e d 9 J u n e 1992 ROWLAND, N. E. AND K. R. MORIAN. Effect of dexfe~fluramine on alcohol intake in alcohol-preferring "P" rats. ALCOHOL 9(6) 559-561, 1992.--The intake of alcohol, in 2-h daily sessions, by the preferring (P) line of rats was reduced in a dose-related manner by acute subcutaneous (SC) administration of dexfenfluramine (DFEN). Ad lib intake of alcohol was reduced by chronic SC administration of DFEN. The effective doses and magnitude of effects of DFEN on alcohol intake are comparable to those previously reported for DFEN anorexia. Because DFEN anorexia is related to increased brain serotonin (5HT) activity, its effect on alcohol consumption may also be via 5HT. Dexfenfluramine
Ethanol
P rat
Serotonin
D E X F E N F L U R A M I N E (DFEN) is an appetite suppressant whose primary mode of action seems to be via increased synaptic concentrations of serotonin (5HT) in brain, achieved by a combination o f 5HT release and uptake inhibition (4,10). Increased brain 5HT activity is thought to suppress alcohol intake, in part because 5HT uptake inhibitors decrease alcohol consumption (2,3,5-7), and also because levels of 5HT are reduced in some brain areas of rats bred selected for high spontaneous ethanol preference ("P" rats) (5,12). Administration of racemic fenfluramine (30 rag/d) reduced alcohol intake of outbred rats by 66070 (8), but both the high dose of the drug and the use of the racemate (the L-enantiomer has effects on dopamine systems) will cause 5HT specificity of the agent to be lost, and thus will limit the interpretation of the data. A recent study (1) reported reduced ethanol intake in chickens given racemic fenfluramine with tryptophan, but there is no body of pharmacologic data with fenfluramine in this species for reference. In the present study, we use P rats consuming unsweetened alcohol to examine the acute and chronic effects of low, pharmacologically specific, doses of DFEN on ethanol intake. METHOD
Chow pellets were available ad lib. The rats were housed individually in standard suspended stainless-steel cages in a vivarium with lights on 0800-2000 h and at 23°C. All procedures and measures were carried out in the middle of the light period.
Experiment 1: Effect o f Acute DFEN on Scheduled Alcohol Intake The rats (mean body weight 456 g) were adapted to 2 h / d access to alcohol, presented in graduated 50-ml tubes, with food absent. Basal intakes were measured for several days prior to this study and the mean of the last 2 days used as baseline. On the first experimental day, 5 rats were injected with DFEN (0.5 mg/kg, SC) 30 min before scheduled access to alcohol, and the other 5 received 1 mg/kg DFEN. Alcohol intake was measured after 30 and 120 min (i.e., 60 and 150 rain after injection). Two days later, the rats received 1.5 or 2 mg/kg DFEN (the previous 0.5 and 1 mg/kg groups, respectively). The intakes after 30 and 120 rain were similar, and so only the 120-min data were formally analyzed, by ANOVA, for dose effects.
Animals and Housing
Experiment 2: Effect o f Chronic DFEN on A d Lib Alcohol Intake
Ten adult male P rats were generously donated by Dr. Lumeng from the Indiana University Medical School colony. These rats were about 4 months old and weighed 400-500 g during these studies. They had been exposed to 10070 ethanol solution (vol/vol) for 2 h / d for about 3 weeks prior to this study. Unless otherwise noted, tap water and Wayne Lab
The rats were than given continuous access to 10070alcohol, as well as food and water, and the 24-h intakes were recorded for l week. At the end of this period, when intakes were stable, the first 5 rats (those who had received the lower acute dosages of DFEN) were briefly anesthetized (Metofane) and received an osmotic minipump (Alzet Model 2001) SC between
I To whom requests for reprints should be addressed. 559
560
ROWLAND AND MORIAN
the shoulders (9,11). The pumps were loaded with a 60 mg D F E N / m l water solution, designed to deliver an average dose of 3 mg D F E N / k g per day for 7 days (mean b.w. 468 g). The other 5 rats received no minipump and served as controls. Intakes of alcohol and water were measured daily, and total intakes and the ratio of alcohol to total fluid were calculated. Data were analyzed by ANOVA for effects of DFEN and days of treatment.
"'
351
30 zo
, .o---o
,
e/
25{
o
/,
RESULTS
a
Experiment 1: Acute Study The results are shown in Fig. 1. DFEN potently inhibited both the 2-h intake of alcohol, F(3, 19) = 4.66, p < 0.05, and the intake expressed as difference from baseline, F(3, 19) = 5.41, p < 0.01. The intakes after 1.5 and 2 mg/kg doses were significantly reduced, and the 50o70 inhibitory dose was between 1 and 1.5 mg DFEN/kg.
Experiment 2: Chronic Study The results are shown in Fig. 2. The volume intake of alcohol was significantly lower in the DFEN group, compared with controls, on days 1-6 of the study (p-values < 0.05). There was some increase in the volume intake of alcohol across treatment days (p < 0.05), but the group x treatment ANOVA interaction was not significant (p > 0.1). Intake of water tended to be increased by DFEN, but this was only significant on day 2 when a net preference for water over alcohol occurred. The ratio of alcohol to total fluid in the control rats (means 81-91070) was significantly decreased on day 2 to 35o70 (p < 0.01) in the DFEN group, and was substantially reduced on days 1 and 3 (means 54-55°70; 0.1 > p > 0.05, two-tailed tests). Total fluid intake was significantly lower in the DFEN group on day 3 only. The main result is thus a sustained decrease in alcohol intake with some compensation by increased water intake. Neither food intake nor weight change were recorded but, based on prior work with DFEN (9,11), it is likely that food intake was suppressed to about the same degree as total fluid intake.
e"
o~ 12
EIO
÷
w v
8
7 --J
o 112 o o --J < o
6 4
t
2 0 0
0.5
1.0
1.5
2.0
DEXFENFLURAMINE ( m g / k g ) FIG. 1. Effect of acute SC administration of various dosages of dexfenfluramine on intake of 10% (vol/vol) ethanol solution in a 2-h dally session by male P rats. Shown are M + SE for 5 rats per condition. *p < 0.05 Difference from intake after placebo (0).
~"
0 40
35 z
30.
_o
25
It.
"
20
~'
15.
"
10. 0
=O~ I
T/~To
.,i ,
o/0----o-----o./9
O '
Closed symbols: CONTROL Open symbols: DFEN
I
I
I
I
I
I
~m/m--m~m\m/m m~
/D~ D
D ~ D / []
D~D./ /x//x
Squares: Total fluid .. A
Triangles: Water intake
t
t
t
t
I
I
I
1
2
3
4
5
6
7 days
FIG. 2. Ad lib intake of 10% (vol/vol) ethanol (top panel), water and total fluid (alcohol + water, lower panel) by groups of 5 P rats given either no treatment (control) or with 7-day SC administration
of dexfenfluramine (DFEN) (3 ms/ks per day via osmotic minipump). Shown are M + SE. The alcohol intake of the DFEN group is lower (p < 0.05) than control on days 1-6.
DISCUSSION
In the acute study, in which food was not available, 2-h intake of ethanol solution was potently attenuated by DFEN. This paradigm is similar to the "dessert" test in which nondeprived rats consume a good-tasting, caloric fluid at a given time each day (11). In this dessert test in common strains of rats, the 50°7o inhibitory dose of DFEN is about 1-1.5 mg/ kg, similar to that observed in the present alcohol paradigm. However, because brain 5HT concentrations are reduced in some brain regions of P rats (6,12), it is possible that DFEN may be less effective on food intake in P rats than in other rat strains. In support of this possibility, about 3 months after the present studies, and after serving in other studies which included implanting a gastric fistula, our P rats were adapted to sweet milk "dessert" (11) and, after baselines were established (mean 12 ml/60-min test) they received DFEN (1.5 mg/ kg, SC) prior to milk. Intake (mean 10 ml) was not significantly inhibited by DFEN. Because of prior DFEN and other experimental treatments in these rats, we are cautious in concluding that P rats are less sensitive than common strains to the anoretic effects of DFEN. We may conclude that in P rats the inhibitory action of DFEN on alcohol intake is at least as potent as its effect on food intake. In the chronic study, intake of alcohol was suppressed throughout the study in the DFEN group. Three points should be made. First, the prior acute injections of DFEN to these rats will, if anything, have produced some tolerance to DFEN (9,1 l), so the effect reported here might have been larger in
A L C O H O L I N T A K E IN " P " R A T S
561
TABLE 1 EFFECT OF CHRONIC DEXFENFLURAMINE ON TOTAL FLUID INTAKE (10e/0 ALCOHOL + WATER) AND ALCOHOL PREFERENCE (ALCOHOL/TOTAL) P RATS Alcohol Preference (e/e)
Total fluid (ml/24 h) Day
Control 33.0 34.9 37.4 38.6
+ + + +
2.6 2.0 3.6 1.6
DFEN 22.6 19.8 28.3 29.4
+ + + ±
Control
0.7* 0.5* 2.6 2.2*
81 91 87 81
+ + ± ±
8 4 8 9
DFEN 54 34 55 79
± 12t ± 1" ± 14t ± 8
Shown are mean ± SE for 5 DFEN-treated and 5 untreated control P rats. *p < 0.01, t0.05 < p < 0.1, two-tailed t-tests, DFEN < control.
drug-naive rats. Second, the effect o f D F E N was sustained, with a partial decline, throughout the 7-day regimen. This is again similar to results in a feeding "dessert" paradigm (11) and contrasts with the more complete tolerance to D F E N anorexia in paradigms involving f o o d deprivation/restriction. Furthermore, the effect on f o o d intake should have been quite small in these conditions (9) and no other behavioral changes were evident in these rats. Third, this low chronic dose o f D F E N does not cause depletions o f brain 5 H T , but produces plasma levels o f D F E N and its active metabolite some 10 times those seen in humans (10). Our data are consistent with other observations that 5HTactive agents decrease both alcohol and f o o d intake (2,3,5,7). In most o f those studies, decreased alcohol intake could have been secondary to anorexia, as may also be the case in the present Experiment 2. However, in Experiment 1, food was
not available, suggesting that these agents have an effect independent o f meals. Further studies are required on the nature o f these 5HT-ethanol-food interactions. In conclusion, D F E N has potent acute and chronic inhibitory effects on intake of ethanol in P rats. Insofar as the known neurochemical action of D F E N at these low doses is to p r o m o t e release and inhibit uptake o f 5 H T (4,10), these data are consistent with a body o f data (e.g., 2,3,5-7) that suggest an inhibitory role for 5HT on alcohol intake. ACKNOWLEDGEMENTS The P rats used in this study were generously supplied by Dr. L. Lumeng of the Alcohol Research Center at Indiana University which is supported by PHS Grant P50-AA-07611. Additional grant support from NSF BNS 89-09439 to N.E.R., and the dexfenfluramine was a gift from Servier, France.
REFERENCES 1. Fisher, H.; Hsu, H.-C.; Wagner, G. C. Suppression of ethanol intake in chickens by fenfluramine and dietary tryptophan. Alcohol. Clin. Exp. Res. 15:1056-1059; 1991. 2. Gill, K.; Amit, Z. Effects of serotonin uptake blockade on food, water, and ethanol consumption in rats. Alcohol. Clin. Exp. Res. 11:444-449; 1987. 3. Gill, K.; Filion, Y.; Amit, Z. A further examination of the effects of sertraline on voluntary ethanol consumption. Alcohol 5:355358; 1988. 4. Gobbi, M.; Frittoli, E.; Mennini, T.; Garattini, S. Releasing activities of d-fenfluramine and fluoxetine on rat hippocampal synaptosomes preloaded with [3H] serotonin. NaunynSchmiedeberg's Arch. Pharmacol. 345:1-6; 1992. 5. McBride, W. J.; Murphy, J. M.; Lumeng, L.; Li, T. K. Effects of Rol 5-4513, fluoxetine and desipramine on the intake of ethanol, water and food by the aicohol-preferring (P) and -nonpreferring (NP) lines of rats. Pharmacol. Biochem. Behav. 30:1045-1050; 1988. 6. McBride, W. J.; Murphy, J. M.; Lumeng, L.; Li, T. K. Serotonin
7.
8. 9. 10. 11. 12.
and ethanol preference. In: Galanter, M., ed. Recent developments in alcoholism, vol. 7. New York: Plenum Press; 1989:187-209. Myers, R. D.; Quarfordt, S. D. Alcohol drinking attenuated by sertraline in rats with 6-OHDA or 5,7-DHT lesions of N. accumbens: A caloric response? Pharmacol. Biochem. Behav. 40:923928; 1991. Opitz, K. Beobachtungen bei alkohol trinkenden ratten-einfluss von fenfluramin. Pharmakopsychiatrie 2:202-205; 1969. Rowland, N. E. Effect of continuous infusions of dexfenfluramine on food intake, body weight and brain amines in rats. Life Sci. 39:2581-2586; 1986. Rowland, N. E.; Carlton, J. Neurobiology of an anorectic drug: Fenfluramine. Prog. Nenrobiol. 27:13-62; 1986. Souquet, A. M.; Rowland, N. E. Effect of chronic administration of dexfenfluramine on stress- and palatability-induced food intake in rats. Physiol. Behav. 46:145-149; 1989. Zhou, F.; Bledsoe, S.; Lumeng, L.; Li, T. K. Immunostained serotonergic fibers are decreased in selected brain regions of alcohol-preferring rats. Alcohol 8:425-431; 1991.
0741-8329/92 $5.00 + .00 Copyright©1992PergamonPress Ltd.
Printed in the U.S.A. All rights reserved.
Effect of Dexfenfluramine on Alcohol Intake in Alcohol-Preferring "P" Rats N E l L E. R O W L A N D I A N D K E N N E T H
R. M O R I A N
Department o f Psychology, University o f Florida, Gainesville, FL 32611 Received 18 F e b r u a r y 1992; A c c e p t e d 9 J u n e 1992 ROWLAND, N. E. AND K. R. MORIAN. Effect of dexfe~fluramine on alcohol intake in alcohol-preferring "P" rats. ALCOHOL 9(6) 559-561, 1992.--The intake of alcohol, in 2-h daily sessions, by the preferring (P) line of rats was reduced in a dose-related manner by acute subcutaneous (SC) administration of dexfenfluramine (DFEN). Ad lib intake of alcohol was reduced by chronic SC administration of DFEN. The effective doses and magnitude of effects of DFEN on alcohol intake are comparable to those previously reported for DFEN anorexia. Because DFEN anorexia is related to increased brain serotonin (5HT) activity, its effect on alcohol consumption may also be via 5HT. Dexfenfluramine
Ethanol
P rat
Serotonin
D E X F E N F L U R A M I N E (DFEN) is an appetite suppressant whose primary mode of action seems to be via increased synaptic concentrations of serotonin (5HT) in brain, achieved by a combination o f 5HT release and uptake inhibition (4,10). Increased brain 5HT activity is thought to suppress alcohol intake, in part because 5HT uptake inhibitors decrease alcohol consumption (2,3,5-7), and also because levels of 5HT are reduced in some brain areas of rats bred selected for high spontaneous ethanol preference ("P" rats) (5,12). Administration of racemic fenfluramine (30 rag/d) reduced alcohol intake of outbred rats by 66070 (8), but both the high dose of the drug and the use of the racemate (the L-enantiomer has effects on dopamine systems) will cause 5HT specificity of the agent to be lost, and thus will limit the interpretation of the data. A recent study (1) reported reduced ethanol intake in chickens given racemic fenfluramine with tryptophan, but there is no body of pharmacologic data with fenfluramine in this species for reference. In the present study, we use P rats consuming unsweetened alcohol to examine the acute and chronic effects of low, pharmacologically specific, doses of DFEN on ethanol intake. METHOD
Chow pellets were available ad lib. The rats were housed individually in standard suspended stainless-steel cages in a vivarium with lights on 0800-2000 h and at 23°C. All procedures and measures were carried out in the middle of the light period.
Experiment 1: Effect o f Acute DFEN on Scheduled Alcohol Intake The rats (mean body weight 456 g) were adapted to 2 h / d access to alcohol, presented in graduated 50-ml tubes, with food absent. Basal intakes were measured for several days prior to this study and the mean of the last 2 days used as baseline. On the first experimental day, 5 rats were injected with DFEN (0.5 mg/kg, SC) 30 min before scheduled access to alcohol, and the other 5 received 1 mg/kg DFEN. Alcohol intake was measured after 30 and 120 min (i.e., 60 and 150 rain after injection). Two days later, the rats received 1.5 or 2 mg/kg DFEN (the previous 0.5 and 1 mg/kg groups, respectively). The intakes after 30 and 120 rain were similar, and so only the 120-min data were formally analyzed, by ANOVA, for dose effects.
Animals and Housing
Experiment 2: Effect o f Chronic DFEN on A d Lib Alcohol Intake
Ten adult male P rats were generously donated by Dr. Lumeng from the Indiana University Medical School colony. These rats were about 4 months old and weighed 400-500 g during these studies. They had been exposed to 10070 ethanol solution (vol/vol) for 2 h / d for about 3 weeks prior to this study. Unless otherwise noted, tap water and Wayne Lab
The rats were than given continuous access to 10070alcohol, as well as food and water, and the 24-h intakes were recorded for l week. At the end of this period, when intakes were stable, the first 5 rats (those who had received the lower acute dosages of DFEN) were briefly anesthetized (Metofane) and received an osmotic minipump (Alzet Model 2001) SC between
I To whom requests for reprints should be addressed. 559
560
ROWLAND AND MORIAN
the shoulders (9,11). The pumps were loaded with a 60 mg D F E N / m l water solution, designed to deliver an average dose of 3 mg D F E N / k g per day for 7 days (mean b.w. 468 g). The other 5 rats received no minipump and served as controls. Intakes of alcohol and water were measured daily, and total intakes and the ratio of alcohol to total fluid were calculated. Data were analyzed by ANOVA for effects of DFEN and days of treatment.
"'
351
30 zo
, .o---o
,
e/
25{
o
/,
RESULTS
a
Experiment 1: Acute Study The results are shown in Fig. 1. DFEN potently inhibited both the 2-h intake of alcohol, F(3, 19) = 4.66, p < 0.05, and the intake expressed as difference from baseline, F(3, 19) = 5.41, p < 0.01. The intakes after 1.5 and 2 mg/kg doses were significantly reduced, and the 50o70 inhibitory dose was between 1 and 1.5 mg DFEN/kg.
Experiment 2: Chronic Study The results are shown in Fig. 2. The volume intake of alcohol was significantly lower in the DFEN group, compared with controls, on days 1-6 of the study (p-values < 0.05). There was some increase in the volume intake of alcohol across treatment days (p < 0.05), but the group x treatment ANOVA interaction was not significant (p > 0.1). Intake of water tended to be increased by DFEN, but this was only significant on day 2 when a net preference for water over alcohol occurred. The ratio of alcohol to total fluid in the control rats (means 81-91070) was significantly decreased on day 2 to 35o70 (p < 0.01) in the DFEN group, and was substantially reduced on days 1 and 3 (means 54-55°70; 0.1 > p > 0.05, two-tailed tests). Total fluid intake was significantly lower in the DFEN group on day 3 only. The main result is thus a sustained decrease in alcohol intake with some compensation by increased water intake. Neither food intake nor weight change were recorded but, based on prior work with DFEN (9,11), it is likely that food intake was suppressed to about the same degree as total fluid intake.
e"
o~ 12
EIO
÷
w v
8
7 --J
o 112 o o --J < o
6 4
t
2 0 0
0.5
1.0
1.5
2.0
DEXFENFLURAMINE ( m g / k g ) FIG. 1. Effect of acute SC administration of various dosages of dexfenfluramine on intake of 10% (vol/vol) ethanol solution in a 2-h dally session by male P rats. Shown are M + SE for 5 rats per condition. *p < 0.05 Difference from intake after placebo (0).
~"
0 40
35 z
30.
_o
25
It.
"
20
~'
15.
"
10. 0
=O~ I
T/~To
.,i ,
o/0----o-----o./9
O '
Closed symbols: CONTROL Open symbols: DFEN
I
I
I
I
I
I
~m/m--m~m\m/m m~
/D~ D
D ~ D / []
D~D./ /x//x
Squares: Total fluid .. A
Triangles: Water intake
t
t
t
t
I
I
I
1
2
3
4
5
6
7 days
FIG. 2. Ad lib intake of 10% (vol/vol) ethanol (top panel), water and total fluid (alcohol + water, lower panel) by groups of 5 P rats given either no treatment (control) or with 7-day SC administration
of dexfenfluramine (DFEN) (3 ms/ks per day via osmotic minipump). Shown are M + SE. The alcohol intake of the DFEN group is lower (p < 0.05) than control on days 1-6.
DISCUSSION
In the acute study, in which food was not available, 2-h intake of ethanol solution was potently attenuated by DFEN. This paradigm is similar to the "dessert" test in which nondeprived rats consume a good-tasting, caloric fluid at a given time each day (11). In this dessert test in common strains of rats, the 50°7o inhibitory dose of DFEN is about 1-1.5 mg/ kg, similar to that observed in the present alcohol paradigm. However, because brain 5HT concentrations are reduced in some brain regions of P rats (6,12), it is possible that DFEN may be less effective on food intake in P rats than in other rat strains. In support of this possibility, about 3 months after the present studies, and after serving in other studies which included implanting a gastric fistula, our P rats were adapted to sweet milk "dessert" (11) and, after baselines were established (mean 12 ml/60-min test) they received DFEN (1.5 mg/ kg, SC) prior to milk. Intake (mean 10 ml) was not significantly inhibited by DFEN. Because of prior DFEN and other experimental treatments in these rats, we are cautious in concluding that P rats are less sensitive than common strains to the anoretic effects of DFEN. We may conclude that in P rats the inhibitory action of DFEN on alcohol intake is at least as potent as its effect on food intake. In the chronic study, intake of alcohol was suppressed throughout the study in the DFEN group. Three points should be made. First, the prior acute injections of DFEN to these rats will, if anything, have produced some tolerance to DFEN (9,1 l), so the effect reported here might have been larger in
A L C O H O L I N T A K E IN " P " R A T S
561
TABLE 1 EFFECT OF CHRONIC DEXFENFLURAMINE ON TOTAL FLUID INTAKE (10e/0 ALCOHOL + WATER) AND ALCOHOL PREFERENCE (ALCOHOL/TOTAL) P RATS Alcohol Preference (e/e)
Total fluid (ml/24 h) Day
Control 33.0 34.9 37.4 38.6
+ + + +
2.6 2.0 3.6 1.6
DFEN 22.6 19.8 28.3 29.4
+ + + ±
Control
0.7* 0.5* 2.6 2.2*
81 91 87 81
+ + ± ±
8 4 8 9
DFEN 54 34 55 79
± 12t ± 1" ± 14t ± 8
Shown are mean ± SE for 5 DFEN-treated and 5 untreated control P rats. *p < 0.01, t0.05 < p < 0.1, two-tailed t-tests, DFEN < control.
drug-naive rats. Second, the effect o f D F E N was sustained, with a partial decline, throughout the 7-day regimen. This is again similar to results in a feeding "dessert" paradigm (11) and contrasts with the more complete tolerance to D F E N anorexia in paradigms involving f o o d deprivation/restriction. Furthermore, the effect on f o o d intake should have been quite small in these conditions (9) and no other behavioral changes were evident in these rats. Third, this low chronic dose o f D F E N does not cause depletions o f brain 5 H T , but produces plasma levels o f D F E N and its active metabolite some 10 times those seen in humans (10). Our data are consistent with other observations that 5HTactive agents decrease both alcohol and f o o d intake (2,3,5,7). In most o f those studies, decreased alcohol intake could have been secondary to anorexia, as may also be the case in the present Experiment 2. However, in Experiment 1, food was
not available, suggesting that these agents have an effect independent o f meals. Further studies are required on the nature o f these 5HT-ethanol-food interactions. In conclusion, D F E N has potent acute and chronic inhibitory effects on intake of ethanol in P rats. Insofar as the known neurochemical action of D F E N at these low doses is to p r o m o t e release and inhibit uptake o f 5 H T (4,10), these data are consistent with a body o f data (e.g., 2,3,5-7) that suggest an inhibitory role for 5HT on alcohol intake. ACKNOWLEDGEMENTS The P rats used in this study were generously supplied by Dr. L. Lumeng of the Alcohol Research Center at Indiana University which is supported by PHS Grant P50-AA-07611. Additional grant support from NSF BNS 89-09439 to N.E.R., and the dexfenfluramine was a gift from Servier, France.
REFERENCES 1. Fisher, H.; Hsu, H.-C.; Wagner, G. C. Suppression of ethanol intake in chickens by fenfluramine and dietary tryptophan. Alcohol. Clin. Exp. Res. 15:1056-1059; 1991. 2. Gill, K.; Amit, Z. Effects of serotonin uptake blockade on food, water, and ethanol consumption in rats. Alcohol. Clin. Exp. Res. 11:444-449; 1987. 3. Gill, K.; Filion, Y.; Amit, Z. A further examination of the effects of sertraline on voluntary ethanol consumption. Alcohol 5:355358; 1988. 4. Gobbi, M.; Frittoli, E.; Mennini, T.; Garattini, S. Releasing activities of d-fenfluramine and fluoxetine on rat hippocampal synaptosomes preloaded with [3H] serotonin. NaunynSchmiedeberg's Arch. Pharmacol. 345:1-6; 1992. 5. McBride, W. J.; Murphy, J. M.; Lumeng, L.; Li, T. K. Effects of Rol 5-4513, fluoxetine and desipramine on the intake of ethanol, water and food by the aicohol-preferring (P) and -nonpreferring (NP) lines of rats. Pharmacol. Biochem. Behav. 30:1045-1050; 1988. 6. McBride, W. J.; Murphy, J. M.; Lumeng, L.; Li, T. K. Serotonin
7.
8. 9. 10. 11. 12.
and ethanol preference. In: Galanter, M., ed. Recent developments in alcoholism, vol. 7. New York: Plenum Press; 1989:187-209. Myers, R. D.; Quarfordt, S. D. Alcohol drinking attenuated by sertraline in rats with 6-OHDA or 5,7-DHT lesions of N. accumbens: A caloric response? Pharmacol. Biochem. Behav. 40:923928; 1991. Opitz, K. Beobachtungen bei alkohol trinkenden ratten-einfluss von fenfluramin. Pharmakopsychiatrie 2:202-205; 1969. Rowland, N. E. Effect of continuous infusions of dexfenfluramine on food intake, body weight and brain amines in rats. Life Sci. 39:2581-2586; 1986. Rowland, N. E.; Carlton, J. Neurobiology of an anorectic drug: Fenfluramine. Prog. Nenrobiol. 27:13-62; 1986. Souquet, A. M.; Rowland, N. E. Effect of chronic administration of dexfenfluramine on stress- and palatability-induced food intake in rats. Physiol. Behav. 46:145-149; 1989. Zhou, F.; Bledsoe, S.; Lumeng, L.; Li, T. K. Immunostained serotonergic fibers are decreased in selected brain regions of alcohol-preferring rats. Alcohol 8:425-431; 1991.
