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Increased GH responsiveness to dopamine receptor stimulation in alcohol addicts during the late withdrawal syndrome
Life Sciences, Vol. 33, pp. 2651-2655 Printed in the U.S.A.
Pergamon Press
INCREASED GH RESPONSIVENESS TO DOPAMINE RECEPTOR STIMULATION ALCOHOL ADDICTS DURING THE LATE WITHDRAWAL SYNDROME
IN
Lucio Annunziato,Salvatore Amoroso,Gianfranco Di Renzo,Filomena Argenzio, Caterina Aurilio,Antonio Grella and Aldo Quattrone Department of Pharmacology,2nd Clinical Toxicology,Unlversity
School o£ Medicine and Department of of Naples,Vla S.Pansini 5,80131 Naples, Italy
(Received in final form October
12, 1983)
Summary In humans the release of growth hormone (GH) elicited by dopamine(DA) and DA agonists may represent a reliable model to assess change in sensitivity of DA receptors.We now report that in chronic alcoholics, 4-7 days after the suspension of alcohol consumption,the increase of GH response to DA infusion was higher than that seen in non alcoholic volunteers.The specificity of this GH response to DA administration was demonstrated by the use of domperidone,a novel peripheral antagonist of DA receptors.These results suggest the development of hyperresponsiveness of DA receptors involved In the control of GH secret~n in chronic alcoholics during the later phases of the"withdrawal syndreme". The abrupt cessatlon of prolonged ethanol consumption causes abnormal physiological and behavioral changes in humans and animals known as "wlthdrawal syndrome" (I). Several lines of evidence suggest that central dopaminerglc neurotransmission may be involved in the clinlcal expression of the withdrawal syndrome (2). In fact changes in synthesls,release,and receptor ~unction of central dopaminel gic synapses have been reported after the abrupt cessation of long-term admini~ tration of alcohol (3). The present study was undertaken to investigate whether any change in sensitivity of DA receptors occurs in alcoholics. Since in humans the stlmulatlon of postsynaptlc dopamine (DA) receptors in the tuberoinfundibular region stimulates the release of circulating growth hormone IGH# (4),a hormone whose level can be accurately quantified using radloimmunological assays,this neuroendocrinological model was chosen to assess chang~ in sensitivlty of DA receptors in alcoholics.Thus we investlgated the response of radioimmunological GH secretion to DA infusion in a group of chronic alcoholics 4-7 days after the suspension of alcohol consumption and this response wa~ compared to that obtained in a population of control volunteers.Furthermore, 0024-3205/83 $3.00 + .00 Copyright (c) 1983 Pergamon Press Ltd.
2652
Increased GH Responsiveness
in Alcohol Addicts
Vol. 33, No. 26, 1983
to determine whether the effect of DA on GH secretion was specifically mediated by a stimulation of DA receptors,domperldone,an antagonist of DA receptors (5), was administered in the same alcoholic subjects. Methods Ten chronic alcoholics (age range 32.6 ~ 2.4 years,mean body weight 67.8 2 Kg,5 men and 5 women),without any blochemical and clinical symptoms of alcohol-induced llver disease,were considered in the present study.They admitted to a chronic alcohol abuse for 3.9 +_ 0.7 years and voluntarly interrupted alcohol consumption and showed signs of the withdrawal syndrome.The alcoholics did not experience any recent weight loss.The experiments were begun 4-7 days after the suspension of alcohol consumption,i.d. 24-48 hours after the disappearance of signs and symptoms of ethanol withdrawal syndrome.The control group consisted of healthy nonalcoholic volunteers (age range 35~ 3.3,mean body weight 65~ 3, 5 men and 4 women).All tests were carried out between 09.00 and II.OO after overnight fasting.Sixty mlnutes before starting each test,an indwelling catheter was place~ in an antecubltal veln.At this time blood ethanol was measured to be sure that both alcoholics and non-~rinker volunteers had not consumed any alcohol.Both groups were not taking any drug.Plasma GH levels were determined by radioimmunoassay using materials supplled by Blodata (Milan,ltaly~. Since it has been found that alcoholic (6) and nonalcoholic (7) subjects with severe liver disease display an abnormal GH rlse to a TRH intravenous bolus,the tripeptide was preliminarly administered to chronic alcoholics and volunteers to determine if an exagerated response of GH was present.No GH response to the hypothalamic releasing hormone was observed in the subjects under study. Results The control group (non-drinking volunteers) were infused in different days with saline or DA (4 ~g/kg/min diluted in sallne). 6 (3 men and 3 women) of the 9 control subjects had a rise in plasma GH tollowing the infusion of DA.The integrated mean area under the plasma GH curve during DA infusion was significantly higher (p
Vol. 33, No. 26, 1983
Increased GH Responsiveness in Alcohol Addicts
2653
40 NORMAL SUBJECTS m
E
30
20
~"
O <~ u)
<
.-I
10
CL
I
- 60
I
-30
I
I
0
i
i
i
30
60
90
120
150
MINUTES FIG.I E£fect of DA infusion on GH plasma levels in control subjects and chronic alcoholics.Each point represents the mean of GH values of ten alcoholics or six normal DA responders.Total GH secretion of each single control or alcoholic subject in response to DA infusion was expressed as the integrated area under plasma GH levels from 0150 minutes.Statlstical significance of the difference between the means ~ S.E. of the areas of alcoholics and control subjects was determined by Student's 2-tailed t test,and resulted statlstically signiflcant at p < O . O 5 . T h e integrated mean area under the plasma GH curve for the control subjects was significantly lower ( p < O . 0 5 ) than that of the chronic alcoholics ( 461!48 vs 1333~351 ~IU/ml/min). During the whole period of DA infusion blood glucose levels were monitored and no signiflcant change was observed (data not shown). Domperidone (administered intravenously in a bolus dose of 4 mg 30 minutes before DA infusion) was capable of completely counteracting the GH-releasing effect of DA in the same chronic alcoholics IO days after the first experiment (Figure 2).
2654
Increased GH Responsiveness in Alcohol Addicts
Vol. 33, No. 26, 1983
40
30
DOMiERIDONE
DA DOMPERIDONE ÷DA
~,b~i
2o
lO
- 30
0
30
60
90
120
150
MINUTES FIG. 2 Effect of domperidone pretreatment (4 mg iv) on GH response to DA infusion in alcoholic subjects.For other experimental details see legend of Fig.l. Total GH response (expressed as the integrated area under plasma GH levels from 0-150 minutes) to DA infusion in chronic alcoholics was statistically different (p~O.Ol) from domperidone pretreated addicts.The integrated mean area under the plasma GH curve for the chronic alcoholics pretreated with domperidone was significantly lower ( p < 0.01 Student's 2-tailed test) than that of the same chronic alcoholics not pretreated with domperidone (151 ~ 87 vs 1333 ~ 351 ~IU/ml/min). Discussion The results of the present study reveal that chronic alcoholics,4-7 days after ethanol withdrawal,exhibit an increased GH response to DA infusion. The reversal by domperidone,a novel peripheral DA antagonist,of DA effect on GH secretion demonstrated the specific involvement of DA receptors. Although DA and domperidone do not cross blood-brainbarrier it should be noted that both median eminence and adenohypophisis appear to lie outside this barrier (I0). Therefore DA and domperidone may affect GH secretion either at the median eminence level or acting on the pituitary.
Vol. 33, No. 26, 1983
Increased GH Responsiveness
in Alcohol Addicts
2655
The increased response of DA receptors we found in alcoholics is consiste~ with the results of animal studies (3,9).In fact,if rats are treated with ethanol for 9 months,a period of time comparable to the history of alcohol consumption of the patients considered in the present study,two phases,biochemically separable,occur during the withdrawal syndrome.The first phase,lasting approximately 24 hours,is characterized by a reduced synthesis and release of DA in the brain;during the second phase,occurring 3-5 days after witbdrawal,DA synthe sis is increased and an apparent supersensitivity of DA receptors in the brain develops (3).The development in alcoholics of GH hyperresponslveness to DA receptor stimulation 4-7 days after ethanol withdrawal might result from a decrease of DA release from tuberoinfundibular neurons in the hypothalamus and,indeed,a diminished release of the catecholamine has been measured,by dlfferent authors,in another brain area,the strlatum,several hours after ethanol suspension (3,11). The results of the present study suggest that the evaluation of GH response to DA receptor stimulation may represent a new neuroendocrine model to asses~ in humans changes in functional state of central DA receptors in the natural history of alcoholism. References I. E. MAJCHROWICZ, Fed. Proc. 40 2065-2072 (1981) 2. W.A. HUNT,E. MAJCHROWICZ,T.K. DALTON,H.S. SWARTZWELDER and H. WIXON, Alcohol:Clin. Exp.Res. 3 359-363 (1979) 3. H. LAI,W.L. MAKAUS,A. HORITA and H. LEUNG,Psychopharmacology 6 1 1-9 (1979) 4. G.N. BURROW,P.B. MAY,S.W. SPAULDING and R.K. DONABEDIAN, J.Clin.Endocrinol. Metab. 45 65-72 (1977) 5. D. COCCHI, I. GIL-AD,M. PARENTI,E. STEFANINI,V. LOCATELLI and E.E. MULLER, Neuroendocrinology 3 0 65-69 (1980) 6. D.H. VAN THIEL,W.I. SMITH Jr,C. J. MC CLAIN and R. LESTER,Curr.Alcohol 5 71-79 (1979) 7. A.E. PANERAI,F. SALERNO,M. MANNESCHI,D. COCCHI and E.E. MULLER, J. Clin. Endocrinol. Metab. 45 123-140 (1977) 8. P. ETTIGI, S. LAL,J.B. MARTIN and H.G. FRIESEN, J. Clin.Endocrinol. Metab. 40 1094-1098 (1975) 9. W. A. HUNT, Fed. Proc. 40 2077-2081 (1981) IO.A.BERTLER,B. FALCK and E. ROSENGREN, Acta Pharmacol.Toxicol. 20 317-320 (1963) II.K. GYSLING,G. BUSTOS,I. CONCHA and G. MARTINEZ, Biochem. Pharm. 25 157-162 (1976)
Pergamon Press
INCREASED GH RESPONSIVENESS TO DOPAMINE RECEPTOR STIMULATION ALCOHOL ADDICTS DURING THE LATE WITHDRAWAL SYNDROME
IN
Lucio Annunziato,Salvatore Amoroso,Gianfranco Di Renzo,Filomena Argenzio, Caterina Aurilio,Antonio Grella and Aldo Quattrone Department of Pharmacology,2nd Clinical Toxicology,Unlversity
School o£ Medicine and Department of of Naples,Vla S.Pansini 5,80131 Naples, Italy
(Received in final form October
12, 1983)
Summary In humans the release of growth hormone (GH) elicited by dopamine(DA) and DA agonists may represent a reliable model to assess change in sensitivity of DA receptors.We now report that in chronic alcoholics, 4-7 days after the suspension of alcohol consumption,the increase of GH response to DA infusion was higher than that seen in non alcoholic volunteers.The specificity of this GH response to DA administration was demonstrated by the use of domperidone,a novel peripheral antagonist of DA receptors.These results suggest the development of hyperresponsiveness of DA receptors involved In the control of GH secret~n in chronic alcoholics during the later phases of the"withdrawal syndreme". The abrupt cessatlon of prolonged ethanol consumption causes abnormal physiological and behavioral changes in humans and animals known as "wlthdrawal syndrome" (I). Several lines of evidence suggest that central dopaminerglc neurotransmission may be involved in the clinlcal expression of the withdrawal syndrome (2). In fact changes in synthesls,release,and receptor ~unction of central dopaminel gic synapses have been reported after the abrupt cessation of long-term admini~ tration of alcohol (3). The present study was undertaken to investigate whether any change in sensitivity of DA receptors occurs in alcoholics. Since in humans the stlmulatlon of postsynaptlc dopamine (DA) receptors in the tuberoinfundibular region stimulates the release of circulating growth hormone IGH# (4),a hormone whose level can be accurately quantified using radloimmunological assays,this neuroendocrinological model was chosen to assess chang~ in sensitivlty of DA receptors in alcoholics.Thus we investlgated the response of radioimmunological GH secretion to DA infusion in a group of chronic alcoholics 4-7 days after the suspension of alcohol consumption and this response wa~ compared to that obtained in a population of control volunteers.Furthermore, 0024-3205/83 $3.00 + .00 Copyright (c) 1983 Pergamon Press Ltd.
2652
Increased GH Responsiveness
in Alcohol Addicts
Vol. 33, No. 26, 1983
to determine whether the effect of DA on GH secretion was specifically mediated by a stimulation of DA receptors,domperldone,an antagonist of DA receptors (5), was administered in the same alcoholic subjects. Methods Ten chronic alcoholics (age range 32.6 ~ 2.4 years,mean body weight 67.8 2 Kg,5 men and 5 women),without any blochemical and clinical symptoms of alcohol-induced llver disease,were considered in the present study.They admitted to a chronic alcohol abuse for 3.9 +_ 0.7 years and voluntarly interrupted alcohol consumption and showed signs of the withdrawal syndrome.The alcoholics did not experience any recent weight loss.The experiments were begun 4-7 days after the suspension of alcohol consumption,i.d. 24-48 hours after the disappearance of signs and symptoms of ethanol withdrawal syndrome.The control group consisted of healthy nonalcoholic volunteers (age range 35~ 3.3,mean body weight 65~ 3, 5 men and 4 women).All tests were carried out between 09.00 and II.OO after overnight fasting.Sixty mlnutes before starting each test,an indwelling catheter was place~ in an antecubltal veln.At this time blood ethanol was measured to be sure that both alcoholics and non-~rinker volunteers had not consumed any alcohol.Both groups were not taking any drug.Plasma GH levels were determined by radioimmunoassay using materials supplled by Blodata (Milan,ltaly~. Since it has been found that alcoholic (6) and nonalcoholic (7) subjects with severe liver disease display an abnormal GH rlse to a TRH intravenous bolus,the tripeptide was preliminarly administered to chronic alcoholics and volunteers to determine if an exagerated response of GH was present.No GH response to the hypothalamic releasing hormone was observed in the subjects under study. Results The control group (non-drinking volunteers) were infused in different days with saline or DA (4 ~g/kg/min diluted in sallne). 6 (3 men and 3 women) of the 9 control subjects had a rise in plasma GH tollowing the infusion of DA.The integrated mean area under the plasma GH curve during DA infusion was significantly higher (p
Vol. 33, No. 26, 1983
Increased GH Responsiveness in Alcohol Addicts
2653
40 NORMAL SUBJECTS m
E
30
20
~"
O <~ u)
<
.-I
10
CL
I
- 60
I
-30
I
I
0
i
i
i
30
60
90
120
150
MINUTES FIG.I E£fect of DA infusion on GH plasma levels in control subjects and chronic alcoholics.Each point represents the mean of GH values of ten alcoholics or six normal DA responders.Total GH secretion of each single control or alcoholic subject in response to DA infusion was expressed as the integrated area under plasma GH levels from 0150 minutes.Statlstical significance of the difference between the means ~ S.E. of the areas of alcoholics and control subjects was determined by Student's 2-tailed t test,and resulted statlstically signiflcant at p < O . O 5 . T h e integrated mean area under the plasma GH curve for the control subjects was significantly lower ( p < O . 0 5 ) than that of the chronic alcoholics ( 461!48 vs 1333~351 ~IU/ml/min). During the whole period of DA infusion blood glucose levels were monitored and no signiflcant change was observed (data not shown). Domperidone (administered intravenously in a bolus dose of 4 mg 30 minutes before DA infusion) was capable of completely counteracting the GH-releasing effect of DA in the same chronic alcoholics IO days after the first experiment (Figure 2).
2654
Increased GH Responsiveness in Alcohol Addicts
Vol. 33, No. 26, 1983
40
30
DOMiERIDONE
DA DOMPERIDONE ÷DA
~,b~i
2o
lO
- 30
0
30
60
90
120
150
MINUTES FIG. 2 Effect of domperidone pretreatment (4 mg iv) on GH response to DA infusion in alcoholic subjects.For other experimental details see legend of Fig.l. Total GH response (expressed as the integrated area under plasma GH levels from 0-150 minutes) to DA infusion in chronic alcoholics was statistically different (p~O.Ol) from domperidone pretreated addicts.The integrated mean area under the plasma GH curve for the chronic alcoholics pretreated with domperidone was significantly lower ( p < 0.01 Student's 2-tailed test) than that of the same chronic alcoholics not pretreated with domperidone (151 ~ 87 vs 1333 ~ 351 ~IU/ml/min). Discussion The results of the present study reveal that chronic alcoholics,4-7 days after ethanol withdrawal,exhibit an increased GH response to DA infusion. The reversal by domperidone,a novel peripheral DA antagonist,of DA effect on GH secretion demonstrated the specific involvement of DA receptors. Although DA and domperidone do not cross blood-brainbarrier it should be noted that both median eminence and adenohypophisis appear to lie outside this barrier (I0). Therefore DA and domperidone may affect GH secretion either at the median eminence level or acting on the pituitary.
Vol. 33, No. 26, 1983
Increased GH Responsiveness
in Alcohol Addicts
2655
The increased response of DA receptors we found in alcoholics is consiste~ with the results of animal studies (3,9).In fact,if rats are treated with ethanol for 9 months,a period of time comparable to the history of alcohol consumption of the patients considered in the present study,two phases,biochemically separable,occur during the withdrawal syndrome.The first phase,lasting approximately 24 hours,is characterized by a reduced synthesis and release of DA in the brain;during the second phase,occurring 3-5 days after witbdrawal,DA synthe sis is increased and an apparent supersensitivity of DA receptors in the brain develops (3).The development in alcoholics of GH hyperresponslveness to DA receptor stimulation 4-7 days after ethanol withdrawal might result from a decrease of DA release from tuberoinfundibular neurons in the hypothalamus and,indeed,a diminished release of the catecholamine has been measured,by dlfferent authors,in another brain area,the strlatum,several hours after ethanol suspension (3,11). The results of the present study suggest that the evaluation of GH response to DA receptor stimulation may represent a new neuroendocrine model to asses~ in humans changes in functional state of central DA receptors in the natural history of alcoholism. References I. E. MAJCHROWICZ, Fed. Proc. 40 2065-2072 (1981) 2. W.A. HUNT,E. MAJCHROWICZ,T.K. DALTON,H.S. SWARTZWELDER and H. WIXON, Alcohol:Clin. Exp.Res. 3 359-363 (1979) 3. H. LAI,W.L. MAKAUS,A. HORITA and H. LEUNG,Psychopharmacology 6 1 1-9 (1979) 4. G.N. BURROW,P.B. MAY,S.W. SPAULDING and R.K. DONABEDIAN, J.Clin.Endocrinol. Metab. 45 65-72 (1977) 5. D. COCCHI, I. GIL-AD,M. PARENTI,E. STEFANINI,V. LOCATELLI and E.E. MULLER, Neuroendocrinology 3 0 65-69 (1980) 6. D.H. VAN THIEL,W.I. SMITH Jr,C. J. MC CLAIN and R. LESTER,Curr.Alcohol 5 71-79 (1979) 7. A.E. PANERAI,F. SALERNO,M. MANNESCHI,D. COCCHI and E.E. MULLER, J. Clin. Endocrinol. Metab. 45 123-140 (1977) 8. P. ETTIGI, S. LAL,J.B. MARTIN and H.G. FRIESEN, J. Clin.Endocrinol. Metab. 40 1094-1098 (1975) 9. W. A. HUNT, Fed. Proc. 40 2077-2081 (1981) IO.A.BERTLER,B. FALCK and E. ROSENGREN, Acta Pharmacol.Toxicol. 20 317-320 (1963) II.K. GYSLING,G. BUSTOS,I. CONCHA and G. MARTINEZ, Biochem. Pharm. 25 157-162 (1976)