- Email: [email protected]
Failure of gammahydroxy butyric acid to stimulate growth hormone secretion in cocaine addicts
Neuropeptides(1997) 31 (5), 459-462 © HarcourtBraceand CompanyLtd 1997
Failure of g a m m a h y d r o x y butyric acid to stimulate growth hormone secretion in cocaine addicts P, P. Vescovi, C. Di Gennaro Centre for Alcohology, Institute of Internal Medicine, University of Parma, via Gramsci 14, 43100 Parma, Italy
Summary This study discusses the effect of gammahydroxy butyric acid (GHB) on growth hormone (GH) secretion changes in cocaine addicts. Ten male cocaine users and 10 normal controls were tested with a single oral administration of GHB at a dose of 25 mg/kg body weight. Cocaine addicts were tested before and after 30 days of abstinence. All subjects underwent a control with a placebo. Basal GH levels were similar in normal controls and cocaine users and remained unmodified during the control test. In the normal control subjects, plasma GH levels rose significantly after the administration of GHB; in contrast, plasma GH concentrations failed to increase after GHB treatment in cocaine addicts. These data show that a chronic abuse of cocaine induces alterations of the GABAergic system which were unmasked by the absent GH response to GHB.
INTRODUCTION
MATERIALS AND METHODS
A number of changes in the hypothalamus-pituitary axis have been found in cocaine addicts. 1-4 However, only a few studies have been made on the relationship between cocaine addiction and growth hormone (GH) secretion. High basal GH secretion has been reported by Garwin 5 in chronic cocaine addicts. In our previous study we observed normal basal GH 4 in patients withdrawing from cocaine after 15 days of abstinence. Gammahydroxy butyric acid (GHB) is a breakdown product of gamma-aminobutyric acid (GABA), a neurotransmitter that is widely distributed in the central nervous system, particularly in the basal ganglion and hypothalamus. ~ GHB administration has been shown to produce a significant stimulation of GH secretion in normal human subjects. 7 In the present study we examined the responses to GHB administration in chronic cocaine addicts before and after withdrawal.
Ten male cocaine addicts (aged 25-31 years, weight 70 _+ 8.2 kg) and 10 normal men (aged 23-34 years, weight 71 _+7.8 kg) voluntered to participate in the study. All subjects gave their informed consent to participate in the study. The cocaine addicts were recruited when they came to a recovery community for drug abusers. These subjects had been cocaine abusers for at least 3 years, and at the time of the study they were consuming cocaine in doses ranging between 1 and 1.S g/day. Cocaine was withdrawn as soon as the patients entered the recovery community, and all patients were treated with a neuroleptic agent for 4 days, for withdrawal symptoms. Thereafter, the patients were not allowed to consume any drugs and were kept under careful control while they were in the community. Urine samples were obtained from each patient twice a week and were used for toxicological assays. All of the men were within 10% of their ideal body weight, were well nourished and were without clinical or laboratory evidence of renal cardiovascular or endocrine abnormalities. In all subjects, the laboratory parameters of liver function were within the normal range at the time of the study. All subjects were assessed with the Hamilton depression rating scale with negative resuks.
Received 9 April 1997 Accepted 29 July 1997 Correspondence to: Prof. Pier Paolo Vescovi, Centre of Alcohology, Via Gramsci 14, 43100 Parma, Italy. Tel/fax: 39 521 986677. Email: [email protected]
459
460
Vescovi & Di Gennaro
Table
Serum GH (ng/mi) during GHB and placebo tests in normal controls (n = 10) and cocaine addicts (n = 10) (mean + SEM) on the day following their admission to the community and after 30 days
Time (rain) --30 0 Cocaine addicts (control) GHB Mean SEM Placebo Mean SEM Cocaine addicts (control at 30 days) GHB Mean SEM Placebo Mean SEM Controls GHB Mean SEM Placebo Mean SEM
10
20
30
60
90
120
1.9 0.2
2.0 0.3
2.1 0.2
1.8 0.1
1.9 0.2
2.0 0.1
1.8 0,2
1.7 0.1
1.9 0.2
2.1 0,2
1.9 0.08
1.6 0.09
1.8 0.08
2,0 0.1
1.9 0.1
1.9 0,08
1.8 0.1
2.0 0.09
2.0 0.1
2.2 0.2
1.9 0.1
2.3 0.2
2,2 0,09
2.5 0.08
2.6 0,05
2.0 0.1
1.9 0.2
2.2 0.08
2.0 0,09
2.1 0.1
2.0 0.1
1,9 0.08
1.9 0.1
2.0 0.09
2.0 0.09
1.9 0.08
1.6 0.08
1,7 0,1
2.5 0.08
2.8 0.1
5.0 0.2
9.1 0.09
9.8 0.2
8,8 0.3
3.3 0,2
2.0 0.09
1.9 0.08
2.0 0.1
1.9 0.1
2.0 0.09
2.0 0.1
1.9 0.08
2.1 0.1
2.1 0.1
Experimental procedure
The cocaine addicts were tested with GHB or placebo (water with sorbitol 70%, sour black cherry flavour) on the day following their arrival at the community centre and 4-5 days later. Patients were all at a similar level of drug abuse, as evidenced by resuks of urinary tests for cocaine catabolites. Tests were performed double-blind in random order. After 30 days of permanence in the community, the patients were tested with GHB or placebo in random order on 2 different days at 5-day intervals. On the morning of the tests, urine samples were taken for toxicological assay. Normal controls were tested once with GHB or placebo in random order on 2 different days at 5-day intervals. At 09:00 on the experimental day, a 19 gauge intravenous indwelling needle was inserted into an antecubital vein, with the subject lying in the recumbent position and fasting from the previous evening. The needle was kept pervious with a slow infusion of normal saline (NaC1 0.9%). A basal blood sample was taken 30 rain after insertion of the needle, just before the oral administration of 25 mg/kg body weight GHB (Alcover CT, Sanremo, Italy) or placebo. Blood samples were taken at 10, 20, 30, 45, 60, 90 and 120rain after GHB or placebo administration. Blood pressure and heart rate were measured with a chronometer and a mercury sphygmomanometer, respectively, at each sampling time during the tests. Blood samples were centrifuged at 5000 rpm at 4°C after each experiment and plasma was stored at -20°C until assay. Plasma GH levels were determined Neuropeptides (1997) 31(5), 459-462
45
by radioimmunoassay (RIA),8 using commercial kits, and using the double antibody technique. Sensitivity, intraand inter-assay coefficients of variation were 0.5 ng/ml, 3.6% and 6%, respectively. Plasma IGF-1 and cortisol levels were also measured, in samples taken at the time of the GHB and placebo tests, as both hormones are known to exert a negative influence on GH secretion. IGF-1 was evaluated by RIA using kits obtained from Nichols Institute Diagnostic, San Juan Capistrano, CA, USA. Cortisol was determined with a commercial RIA kit (Amec Inc, Westbrook, Maine, USA). The sensitivity of this method is 4.7 ng/ml and the within- and betweenCVs are 6.3% and Z2%, respectively. In our laboratory, the mean (+_ SEM) normal hormonal values in samples taken from a large population of adult men (aged 20-50 years) are 144.5 _+4 ng/mI. Results were analysed by two- or three-way analysis of variance (ANOVA) with repeated measures and Wilcoxon's matched-pair rank sum test, as appropriate. Values are expressed as mean + SEM.
RESULTS
The basal concentrations of GH were similar in normal control and cocaine addicts (Table). During all control tests, GH levels remained unmodified in both the normal men and the cocaine addicts. The administration of GHB in the normal controls induced a significant increase in plasma GH levels (Figure) with a mean peak response at 60m in (P < 0.01) vs basal value (Wilcoxon's test): © Harcourt Brace and Company Ltd 1997
Failure of GHB to stimulate GH secretion in cocaine addicts
900" 8007OO ,r.,. × 'T
6OO
~=_. E 5OO x "T
400 i
300
////// /ti//z //i~// ////// ////// 9"///~ /////1
z///// iz//// //////
*-,-,1,~._ ,--
//#///
(5
20(
//¢//~
V///G
Y///~ //////
V///~ /i////
100 ////// //////
0
Normals
Cocaineaddictsbefore
Cocaineaddic~a~er
Figure GH secretory areas during placebo ([~) and GHB (/~) tests in controls (n = 1 O) and cocaine addicts (n = 10). Each represents the mean + SEM of the observations. *P < 0.001 GHB vs placebo test.
? = 18.02, P < 0.001 vs control test (ANOVA). In contrast, GHB was unable to increase the circulating concentrations of GH in cocaine addicts both before and after 30 days of abstinence (NS vs time 0 and vs control test). Plasma IGF-1 levels were significantly higher in the controls (230 + 17ng/ml) than in the cocaine addicts (144 + 16 ng/ml, P < 0.001; 151 + 17ng/ml, P < 0.001). Plasma cortisol levels were similar in the controls (146 + 9.8) and the cocaine addicts (141 + 10.9; 139 + 9.8). GHB did not produce side-effects in any subject. Blood pressure and heart rate remained unchanged after GHB administration. DISCUSSION
Studies of cocaine addicts have provided evidence of wide alterations in hypothalamic-pituitary function. Various hormonal systems appear to change in cocaine addicts; in fact w e observed that elevated plasma adrenocorticotropin (ACTH) and [3-endorphin ([3-EP) in chronic cocaine addicts became normal during withdrawal, 4 while plasma prolactin (PRL) appeared to be very variable during both consumption and withdrawal from cocaine. 3,9,1°,~ In addiction, a blunted thyroid stimulating hormone secretion in response to thyroid releasing hormone has been reported22 Basal plasma levels of GH were normal during cocaine consumption as well as during withdrawal in agreement with our own data. Amphetamine stimulation produces no or very blunted responses? ,1°,~3 In the present study we found that GHB is unable to stimulate GH secretion in cocaine addicts. At present, the site of action of GABA or GABAergic drug in the control © Harcourt Brace and Company Ltd 1997
461
of GH secretion is uncertain. However, direct GABAergic effects at the pituitary level are,unlikely, because in vitro studies with GABA or GABAergic drugs do not show stimulatory effects on GH secretion. 14 In contrast, a tuberoinfundibular GABAergic pathway is located in the medio-basal hypothalamus, and it is thought to modulate pituitary GH secretion, acting on GH-RH and/or somatostatin via some unknown mechanism. 1~ The absent GH response to GHB in cocaine addicts cannot be attributed to a greater degree of inhibition by either IGF1 or cortisol, as plasma IGF-1 levels were lower in cocaine addicts then in normal controls and levels of cortisol were similar between the two groups. At present it is unknown whether the failure of GHB to stimulate GH secretion is peculiar to GH secretion, or rather represents part of a more general impairment of GABAergic neurotransmission in the cocaine addicts. In previous studies we have shown an impairment of the ACTH/cortisol, [3-EP and prolactin responses to hyperthermia in cocaine abusers. I6 The increased basal prolactin levels and absent prolactin response suggest that alterations are present in the dopaminergic control of PRL secretion in cocaine-dependent individuals. In chronically cocaine-treated rats, the density of postsynaptic dopaminergic receptors decreases, lz indicating that chronic cocaine administration reduces the dopaminergic activity in the brain. In agreement with this hypothesis, long-term addiction to cocaine is thought to produce dopaminergic depletion in the central nervous system, lz~s In fact, a reduction in symptoms of cocaine craving after treatment with the dopaminergic agonist, bromocriptine, has been reported. 19 GABAergic neurotransmission is known to regulate monoamine release in the central nervous system. The stimulating effect of GABA and GABAergic drugs on GH secretion is thought to be mediated by monoaminergic (particularly dopaminergic) neurons. 2° Our observations suggest that chronic abuse of cocaine induces alterations of the hypothalamic-limbic GABAergic system which were unmasked by the absent GH response to GHB. These neuroendocrine alterations represent a consequence of long-term cocaine abuse, and persist after a relatively short drug-free period. REFERENCES
1. CocoresJA, Dakins CA, GoldMS. Sexualdysfunctionsecondaryto cocaine abuse in two patients.J Clin Psychiatr 1986; 47: 384-385. 2. FormerEJ, EstilowS. Cocaine influences beta-endorphin levels and release. LifeSci 1989; 43: 309-315. 3. MendelsonJH, MelloMK, Teoh SK, EllingboeJ, CochinJ. Cocaine effectson pulsatile secretion of anterior pituitary gonadal and adrenal hormones.J Clin EndocrinolMetab 1989; 69: 1256-1260. 4. VescoviPP, Coiro V, VolpiR, Passeri M. Diurnal variations in plasma ACTH,cortisol and B-EPlevels in cocaine addicts. Horm Res 1992; 37: 221-224. Neuropeptides (1997) 31 (5), 459-462
462
Vescovi & Di Gennaro
5. Galnvin FH, Kleber HD. Neuroendocrine findings in chronic cocaine abusers: a preliminary report. Br J Psychiatry 1985; 147: 569-573.
6. Snead OC, Morley BJ. Ontogeny of GHB acid. Regional concentration in developing rat, monkey and human brain. Brain Res 1981; 227: 579-583. 7. Takahara J, Yunori S, Yakusyi. Stimulatory effects of gammahydroxy butiric acid on growth hormone and prolactin release in humans. Endocrinol Metab 1977; 44: 1014-1018. 8. Morley JE, Krahn DD. Endocrinology for the psychiatry. In: Nemeroff C, Loosen PT, eds. Clinical psychoneuroendocl~rlology. New York: Gufldary Press, 1987: 37-45. 9. Hollander E, Numes E, De Ceria CM et al. Dopaminergic sensitivity and cocaine abuse: response to apomorphine. Psychiatr Res 1990; 33: 161-170. 10. Lee MA, Bowers MM, Nash JF, Meltzer HY. Neuroendocrine measures of dopaminergic function in chronic cocaine users. Psychiatr Res 1990; 33: 151-160. 11. Theo KS, Mendelson JH, Mello NK, Weiss R, McEbroy S, McAfee B. Hyperprolactinemia and risk for relapse of cocaine abuse. Biol Psychiatr 1990; 28: 824-828. 12. Dakis CA, Estroff TW, Sweeney DR, Pottesh ALC, Gold MS. Specificity of the TRH test for major depression in patients with serious abuse. AmJ Psychiatr 1985; 142: 1097-1099. 13. Lee MA, Bowers MM, Nash JF, Meltzer HY. Neuroendocrine measures of dopaminergic function in chronic cocaine users. Psychiatr Res 1990; 33: 151-159.
Neuropeptides (1997) 31(5), 459-462
14. McCann SM, Vujayan E, Negro Vilar A. Gamma-aminobutyric acid (GABA),a modulator of anterior pituitary hormone secretion by hypothalamic and pituitary action. Psychoneuroendocrinology 1984; 9: 97-104. 15. Steardo L, Iovino M, Monteleone P. Pharmacological evidence for a dual Gabaergic regulation of growth hormone release in human. Life Sci 1986; 39: 979-983. 16. Vescovi PP, Coiro V, Volpi R, Giannini A, Passeri M. Hyperthermia in sauna is unable to increase the plasma levels of ACTH-Cortisol, ~-endorphin and prolactin in cocaine addicts. J Endocrinol Invest 1992; 15: 671-675. 17. Memo M, Prahhan S, Handbauer I. Cocaine-induced supersensitivity of striatal dopamine receptor. Role of endogenous calmodulin. Neuropharmacology 1981; 20: 1145-1150. 18. Dakis CA, Gold MS. New concepts in cocaine addiction: the dopamine depletion hypothesis. Neurosci Biobehav Rev 1987; 9: 469-471. 19. Dackis CA, Gol MS, Sweeney DR, Byron JP Jr, Climko R. Singledose bromocriptine reverses cocaine craving. Psychiatr Res 1987; 20: 261-264. 20. Laakmann G, Treusch J, Eicheier A. Inhibitory effect of phentolamine on diazepam induced growth-hormone secretion on lack of effect of diazepam on prolactin secretion in men. Psychoneuroendocrinology 1982; 7: 135-140.
© Harcourt Brace and Company Ltd 1997
Failure of g a m m a h y d r o x y butyric acid to stimulate growth hormone secretion in cocaine addicts P, P. Vescovi, C. Di Gennaro Centre for Alcohology, Institute of Internal Medicine, University of Parma, via Gramsci 14, 43100 Parma, Italy
Summary This study discusses the effect of gammahydroxy butyric acid (GHB) on growth hormone (GH) secretion changes in cocaine addicts. Ten male cocaine users and 10 normal controls were tested with a single oral administration of GHB at a dose of 25 mg/kg body weight. Cocaine addicts were tested before and after 30 days of abstinence. All subjects underwent a control with a placebo. Basal GH levels were similar in normal controls and cocaine users and remained unmodified during the control test. In the normal control subjects, plasma GH levels rose significantly after the administration of GHB; in contrast, plasma GH concentrations failed to increase after GHB treatment in cocaine addicts. These data show that a chronic abuse of cocaine induces alterations of the GABAergic system which were unmasked by the absent GH response to GHB.
INTRODUCTION
MATERIALS AND METHODS
A number of changes in the hypothalamus-pituitary axis have been found in cocaine addicts. 1-4 However, only a few studies have been made on the relationship between cocaine addiction and growth hormone (GH) secretion. High basal GH secretion has been reported by Garwin 5 in chronic cocaine addicts. In our previous study we observed normal basal GH 4 in patients withdrawing from cocaine after 15 days of abstinence. Gammahydroxy butyric acid (GHB) is a breakdown product of gamma-aminobutyric acid (GABA), a neurotransmitter that is widely distributed in the central nervous system, particularly in the basal ganglion and hypothalamus. ~ GHB administration has been shown to produce a significant stimulation of GH secretion in normal human subjects. 7 In the present study we examined the responses to GHB administration in chronic cocaine addicts before and after withdrawal.
Ten male cocaine addicts (aged 25-31 years, weight 70 _+ 8.2 kg) and 10 normal men (aged 23-34 years, weight 71 _+7.8 kg) voluntered to participate in the study. All subjects gave their informed consent to participate in the study. The cocaine addicts were recruited when they came to a recovery community for drug abusers. These subjects had been cocaine abusers for at least 3 years, and at the time of the study they were consuming cocaine in doses ranging between 1 and 1.S g/day. Cocaine was withdrawn as soon as the patients entered the recovery community, and all patients were treated with a neuroleptic agent for 4 days, for withdrawal symptoms. Thereafter, the patients were not allowed to consume any drugs and were kept under careful control while they were in the community. Urine samples were obtained from each patient twice a week and were used for toxicological assays. All of the men were within 10% of their ideal body weight, were well nourished and were without clinical or laboratory evidence of renal cardiovascular or endocrine abnormalities. In all subjects, the laboratory parameters of liver function were within the normal range at the time of the study. All subjects were assessed with the Hamilton depression rating scale with negative resuks.
Received 9 April 1997 Accepted 29 July 1997 Correspondence to: Prof. Pier Paolo Vescovi, Centre of Alcohology, Via Gramsci 14, 43100 Parma, Italy. Tel/fax: 39 521 986677. Email: [email protected]
459
460
Vescovi & Di Gennaro
Table
Serum GH (ng/mi) during GHB and placebo tests in normal controls (n = 10) and cocaine addicts (n = 10) (mean + SEM) on the day following their admission to the community and after 30 days
Time (rain) --30 0 Cocaine addicts (control) GHB Mean SEM Placebo Mean SEM Cocaine addicts (control at 30 days) GHB Mean SEM Placebo Mean SEM Controls GHB Mean SEM Placebo Mean SEM
10
20
30
60
90
120
1.9 0.2
2.0 0.3
2.1 0.2
1.8 0.1
1.9 0.2
2.0 0.1
1.8 0,2
1.7 0.1
1.9 0.2
2.1 0,2
1.9 0.08
1.6 0.09
1.8 0.08
2,0 0.1
1.9 0.1
1.9 0,08
1.8 0.1
2.0 0.09
2.0 0.1
2.2 0.2
1.9 0.1
2.3 0.2
2,2 0,09
2.5 0.08
2.6 0,05
2.0 0.1
1.9 0.2
2.2 0.08
2.0 0,09
2.1 0.1
2.0 0.1
1,9 0.08
1.9 0.1
2.0 0.09
2.0 0.09
1.9 0.08
1.6 0.08
1,7 0,1
2.5 0.08
2.8 0.1
5.0 0.2
9.1 0.09
9.8 0.2
8,8 0.3
3.3 0,2
2.0 0.09
1.9 0.08
2.0 0.1
1.9 0.1
2.0 0.09
2.0 0.1
1.9 0.08
2.1 0.1
2.1 0.1
Experimental procedure
The cocaine addicts were tested with GHB or placebo (water with sorbitol 70%, sour black cherry flavour) on the day following their arrival at the community centre and 4-5 days later. Patients were all at a similar level of drug abuse, as evidenced by resuks of urinary tests for cocaine catabolites. Tests were performed double-blind in random order. After 30 days of permanence in the community, the patients were tested with GHB or placebo in random order on 2 different days at 5-day intervals. On the morning of the tests, urine samples were taken for toxicological assay. Normal controls were tested once with GHB or placebo in random order on 2 different days at 5-day intervals. At 09:00 on the experimental day, a 19 gauge intravenous indwelling needle was inserted into an antecubital vein, with the subject lying in the recumbent position and fasting from the previous evening. The needle was kept pervious with a slow infusion of normal saline (NaC1 0.9%). A basal blood sample was taken 30 rain after insertion of the needle, just before the oral administration of 25 mg/kg body weight GHB (Alcover CT, Sanremo, Italy) or placebo. Blood samples were taken at 10, 20, 30, 45, 60, 90 and 120rain after GHB or placebo administration. Blood pressure and heart rate were measured with a chronometer and a mercury sphygmomanometer, respectively, at each sampling time during the tests. Blood samples were centrifuged at 5000 rpm at 4°C after each experiment and plasma was stored at -20°C until assay. Plasma GH levels were determined Neuropeptides (1997) 31(5), 459-462
45
by radioimmunoassay (RIA),8 using commercial kits, and using the double antibody technique. Sensitivity, intraand inter-assay coefficients of variation were 0.5 ng/ml, 3.6% and 6%, respectively. Plasma IGF-1 and cortisol levels were also measured, in samples taken at the time of the GHB and placebo tests, as both hormones are known to exert a negative influence on GH secretion. IGF-1 was evaluated by RIA using kits obtained from Nichols Institute Diagnostic, San Juan Capistrano, CA, USA. Cortisol was determined with a commercial RIA kit (Amec Inc, Westbrook, Maine, USA). The sensitivity of this method is 4.7 ng/ml and the within- and betweenCVs are 6.3% and Z2%, respectively. In our laboratory, the mean (+_ SEM) normal hormonal values in samples taken from a large population of adult men (aged 20-50 years) are 144.5 _+4 ng/mI. Results were analysed by two- or three-way analysis of variance (ANOVA) with repeated measures and Wilcoxon's matched-pair rank sum test, as appropriate. Values are expressed as mean + SEM.
RESULTS
The basal concentrations of GH were similar in normal control and cocaine addicts (Table). During all control tests, GH levels remained unmodified in both the normal men and the cocaine addicts. The administration of GHB in the normal controls induced a significant increase in plasma GH levels (Figure) with a mean peak response at 60m in (P < 0.01) vs basal value (Wilcoxon's test): © Harcourt Brace and Company Ltd 1997
Failure of GHB to stimulate GH secretion in cocaine addicts
900" 8007OO ,r.,. × 'T
6OO
~=_. E 5OO x "T
400 i
300
////// /ti//z //i~// ////// ////// 9"///~ /////1
z///// iz//// //////
*-,-,1,~._ ,--
//#///
(5
20(
//¢//~
V///G
Y///~ //////
V///~ /i////
100 ////// //////
0
Normals
Cocaineaddictsbefore
Cocaineaddic~a~er
Figure GH secretory areas during placebo ([~) and GHB (/~) tests in controls (n = 1 O) and cocaine addicts (n = 10). Each represents the mean + SEM of the observations. *P < 0.001 GHB vs placebo test.
? = 18.02, P < 0.001 vs control test (ANOVA). In contrast, GHB was unable to increase the circulating concentrations of GH in cocaine addicts both before and after 30 days of abstinence (NS vs time 0 and vs control test). Plasma IGF-1 levels were significantly higher in the controls (230 + 17ng/ml) than in the cocaine addicts (144 + 16 ng/ml, P < 0.001; 151 + 17ng/ml, P < 0.001). Plasma cortisol levels were similar in the controls (146 + 9.8) and the cocaine addicts (141 + 10.9; 139 + 9.8). GHB did not produce side-effects in any subject. Blood pressure and heart rate remained unchanged after GHB administration. DISCUSSION
Studies of cocaine addicts have provided evidence of wide alterations in hypothalamic-pituitary function. Various hormonal systems appear to change in cocaine addicts; in fact w e observed that elevated plasma adrenocorticotropin (ACTH) and [3-endorphin ([3-EP) in chronic cocaine addicts became normal during withdrawal, 4 while plasma prolactin (PRL) appeared to be very variable during both consumption and withdrawal from cocaine. 3,9,1°,~ In addiction, a blunted thyroid stimulating hormone secretion in response to thyroid releasing hormone has been reported22 Basal plasma levels of GH were normal during cocaine consumption as well as during withdrawal in agreement with our own data. Amphetamine stimulation produces no or very blunted responses? ,1°,~3 In the present study we found that GHB is unable to stimulate GH secretion in cocaine addicts. At present, the site of action of GABA or GABAergic drug in the control © Harcourt Brace and Company Ltd 1997
461
of GH secretion is uncertain. However, direct GABAergic effects at the pituitary level are,unlikely, because in vitro studies with GABA or GABAergic drugs do not show stimulatory effects on GH secretion. 14 In contrast, a tuberoinfundibular GABAergic pathway is located in the medio-basal hypothalamus, and it is thought to modulate pituitary GH secretion, acting on GH-RH and/or somatostatin via some unknown mechanism. 1~ The absent GH response to GHB in cocaine addicts cannot be attributed to a greater degree of inhibition by either IGF1 or cortisol, as plasma IGF-1 levels were lower in cocaine addicts then in normal controls and levels of cortisol were similar between the two groups. At present it is unknown whether the failure of GHB to stimulate GH secretion is peculiar to GH secretion, or rather represents part of a more general impairment of GABAergic neurotransmission in the cocaine addicts. In previous studies we have shown an impairment of the ACTH/cortisol, [3-EP and prolactin responses to hyperthermia in cocaine abusers. I6 The increased basal prolactin levels and absent prolactin response suggest that alterations are present in the dopaminergic control of PRL secretion in cocaine-dependent individuals. In chronically cocaine-treated rats, the density of postsynaptic dopaminergic receptors decreases, lz indicating that chronic cocaine administration reduces the dopaminergic activity in the brain. In agreement with this hypothesis, long-term addiction to cocaine is thought to produce dopaminergic depletion in the central nervous system, lz~s In fact, a reduction in symptoms of cocaine craving after treatment with the dopaminergic agonist, bromocriptine, has been reported. 19 GABAergic neurotransmission is known to regulate monoamine release in the central nervous system. The stimulating effect of GABA and GABAergic drugs on GH secretion is thought to be mediated by monoaminergic (particularly dopaminergic) neurons. 2° Our observations suggest that chronic abuse of cocaine induces alterations of the hypothalamic-limbic GABAergic system which were unmasked by the absent GH response to GHB. These neuroendocrine alterations represent a consequence of long-term cocaine abuse, and persist after a relatively short drug-free period. REFERENCES
1. CocoresJA, Dakins CA, GoldMS. Sexualdysfunctionsecondaryto cocaine abuse in two patients.J Clin Psychiatr 1986; 47: 384-385. 2. FormerEJ, EstilowS. Cocaine influences beta-endorphin levels and release. LifeSci 1989; 43: 309-315. 3. MendelsonJH, MelloMK, Teoh SK, EllingboeJ, CochinJ. Cocaine effectson pulsatile secretion of anterior pituitary gonadal and adrenal hormones.J Clin EndocrinolMetab 1989; 69: 1256-1260. 4. VescoviPP, Coiro V, VolpiR, Passeri M. Diurnal variations in plasma ACTH,cortisol and B-EPlevels in cocaine addicts. Horm Res 1992; 37: 221-224. Neuropeptides (1997) 31 (5), 459-462
462
Vescovi & Di Gennaro
5. Galnvin FH, Kleber HD. Neuroendocrine findings in chronic cocaine abusers: a preliminary report. Br J Psychiatry 1985; 147: 569-573.
6. Snead OC, Morley BJ. Ontogeny of GHB acid. Regional concentration in developing rat, monkey and human brain. Brain Res 1981; 227: 579-583. 7. Takahara J, Yunori S, Yakusyi. Stimulatory effects of gammahydroxy butiric acid on growth hormone and prolactin release in humans. Endocrinol Metab 1977; 44: 1014-1018. 8. Morley JE, Krahn DD. Endocrinology for the psychiatry. In: Nemeroff C, Loosen PT, eds. Clinical psychoneuroendocl~rlology. New York: Gufldary Press, 1987: 37-45. 9. Hollander E, Numes E, De Ceria CM et al. Dopaminergic sensitivity and cocaine abuse: response to apomorphine. Psychiatr Res 1990; 33: 161-170. 10. Lee MA, Bowers MM, Nash JF, Meltzer HY. Neuroendocrine measures of dopaminergic function in chronic cocaine users. Psychiatr Res 1990; 33: 151-160. 11. Theo KS, Mendelson JH, Mello NK, Weiss R, McEbroy S, McAfee B. Hyperprolactinemia and risk for relapse of cocaine abuse. Biol Psychiatr 1990; 28: 824-828. 12. Dakis CA, Estroff TW, Sweeney DR, Pottesh ALC, Gold MS. Specificity of the TRH test for major depression in patients with serious abuse. AmJ Psychiatr 1985; 142: 1097-1099. 13. Lee MA, Bowers MM, Nash JF, Meltzer HY. Neuroendocrine measures of dopaminergic function in chronic cocaine users. Psychiatr Res 1990; 33: 151-159.
Neuropeptides (1997) 31(5), 459-462
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