Apomorphine-induced Growth Hormone Research Articles

Influence of DRD2 and ANKK1 genotypes on apomorphine-induced growth hormone (GH) response in alcohol-dependent patients

D(2) receptor function can be assessed by growth hormone (GH) response to apomorphine. Several association studies between dopamine receptor polymorphisms and results of the apomorphine challenge test with normal and alcohol-dependent subjects yielded inconsistent results. In this pilot study, we tested polymorphisms from the DRD2 region for GH response to apomorphine challenge in more detail. Apomorphine challenge tests measuring GH responses on 5 time points were performed on day 1 of alcohol detoxification in 43 patients with alcohol dependence; patients were genotyped for 11 polymorphisms including DRD2, ANKK1, NCAM1 and TTC12. Associations (p<0.05) were found for ANKK1 (rs11604671, rs1800497) and DRD2 (rs6276, rs1076560), which are located on adjacent chromosomal positions. Consistent with PET studies suggesting a reduced D(2) receptor availability in patients carrying the ANKK1 rs1800497 T polymorphism (formerly known as DRD2 TaqI A1) we found a reduced GH response to apomorphine in those subjects. This has been the first study showing significant associations between apomorphine-induced GH response and SNPs in DRD2 and ANKK1 in alcohol-dependent patients. In this respect, our preliminary results are in line with other reports which suggested that DRD2 and ANKK1 polymorphisms influence D(2) receptor availability and signal transduction in the dopaminergic pathways. Small sample size in our study limits the generalizability of our results.

GENETIC STUDY: No association of dopamine receptor sensitivity in vivo with genetic predisposition for alcoholism and DRD2/DRD3 gene polymorphisms in alcohol dependence

This study sought to examine dopamine receptor sensitivity among alcoholics in vivo and to explore whether this sensitivity might be associated with functional variations of dopamine D2 (DRD2) and D3 (DRD3) receptor genes along with a genetic predisposition for alcoholism as reflected by an alcohol-dependent first-degree relative. We analyzed the -141C Ins/Del polymorphism in the promoter region of the DRD2 gene and the Ser9Gly (BalI) polymorphism in exon 1 of the DRD3 gene in 74 alcohol-dependent Caucasian men with or without genetic predisposition for alcoholism. In vivo dopamine receptor sensitivity was assessed by measuring apomorphine-induced growth hormone release. A three-way analysis of variance revealed no significant effects of DRD2, DRD3 genotypes and genetic predisposition on dopamine receptor sensitivity. Given the explorative and preliminary character of this investigation, we cannot provide evidence that in alcohol-dependent Caucasian men a genetic predisposition for alcoholism along with functional variants of the DRD2 and DRD3 genes are associated with differences in dopamine receptor sensitivity.

Neuroendocrinological and neuropsychological correlates of dopaminergic function in nicotine dependence.

There is multiple evidence that nicotine--as with ethanol and other drugs of abuse--stimulates dopamine release in the ventral striatum as a central part of the brain reward circuits. Chronic nicotine exposure leads to changes in these dopaminergic reward circuits. During nicotine withdrawal, an impaired dopaminergic function has been reported. On the behavioral level, this seems to result in motivational disturbances in abstaining smokers. To investigate the impact of smoking on dopaminergic function in humans both on a neuroendocrinological and on a neuropsychological level. Thirty-seven healthy smokers were assessed whilst smoking (test 1) and after abstaining overnight for 12 h (test 2). A control group of 18 non-smokers was also examined twice. Severity of nicotine dependence, incentive motivation, digit span and verbal fluency were assessed. The sensitivity of central dopamine (DA) D2 receptors was assessed with the apomorphine-induced growth hormone (GH) secretion. ANOVA revealed that GH response was significantly lower in smokers than in non-smokers (P=0.04). The GH response was significantly inversely correlated with severity of nicotine dependence (r=-0.39). Neuropsychological performance was not influenced by smoking status. After overnight abstinence from nicotine GH response, digit span and verbal fluency were not affected, whereas incentive motivation was significantly impaired in smokers (P=0.04). Smoking is significantly associated with a reduced sensitivity of central DA D2 receptors. This alteration of dopaminergic sensitivity is stable even after 12 h of abstinence from nicotine. Therefore, the hypothesis that the motivational impairment during withdrawal from nicotine is associated with an altered sensitivity of central DA D2 receptors cannot be supported.

Mu-opioid receptor variants and dopaminergic sensitivity in alcohol withdrawal.

The endogenous opioid system plays an important role in the reinforcing properties of alcohol by an interconnected activation of the mesolimbic dopamine system. The Asn40Asp substitution polymorphism of the human mu-opioid-receptor (OPRM) influences binding of opioids and signal transduction and may, thereby, contribute to the development of alcoholism. The present study tested whether the Asn40Asp substitution polymorphism of the OPRM gene is associated with a variation in central dopaminergic sensitivity during alcohol withdrawal in alcoholics. Sensitivity of central dopamine receptors was assessed by apomorphine-induced growth hormone (GH) secretion in 97 alcohol-dependent patients before and 1 week after alcohol cessation, and in a subgroup of 19 alcoholics after 3 months of abstinence. GH response was defined as area under the hormone/time curve. Comparisons of the GH response were conducted between alcoholics carrying the Asn40Asp genotype versus those with the Asn40Asn genotype using U-test statistics. Marginal differences in apomorphine-induced GH response were found between both genotype groups before detoxification (P = 0.799 (n = 97)/P = 0.459 (n = 19)) and after 3 months of abstinence (P = 0.331 (n = 19)). In contrast, the GH response measured seven days after alcohol withdrawal was significantly increased in alcoholics with the Asn40Asp genotype compared with those carrying the Asn40Asn genotype (P = 0.013 (n = 97)/P = 0.026 (n = 19)). Our results suggest that genetic variation of the mu-opioid receptor modulates the central dopaminergic sensitivity during acute alcohol withdrawal.

Psychopathological and behavioral correlates of dopaminergic sensitivity in alcohol-dependent patients.

To explore 2 facets of dopamine receptor sensitivity in alcoholics: (1) whether reduced sensitivity of central dopamine receptors is correlated with anxiety, depression, or novelty seeking and (2) whether this reduction is associated with poor treatment outcome. Sixty-four alcohol-dependent patients were assessed according to their clinical outcome, sensitivity of central dopamine receptors (apomorphine-induced growth hormone secretion), mood states, and personality traits before and after detoxification. Patients with poor treatment outcome displayed a blunted growth hormone response before, but not after, detoxification. Growth hormone response was not significantly correlated with novelty seeking. Relapsing patients tended to be less depressed than patients who remained abstinent during observation. This study did not support the hypothesis that reduced sensitivity of dopamine receptors is associated with anxiety, depressed mood, or high novelty seeking in alcoholism.

Influence of dopaminergic transmission on severity of withdrawal syndrome in alcoholism.

Dysfunction of dopaminergic transmission has been suggested as influencing withdrawal syndrome in alcohol-dependent patients. Therefore, dopamine levels and sensitivity of dopamine receptors were correlated with the severity of withdrawal syndrome in 40 alcoholics. Dopamine blood plasma levels and apomorphine-induced Growth Hormone (GH) release were measured on the first day of detoxification (Day 1) and after 8 days of abstinence (Day 8). Severity of withdrawal syndrome was assessed daily by the Clinical Institute Withdrawal Assessment (CIWA) score. In the 22 patients (out of the 40) treated by chlormethiazole, severity of withdrawal was measured by the required chlormethiazole dose. A positive correlation was found between dopamine levels on Day 1 and the total CIWA score and necessary chlormethiazole dose, respectively. Correlation with the CIWA score was even stronger when the sensitivity of post-synaptic dopamine receptors was taken into account. No significant correlation between dopamine levels on Day 8 and withdrawal syndrome was found. Our findings indicate an influence of dopaminergic transmission on withdrawal syndrome during early withdrawal.

Lack of allelic association of dopamine D1 and D2 (TaqIA) receptor gene polymorphisms with reduced dopaminergic sensitivity to alcoholism.

Our study tested the hypothesis of whether the sensitivity of central dopamine receptors corresponds to the genotypic constitution of DNA-polymorphisms of the dopamine D1 and D2 receptor (DRD1, DRD2) genes and is associated with poor treatment outcome. Therefore, 97 alcohol-dependent patients were assessed according to their sensitivity of central dopamine receptors (apomorphine-induced secretion of growth hormone), clinical outcome during a 6-month observation period, and genotypic constitution of the TaqIA restriction fragment length polymorphism (RFLP) at the DRD2 locus and of the Bsp1286I RFLP at the DRD1 locus. On the 1st day of detoxification, dopamine receptor hyposensitivity was found in treatment nonresponders, but not in responders. Apomorphine-induced growth hormone release did not differ significantly in alcoholics with different genotypes of the DRD1 and DRD2 RFLPs. Neither did we find a significant allelic association with treatment response. Thus, we did not find evidence for a genetic determination of dopamine receptor hyposensitivity in alcoholics with poor treatment outcome.

Evidence for prolonged recovery of dopaminergic transmission after detoxification in alcoholics with poor treatment outcome.

It has been hypothesized that dysfunction of dopaminergic neurotransmission is involved in the pathogenesis of alcohol addiction. Therefore, peripheral dopamine levels, sensitivity of central dopamine receptors (apomorphine-induced Growth Hormone (GH) secretion), and the inhibitory efficacy of G-proteins on adenylyl cyclase activity (as an indicator for dopamine D2-receptor coupled second messenger mechanisms) were measured in 45 alcohol-dependent patients before and after detoxification and in 10 healthy controls. The time needed to adjust to abstinence conditions differed between patients with good and poor treatment outcome. In subsequent abstainers, effects of alcohol withdrawal were already found during the first 24 hours of abstinence (normalisation of GH response, increases in dopamine levels and the inhibitory efficacy of G-proteins). During the next 7 days of abstinence, no more significant changes were observed in the assessed variables. In subsequent relapsers, no significant effect of acute ethanol withdrawal on the same measures was found. However, at day 8 of abstinence, increases in apomorphine-induced GH secretion (towards normalisation), in dopamine plasma levels, and in the inhibitory efficacy of G-proteins (towards above-normal levels) were observed. This retarded adjustment of dopaminergic signal transduction seems to reflect the relapse risk of treatment nonresponders.

Effect of oestradiol treatment on 5-HT and dopamine-mediated neuroendocrine responses

We assessed the effect of oestradiol treatment in women on the endocrine responses to the 5-hydroxytryptamine (5-HT) precursor, L-tryptophan (LTP) (5 g i.v.) and the dopamine agonist, apomorphine (0.005 mg/kg s.c.). Following oestradiol implant (100 mg s.c.) the prolactin (PRL) response to LTP was significantly enhanced but there was no change in the growth hormone (GH) response to apomorphine. There was, however, a significant correlation between post-implant oestradiol concentrations and post-implant apomorphine-induced GH release. The results indicate that oestrogen treatment may facilitate 5-HT-mediated PRL release and could also influence the regulation of dopamine-mediated GH responses. However, further studies are needed to exclude direct effects of oestradiol on the pituitary release of PRL and GH.

Reduced growth hormone response to apomorphine in schizophrenic patients with poor premorbid social functioning.

The apomorphine-induced growth hormone (GH) response of 16 drug-free schizophrenic patients and nine control subjects were studied. The subgroup of nine patients with poor premorbid psychosocial functioning had a significantly lower GH response than the controls. Additional evidence for state dependent effects is provided.

Relationship of psychotic symptom clusters in schizophrenia to neuroleptic treatment and growth hormone response to apomorphine

The authors propose an alternative model for relating clinically rated psychotic symptoms to biological measures in schizophrenic patients. They suggest that clinical presentation in schizophrenic patients comprises at least four distinct psychotic symptom clusters and that at most one or two of the symptom clusters are closely associated with central dopamine (DA) activity as measured by growth hormone (GH) response to apomorphine. Factor and cluster analytic techniques both identified the same four psychotic symptom clusters, three of which were similar to the major subtypes of schizophrenia: paranoid delusions (paranoid type), thought disorder (disorganized type), and catatonia (catatonic type). The fourth psychotic symptom cluster was auditory hallucinations, a prominent clinical feature of schizophrenia. The authors compared clinical symptom cluster scores to apomorphine-induced GH response by creating a new data set containing the output of the factor analysis of each patient's symptoms and GH response, and performing regression modeling of the patient's symptom cluster scores on GH response. Patients with elevated thought disorder cluster scores also had elevated GH responses to apomorphine, suggesting an association between thought disorder and central DA receptor supersensitivity. A fixed-dose neuroleptic trial showed that thought disorder and auditory hallucinations respond rapidly to treatment with a DA receptor blocker (haloperidol), while no significant effect on other symptom cluster scores occured during the initial 2 weeks of treatment. These data suggest that two of the identified symptom clusters, thought disorder and auditory hallucinations, may be preferentially associated with central DA hyperactivity.

CCK-8 antagonizes apomorphine-induced growth hormone secretion in normal subjects.

Cholecystokinin octapeptide (CCK-8) (5 ug iv over 10 minutes) administered to normal men had no effect on basal growth hormone (GH) or prolactin secretion but significantly antagonized the GH response to the dopamine (DA) receptor agonist, apomorphine HCI (Apo) (0.5 mg sc), 30 (P less than 0.05) and 45 minutes (P less than 0.01) after Apo injection (n = 8). These results are compatible with an inhibitory effect of CCK-8 on certain DA mechanisms in the hypothalamic-pituitary axis. Whether CCK-8 affects DA function in other brain regions in man is unknown.

Advances in medical social science, vol. 1

1.Interpretation of neuroendocrine studies in schizophrenia requires consideration of (a) the large number of variables that affect drug-induced endocrine responses (b) the effect of prior neuroleptic therapy (c) heterogeneity of schizophrenia (d) heterogeneity of receptors (e) uniqueness of the hypothalamic-pituitary axis (f) selectivity and pharmacokinetics of administered drugs.2.Apomorphine increases growth hormone secretion by an effect on dopamine receptors that are not linked to adenylate cyclase and which are located outside the blood brain barrier.3.Hypothalamic-pituitary histaminergic H2 and α-adrenergic function are unchanged in chronic schizophrenia.4.Schizophrenic symptoms persist despite complete blockade of dopamine receptors modulating prolactin secretion.5.Studies on dopamine receptors modulating prolactin secretion are unlikely to shed light on the pathophysiology of schizophrenia.6.Screening for drugs which block apomorphine-induced growth hormone secretion but do not increase prolactin may provide a way of detecting anti-schizophrenic drugs which are devoid of side effects associated with hyperprolactinemia and which do not induce parkinsonism or tardive dyskinesia.

CCK-33 antagonizes apomorphine-induced growth hormone secretion and increases basal prolactin levels in man

Cholecystokinin (CCK-33) (225 Ivy Dog Units intravenously) had no effect on basal growth hormone (GH) secretion but antagonized the GH response to the dopamine receptor agonist, apomorphine HCl (0.5 mg sc) (N = 7), and induced a transient increase in basal prolactin (PRL) secretion (N = 8) in normal men. These findings are similar to those desoribed with neuroleptics and are compatible with an inhibitory effect of CCK-33, or fragments, on dopamine function in man, at least in the hypothalamic-pituitary axis. However, an inhibitory effect of CCK-33 on the release of GH and a stress-induced increase in PRL secretion cannot be excluded.

Growth hormone and prolactin response to apomorphine in schizophrenia and the major affective disorders. Relation to duration of illness and depressive symptoms.

The responses of serum prolactin (PRL) and growth hormone (GH) to the dopamine agonist apomorphine hydrochloride (0.75 mg subcutaneously) were studied in a large group of unmedicated hospitalized patients with functional psychoses. There were no differences in the GH response in various diagnostic groups. The PRL response was greater in patients with affective disorders. The GH response was inversely related to total duration of illness in the entire sample of patients, but this correlation was independent of age effect only in the group of patients with major depression. In schizophrenics, the effect of the two factors, age and duration of the illness, could not be separated. The apomorphine-induced GH response was significantly correlated with psychosis ratings and negative symptom scale scores. The apomorphine-induced PRL suppression correlated significantly with various measures of depression across diagnostic groups.

Apomorphine induced growth hormone secretion in anorexia nervosa

(1) Five female in-patients suffering from anorexia nervosa of moderate-severe degree were given the dopamine receptor agonist apomorphine. The growth hormone (GH) secretion induced by this stimulation was measured and the results compared with those of age-matched healthy female controls. (2) In contrast to most previous reports we failed to demonstrate elevated basal levels of GH in the anorectic group compared to the controls. (3) None of the anorectic patients showed any increase in GH values after apomorphine compared to 5 out of 9 controls. It is concluded that the failure to respond is not dependent on a high basal level of GH. (4) Our results lend support to the notion that there may be some abnormality in hypothalamic function possible involving dopamin receptor activity in anorexia nervosa.Jan Wglinder, M.D., Ph.D., Professor, Department of Psychiatry, University Hospital, University of Linkoping, S-581 85 Linkoping SwedenJan Balldin, M.D., Ph.D., Consultant, Department of Psychiatry and neuroch...

Effect of CCK-33 on prolactin and apomorphine-induced growth hormone secretion in man.

Effect of CCK-33 on prolactin and apomorphine-induced growth hormone secretion in man.

Neuroendocrine evaluation of CCK-peptides on dopaminergic function in man

1. 1. CCK-33 (225 Ivy Dog Units iv) antagonized the growth hormone response to the dopamine receptor agonist, apomorphine HCl (0.5 mg sc), and increased basal prolactin secretion in normal male volunteers. A stress mediated prolactin effect could not be excluded. 2. 2. CCK-8 (5 ug iv) antagonized the growth hormone response to apomorphine but had no effect on basal prolactin or plasma homovanillic acid. 3. 3. Ceruletide (0.3 ug/kg im) had no effect on basal prolactin or apomorphine-induced growth hormone secretion. 4. 4. CCK-33, CCK-8 and ceruletide had no effect on basal growth hormone secretion which suggests that they do not inhibit the release of growth hormone. 5. 5. These findings are compatible with an inhibitory effect of CCK-33 and CCK-8 (or fragments) on dopaminergic function in man, at least in the hypothalamic-pituitary axis and point to a simple way to study the effect of peptides on dopaminergic function in man including those which may not cross the blood brain barrier.

Biological studies of DSM-III psychotic disorders. I. Platelet measures and apomorphine-induced growth hormone response.

The relationship between DSM-III schizophrenia, major affective disorders, and the psychotic disorders not elsewhere classified (PDNEC) can be explored through studies which attempt to determine whether these disorders can be differentiated from one another and normal controls by biological measures. Preliminary results of an ongoing project which utilizes measures of blood platelet monoamine oxidase (MAO), serotonin (5-HT) uptake, and 5-HT content, and the apomorphine-induced increase in growth hormone (GH) to accomplish these goals are reported here. DSM-III major affective disorders (bipolar disorder and major depression) can be differentiated from normal controls by the V max of platelet 5-HT. Platelet 5-HT V max of bipolar disorder, depressed type, is significantly different from that of schizophrenia and PDNEC. Elevated platelet 5-HT content is present in black schizophrenic patients compared to black normal controls. Platelet MAO was increased in a small group of schizophreniform female patients. There was no difference in the apomorphine-induced GH response between any of the diagnostic groups. If confirmed in a larger series of patients, these results tend to identify the PDNEC more closely with schizophrenia than the major affective disorders.

Effect of sulpiride, an atypical neuroleptic, on apomorphine-induced growth hormone secretion

NAIR, N. P. V., S. LAL, H. I. ISKANDAR, P. ETIENNE, P. L. WOOD AND H. GUYDA. Effect of sulpiride, an atypical neuroleptic, on apomorphine-induced growth hormone secretion. BRAIN RES. BULL. 8(6) 587–591, 1982.—Sulpiride (100 mg IM), an atypical neuroleptic, which does not block dopamine (DA) receptors that are linked to adenylate cyclase, abolished the growth hormone (GH) response to the DA receptor agonist, apomorphine (Apo) HC1 (0.5 mg SC) in seven healthy male subjects. These results suggest that Apo increases GH secretion in man by an effect on DA receptors that are not linked to adenylate cyclase.