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Schizophrenia may reflect a sensitization of dopaminergic (DA) function. Apomorphine (Apo), a DA receptor agonist, induces both sensitization and tolerance of DA function in rodents depending on dose intervals. We investigated sensitization and tolerance to Apo in healthy male volunteers. After a period of acclimatization to the experimental setting (Day 1) subjects were assigned randomly to two groups: Group A subjects received seven injections of placebo (physiological saline) (PLA) and Group B subjects received seven injections of Apo HCl (7 microg/kg sc) under double-blind conditions at 2 h intervals commencing at 0930 hours (Day 2) after an overnight fast. Twelve hours after the seventh injection, i.e. on Day 3, after an overnight fast all subjects received an injection of Apo. Serial samples of blood commencing at 0900 hours were drawn after the first and last injection in both groups for assay of growth hormone (GH), prolactin (PRL) and cortisol by radioimmunoassay; sleepiness was measured using the Analog Sleepiness Rating Scale and yawning recorded by video recorder. The GH response in Group B (N = 8) was (a) decreased after the eighth injection of Apo compared with the first injection of Apo (P = 0.03) and (b) decreased after the eighth injection of Apo compared with the first injection of Apo in Group A (N = 10) (P = 0.001). The number of yawns in Group B was significantly decreased after the eighth injection of Apo compared with the first injection of Apo (P = 0.042). PRL, cortisol and sleepiness were not significantly different between the first and eighth injection of Apo. Sensitization was not observed in any of the measures studied. These results are compatible with induction of acute tolerance of DA-mediated GH and yawning responses. The method used provides a safe pharmacological paradigm to examine plasticity of DA mechanisms in man. Results are discussed in the context of possible therapeutic implications for schizophrenia.

Summary Dysfunction of the hypothalamic–pituitary–adrenal (HPA)-axis has been observed in chronic alcoholics and in non-alcoholic sons of alcoholic parents, while genetic and environmental factors, such as stress, may play a significant role in the development of alcoholism. The present study was designed to investigate the response of the HPA-axis to alcohol and stress as a function of family history of alcoholism and chronic alcohol abuse. We determined changes in plasma adrenal corticotrophin (ACTH) and cortisol concentrations in response to a placebo or an alcohol (0.50 g ethanol/kg body wt) drink and to a stress task performed 30 min following ingestion of either the placebo or the alcohol drink in social and heavy drinkers with [high risk (HR)] and without [low risk (LR)] a family history of alcoholism. Thus, four groups of healthy male individuals, low risk with no alcohol-dependence diagnosis (LRNAD), high risk with no alcohol-dependence diagnosis (HRNAD), low-risk alcohol dependent (LRAD) and high-risk alcohol dependent (HRAD), participated in the four experimental sessions given in random order. Basal plasma ACTH levels of LRNAD participants were higher from those of the other three groups of participants. Basal plasma cortisol levels of HRAD participants were higher from those of LRNAD and HRNAD but not of LRAD participants. The stress-induced increases of plasma ACTH and cortisol concentrations were more pronounced in LRNAD participants. The alcohol drink prevented the stress-induced increases in plasma ACTH and cortisol of all groups of participants. The self-ratings of anxiety were attenuated in LRNAD and LRAD participants in the alcohol only session and in HRNAD and HRAD participants in the alcohol plus stress session. In conclusion, there are differences in the activity of the HPA-axis as a function of family history and alcohol dependence, while the effect of an alcohol drink on the self-rating of anxiety may be influenced by both family history and stress.

Individuals with a family history of alcoholism may present a dysfunction in the activity of the hypothalamic-pituitary-adrenal (HPA) axis that predates the development of alcoholism.The present study investigated the hypothesis that this HPA-axis dysfunction is associated with alterations in the pattern of the circadian (24 h) secretions of adrenal corticotropic hormone (ACTH), cortisol, and beta-endorphin.Men with [high risk (HR)] or without [low risk (LR)] family history of alcoholism participated in the study. Blood samples were drawn every 30 min for 24 h for estimation of the plasma hormone levels. Participants ingested meals at predetermined intervals and filled out mood questionnaires prior to the placement of the catheter and 1 h after each meal.The circadian peaks for beta-endorphin, ACTH, and cortisol occurred between 0800 and 0830 hours in both LR and HR participants. The plasma ACTH and beta-endorphin concentrations were lower in HR than LR participants, while the plasma cortisol concentrations were similar between HR and LR participants. For each hormone, the total 24-h secretion was estimated from the area under the 24-h time-concentration curve (AUC). For ACTH and beta-endorphin, but not the cortisol, AUC were lower in HR than LR participants. LR participants reported being more nervous than HR participants. For the LR participants, but not HR participants, the initial mood ratings of "nervous" were positively correlated with the initial plasma cortisol and beta-endorphin concentrations as well as with the cortisol and beta-endorphin AUC.HR participants presented lower plasma concentrations as well as lower AUC for beta-endorphin and ACTH but not for cortisol. This suggests a dysfunction of the HPA-axis in HR participants that predates the development of alcoholism and a dissociation between plasma ACTH and cortisol levels as a function of family history of alcoholism.

UNLABELLED We report on a 10-year longitudinal study on 24-h serum melatonin secretion (AUC) in healthy human subjects. Fifty women and 53 men (aged 42-83 yr) participated in the study initially. Of these, 18 women and 15 men were followed for 6 consecutive years. RESULTS (a) Cross-sectional analysis (n = 103): A significant (R = -.49, P =.0001) decline in AUC melatonin with age was found in women, but not in men. (b) Longitudinal analysis (n = 33): Repeated-measure ANOVAs for women (n = 18): Time: linear F(1,17) = 5.14, P =.037. The AUC increased by about 40% over the six-year period. In men, there were no significant changes. CONCLUSION In agreement with most cross-sectional studies, an inverse relationship was found between melatonin secretion and age. However, the longitudinal study showed an increase in melatonin secretion, indicating the presence of putative compensatory mechanisms during healthy aging. Changes in melatonin secretion were gender specific, occurring in women only.

Both genetic and environmental factors, such as stress, are important in determining alcohol consumption. Furthermore, both stress and alcohol influence the activity of the hypothalamic-pituitary-adrenal (HPA)-axis. Thus, the present studies investigated the response of the HPA axis to stress and the effect of ethanol on the stress response, in subjects at high (HR) and low (LR) risk of alcoholism as determined from their family history. Twenty HR and 20 LR subjects performed a stress-inducing task 30 min following the ingestion of either a placebo drink or a low dose of ethanol. The levels of plasma adrenal corticotropic hormone (ACTH) and cortisol were measured prior to and for four hours following initiation of the treatment. Changes with time in the plasma hormone levels following ingestion of either a placebo or an ethanol drink, without the performance of the stress task, served as controls to compare the stress-induced changes. Neither the placebo nor the ethanol drink altered the plasma ACTH and cortisol concentrations. High risk subjects presented lower basal ACTH, but not cortisol, levels and a lower stress-induced increase in plasma ACTH concentration than LR subjects. Furthermore, the HR subjects presented a delayed post-stress recovery of the plasma ACTH and cortisol levels. Ethanol consumption prior to the stress task attenuated (ACTH) or abolished (cortisol) the stress-induced increase in the plasma hormone concentrations of both LR and HR subjects. Thus, there are quantitative differences on the response of the HPA-axis to stress between HR and LR subjects, while ingestion of low amounts of ethanol prior to the performance of the stress task had a similar effect on HR and LR individuals.

BACKGROUND Genetic and environmental factors, such as stress, are important for the initiation and maintenance of heavy drinking, whereas beta-endorphin may be important in controlling alcohol consumption. These studies investigated the response of pituitary beta-endorphin to stress and the effect of alcohol on the stress response in subjects at low (LR) and high (HR) risk of alcoholism, as determined from their family history. METHODS Twenty LR and 20 HR subjects were exposed to stress 30 min after ingestion of either a placebo or an alcohol drink. Plasma beta-endorphin was measured before and for 4 hr after the drink. Changes in the concentration of plasma beta-endorphin after ingestion of the placebo or alcohol drink alone served as controls to compare the stress-induced changes. Pulse and diastolic and systolic blood pressure were also measured. RESULTS HR subjects presented higher baseline values of pulse and systolic blood pressure and lower plasma beta-endorphin than LR subjects. Stress induced a small increase in cardiovascular activity, whereas alcohol induced a stronger stimulation. Alcohol before stress did not prevent the stress-induced increase in cardiovascular activity. Stress, but not alcohol, increased the plasma beta-endorphin concentration. LR subjects presented a higher stress-induced increase in plasma beta-endorphin and a faster recovery than HR subjects. Alcohol before stress attenuated the stress-induced increase in plasma beta-endorphin in both LR and HR subjects. This attenuation was stronger in LR subjects. CONCLUSIONS Thus, there are differences in the response of beta-endorphin to stress and the effect of ethanol on stress responses as a function of a family history of alcoholism.

1. Apomorphine (Apo), a dopamine receptor agonist used extensively in clinical research, is known to be chemically unstable. The authors have used a high performance liquid chromatography (HPLC) method to study the long-term stability of pharmaceutical preparations of R(−) Apomorphine hydrochloride (ApoHCl) for parenteral use. 2. In a concentration of 1 mg/ml, ApoHCl in aqueous solutions of sodium metabisulphite (0.125%), kept at 4° and shielded from light, was found to be stable for up to six months. On the other hand, solutions of 0.1 mg/ml were found to decompose after only three weeks, showing extraneous peaks in the HPLC. However, the blue-green discoloration, characteristic of Apo degradation, was only apparent after six weeks storage. 3. The rapidity of the HPLC method used, its reproducibility and sensitivity make it suitable for quality control studies of pharmaceutical preparations of ApoHCl intended for clinical research.

One night's sleep deprivation (SD) increased the growth hormone (GH) response to clonidine (2 ug/kg iv) in 11 normal men (p < 0.005). This finding may indicate that SD enhances alpha-2 adrenergic receptor function or that the GH response to GH releasing factor is increased by SD.

Numerous human and animal studies suggest that certain genetic factors may increase an individual's vulnerability to excessive alcohol consumption. Human and animal studies suggest that some of the reinforcing effects of ethanol may be mediated by the endogenous opioid system. In human studies, plasma levels of subjects genetically at high risk for excessive alcohol consumption showed lower basal activity of beta-endorphin, and more pronounced release of beta-endorphin in response to ethanol. In animal studies, the hypothalamus of mice bred for ethanol preference showed high basal activity of beta-endorphin and more pronounced release of beta-endorphin in response to ethanol than control mice. An important factor in the development of excessive ethanol consumption is the increase in opioidergic activity shortly after individuals begin drinking ethanol. Increased opioidergic activity could mediate the rewarding effects of ethanol, reinforce the act of drinking, and increase ethanol consumption. Human and animal studies, in which the administration of the opioid antagonists naloxone and naltrexone decreased ethanol consumption both by ethanol-preferring animals and by recovering alcoholics, support this hypothesis.

The stereospecificity of the D-2 receptor mediating the growth hormone (GH) response to apomorphine (Apo) and the D-2 receptor regulating prolactin (PRL) secretion were investigated in 10 normal men by examining the effects of cis-flupenthixol (cis-Fx) and trans-flupenthixol (trans-Fx). cis-Fx (1 mg six hourly times four doses) antagonized the GH response to Apo HCl (0.5 mg sc) and increased basal serum PRL concentrations whereas the trans-isomer showed no effect. These findings (a) provide further evidence that the GH response to Apo is mediated by stimulating dopamine (DA) receptors, and, (b) demonstrate stereospecificity of the DA receptor mediating the GH response to Apo and the DA receptor regulating PRL secretion.

1. There is some evidence that androgens affect dopaminergic function in animals and man. We investigated the effect of methyltestosterone (MT) (30 mg po) on the growth hormone (GH) response to the dopamine (DA) receptor agonist, apomorphine (Apo) HC1 (0.5 mg sc), in 9 normal men. MT was given 2 hr before Apo. 2. The peak plasma MT concentration was present 1 hr after administration (19.9 +/- 19.5 ng/ml; X +/- SD); the concentration at 4 hr was 7.2 +/- 4.9 ng/ml. At the time of Apo administration, plasma MT varied from 6.0-24.1 ng/ml. 3. There was no significant effect of MT on Apo-GH secretion (interaction F(7,56) = 1.08; p = NS). The mean individual peak GH concentration after Apo alone was 20.2 +/- 11.9 (X +/- SD) vs 22.2 +/- 9.9 ng/ml when MT preceded Apo (p = NS). 4. These results suggest that exogenous androgens do not affect DA receptor function in males with normal androgenic function. Lack of effect due to an insufficient dose or duration of administration of MT cannot be excluded.

Preliminary findings suggest that patients with borderline personality disorder (BPD) have disturbed serotonin (5-hydroxytryptamine (5HT) neurotransmission. At least some patients have decreased cerebrospinal fluid (CSF) concentrations of the 5HT metabolite, 5-hydroxyindoleacteic acid (5HIAA) (Gardner et al 1990), decreased prolactin responses to both fenfluramine (Coccaro et al 1989), and meta-chlorophenylpiperazine (mCPP) (Hollander et al 1994), and increased cortisol release following mCPP (Hollander et al 1994). Serotonergic disturbances in BPD patients might be different in men and women. Hollander et al (1994) reported that men, but not women patients differed from healthy controls in their mCPP-stimulated release of prolactin and cortisol. As the authors noted, a gender difference might be attributable to circulating ovarian hormones. Perhaps related to this hypothesized difference, prepubertal boys (males who might be hormonally more similar to women than men) with attention deficit hyperactivity disorder (ADHD) plus aggressive features have increased, rather than decreased, prolactin responses to fenfluramine (Halperin et al 1994). The possibility of a gonadal hormone mediated difference in 5HT function among BPD patients indicated the need for an explicit test. Moreover, the relative absence of physiologic studies of BPD women is striking given that the majority of patients are women. Therefore, we investigated 5HT functioning in BPD women as assessed by fenfluramine stimulated pituitaryadrenal activity, and all were tested during their luteal phase. We hypothesized that, if women BPD patients have disturbed serotonergic activity, then, compared to healthy controls, they would have different plasma levels of prolactin and cortisol following the administration of fenfluramine.

Background Evidence indicates that both genetic and environmental factors, such as stress, may play an important role for the development of alcoholism, while beta-endorphin may be implicated in the control of alcohol consumption. The objective of the present studies was to test the hypothesis that there are differences in the response of the pituitary beta-endorphin system to stress as a function of family history of alcoholism and alcohol dependence. Methods The response of the pituitary beta-endorphin to a placebo or an alcohol (0.50 g ethanol/kg) drink and to a stress task performed 30 min following ingestion of either the placebo or the alcohol drink was measured in social and heavy drinkers with [high risk (HR)] and without [low risk (LR)] a family history of alcoholism. Thus, each subject participated in 4 experimental sessions given on different days in a randomized order. Four groups of subjects were investigated: 1) low risk nonalcoholics (LRNA); 2) high risk nonalcoholics (HRNA), 3) low risk alcoholics (LRA); and 4) high risk alcoholics (HRA). Plasma beta-endorphin was estimated prior to and for 3.5 hr post-stress. Changes in the concentration of plasma beta-endorphin following ingestion of either the placebo or alcohol drink without performance of the stress task served as controls to compare the stress-induced changes. Results Basal plasma beta-endorphin levels were higher in LRNA than LRA, HRNA and HRA participants, while basal plasma beta-endorphin levels were higher in LRA than those in HRNA and HRA participants. Furthermore, there was no significant difference in the plasma beta-endorphin levels between HRNA and HRA participants. Stress, induced a significant increase in plasma beta-endorphin concentration in all four groups of participants. However, the stress-induced increase in plasma beta-endorphin levels was more pronounced in LRNA than HRNA, LRA and HRA participants. Thus, alcohol dependence decreased the basal plasma beta-endorphin levels in LR only, as well as the stress induced increase in plasma beta-endorphin levels of participants without, but not of those with, a family history of alcoholism. Alcohol prior to stress attenuated the stress-induced increase in plasma beta-endorphin levels of all four groups of participants. Conclusions The present data indicates that there are differences in both, the basal plasma beta-endorphin levels as well as the response of the pituitary beta-endorphin to stress as a function of family history of alcoholism and alcohol dependence. Thus, in HR individuals a dysfunction in the activity of the pituitary beta-endorphin system predates the development of alcoholism, while in LR individuals it develops following alcohol dependence. Furthermore, alcohol dependence did not alter the alcohol-induced attenuation of beta-endorphin response to stress.

We describe a subject who developed prolonged penile erections on hydroxyzine. Molecular modelling showed that the hydroxyzine metabolite, norchlorcyclizine, has structural and conformational similarities to the trazodone metabolite, m-chlorophenylpiperazine. This suggests that a common pharmacological mechanism may underlie the ability of trazodone and hydroxyzine to induce erections.

We investigated the effect of nicotine on three behavioral markers of risk for schizophrenia: sustained attention (using the Continuous Performance Task (CPT)), antisaccade performance, and smooth pursuit. Smooth pursuit was investigated in two conditions, one in which attention was enhanced (monitoring target changes) and one in which attention was not enhanced (no monitoring). Patients with schizophrenia (n = 15) and controls (n = 14) were given a 14-mg nicotine patch in a double-blind, placebo-controlled, crossover design and plasma nicotine concentrations were monitored. Nicotine concentrations were similar in both groups. A Group x Drug interaction (p.02) on CPT hits indicated that nicotine improved sustained attention in patients but not in controls. Nicotine significantly decreased antisaccade errors (p.01) in both groups. A Drug x Monitoring condition interaction (p.01) on pursuit gain indicated that nicotine significantly increased pursuit gain in the no-monitoring condition in patients and controls equally, but did not improve pursuit in the monitoring condition. Thus, improvement in pursuit may have been mediated via an effect on attention rather than by an effect on oculomotor function per se. In patients, the magnitude of improvement in attention on nicotine was correlated with the improvement on eye movement tasks. Thus, nicotine improves performance on both attention and oculomotor markers of risk for schizophrenia, possibly via common mechanisms.

The exploratory eye movements of patients with schizophrenia reportedly differ from those of patients without schizophrenia and healthy controls. In an attempt to determine whether exploratory eye movements provide valid markers for schizophrenia, the present collaborative study was conducted in six countries to analyze the stability of and variation in the following parameters of exploratory eye movements: the number of eye fixations (NEFs) and mean eye scanning length (MESL) in a retention task; the cognitive search score (CSS) that indicates how frequently the eye focused on each important area of a figure in order to recognize it in a comparison task; and the responsive search score (RSS), which reflects the frequency of eye fixations on each section of a figure in response to questioning in a comparison task. In addition, we investigated the validity of the currently employed discriminant function to extract a common feature of schizophrenia by applying it to the findings of the present study. The exploratory eye movements of 145 patients with schizophrenia, 116 depressed patients and 124 healthy controls at seven WHO collaborative centers in six countries were measured using eye mark recorders during viewing of stationary S-shaped figures in two sequential tasks. The RSSs of patients with schizophrenia were found to be significantly lower than those of depressed patients or healthy controls irrespective of geographical location, with no significant difference existing between the RSSs for depressed patients and those for healthy controls. By inserting the RSS and NEF data for each subject into the formula used to calculate discriminant function, patients with schizophrenia could be discriminated from depressed patients and healthy controls with a sensitivity of 89.0% and a specificity of 86.7%. The RSS is an exploratory eye movement parameter that detected schizophrenia irrespective of culture, race and various other subject variables. Furthermore, it is indicative of the stable, significant difference that exists between subjects with and without schizophrenia. The results of discriminant analysis confirm the previously reported validity of discriminant function.

The yawning response to the dopamine (DA) receptor agonist apomorphine HCl (Apo, 7 μg/kg s.c.) and placebo (physiological saline) were examined in two groups of normal men. One group (n = 11) was investigated in the morning and the other group (n = 16) in the afternoon. The frequency of yawning was polygraphically monitored for 60 min following injection. Apo increased yawning compared with placebo when given in the morning (p < 0.02), but not when given in the afternoon. Yawning frequency was increased after both Apo (p < 0.01) and placebo (p < 0.025) when given in the morning compared with responses in the afternoon. These results suggest that yawning frequency with both Apo and placebo is influenced by time of day, possibly as a result of diurnal variation in DA receptor sensitivity.

Previous studies have demonstrated that, in human, acute consumption of high doses of ethanol, administered in a large quantity of fluid, with or without volume-loading, induced either a decrease or an increase in the plasma content of atrial natriuretic peptide (ANP)-a substance that has a hypotensive effect. The objective of the present study was to examine the effect of low doses of ethanol (0, 0.25, and 0.50 g of ethanol/kg of body weight) administered to six normoten-sive individuals, in a small volume of fluid without prior volume-loading. Before and at various intervals after administration of the placebo or ethanol drinks, heart rate and blood pressure were measured and blood samples were taken for estimation of the plasma ANP, arginine vasopressin, and cortisol contents. Results indicated small changes in blood pressure and heart rate after ingestion of either the placebo or ethanol drinks. On the other hand, a significant increase in the plasma ANP content was observed at 15 min after ingestion of both the 0.25 and 0.50 g of ethanol/kg of body weight doses, but not after the placebo drink. Plasma ANP levels were still elevated at 45 min postethanol intake, but had returned to basal levels at 120 min after the ethanol drink. Interestingly, it was noticed that the higher dose of ethanol (0.50 g) did not induce a higher plasma ANP concentration than the lower dose (0.25 g) of ethanol; however, the plasma ANP content remained elevated for a longer period. Furthermore, the increase in plasma ANP content was not due to ethanol or stress-induced increases in the plasma arginine vasopressin and cortisol contents, because the plasma concentration of these hormones remained either at basal or below basal levels for the duration of the experiment. In conclusion, ingestion of low amounts of ethanol equivalent to 1 or 2 standard drinks induced an increase in plasma ANP content.

One night's sleep deprivation (SD) increased the growth hormone (GH) response to clonidine (20 ug/kg i.v.) in 11 normal men ( p0.005). This finding may indicate that SD enhances alpha-2 adrenergic receptor function or that the GH response to GH releasing factor in increased by SD.

Both clinical symptomatology and stress research suggest that panic attacks might be partially attributable to exaggerated psychophysiological responses to environmental stressors. In the present study, we aimed to explicitly test this idea by measuring the physiological responses to a mild psychological stressor in both healthy controls (n = 8) and fully remitted, medication-free panic disorder patients (n = 8). One hour before the stressor, former patients, compared to healthy controls, exhibited higher diastolic blood pressure. From a blood sample taken 30 min before the stressor, patients, compared to controls, had lower paroxetine platelet binding site densities. During the stressor, patients, compared to controls, had greater increases in plasma levels of cortisol. These preliminary findings suggest that remitted panic disorder patients might have disturbed physiological responses to mild psychological stressors. These disturbances might be related to the development of future episodes.

Background: Previous studies have demonstrated that a moderate dose of ethanol induced a significant increase in the plasma β-endorphin content of subjects from families with a history of alcoholism (high risk [HR]), but not of subjects from families without a history of alcoholism (low risk [LR). The objective of this study was to examine the response of the pituitary β-endorphin and adrenal cortisol systems to various concentrations of ethanol in male and female subjects at high and low risk of the future development of alcoholism. Methods: All subjects participated in four experimental sessions. In each session the subjects were given a drink containing one of the following doses of ethanol: O, 0.25, 0.50, and 0.75 g of ethanol per kilogram of body weight (for a 60- to 70-kg individual). Blood samples were taken at 0 minutes and at 15, 45, 120, and 180 minutes after the drink for estimation of the blood alcohol, plasma β-endorphin, and plasma cortisol levels. Results: The concentration of alcohol in the blood at various intervals after the drink was similar among the subjects, regardless of the risk group. Ethanol increased the plasma level of β-endorphin-related peptides of the HR but not of the LR subjects in a dose-dependent manner. All subjects showed a small decrease in plasma cortisol level with time, but ethanol ingestion did not significantly alter the plasma cortisol levels. Conclusion: This study indicates that the pituitary β-endorphin system, but not the adrenal cortisol system, of the HR subjects shows an enhanced sensitivity to ethanol, which may be an important factor in controlling ethanol consumption.

Apomorphine HCl (Apo) (0.5 mg sc), but not placebo, induced an erectile response (monitored with a mercury strain gauge) lasting 40 min in an impotent hyperprolactinemic patient. Serial blood sampling modified the 40 min erectile response. Prompt detumescence followed by complete or partial restoration of tumescence occurred each time blood was drawn. This observation points to the sensitivity of the Apo-erectile response to experimental procedures subjectively perceived as anxiogenic.

Objective: To compare the cardiac safety and therapeutic efficacy of trirnipramine and doxepin. Design: A 1-week single-blind placebo period followed by a 5-week randomized double-blind parallel group clinical trial. Setting: Psychiatric out-patient clinic of a general hospital. Patients: 37 young-elderly patients with a diagnosis of Major Depressive Episode (DSM-III criteria). Interventions: Placebo for 1 week, 2 weeks of titration with either drug in the dosage range of 75 mg/day up to a maximum of 200 mg/day. Measurements: We measured the psychiatric effects with the Hamilton Rating Scale for Depression, the Hamilton Anxiety Rating Scale, and the Clinical Global Impression Scale. Cardiovascular effects were assessed on 12-lead standard electrocardiograms plus 1-minute rhythm and high speed recordings; orthostatic (lying/standing) blood pressures were also taken. Physical exams, lab tests, cognitive functions (Buschke Selective Reminding Test, Hierarchic Dementia Scale, Word Fluency) and adverse reactions were also noted. Results: Both drugs were equally effective in relieving symptoms of depression and anxiety. The cardiovascular effects of both drugs were minimal. Trimipramine did lower blood pressure but this was without clinical significance. Three trimipramine patients and five doxepin patients developed occasional premature ventricular or atrial contractions. Of these, two trimipramine patients and one doxepin patient were among those with abnormal ECG's at entry. The doxepin patient was withdrawn from the study after 21 days of treatment when the PVC's became increasingly frequent. Conclusions: Trimipramine and doxepin are equally safe and effective antidepressants in the young-elderly.

An open pilot study was undertaken to investigate the therapeutic effect of the dopaminergic agent, bromocriptine (BC), in impotent patients who developed an erectile response to the dopamine receptor agonist, apomorphine. Eight out of 17 patients reported improvement in ability to obtain an erection; five of these 8 subjects were able to achieve penetration. The optimum dose of BC was 2.5 - 11.25 mg/day. A double-blind placebo-controlled study is merited.

The stereospecificity of the D-2 receptor mediating the growth hormone (GH) response to apomorphine (Apo) and the D-2 receptor regulating prolactin (PRL) secretion were investigated in 10 normal men by examining the effects of cis-flupenthixol (cis-Fx) and trans-flupenthixol (trans-Fx). cis-Fx (1 mg six hourly times four doses) antagonized the GH response to Apo HCl (0.5 mg sc) and increased basal serum PRL concentrations whereas the trans-isomer showed no effect. These findings (a) provide further evidence that the GH response to Apo is mediated by stimulating dopamine (DA) receptors, and, (b) demonstrate stereospecificity of the DA receptor mediating the GH response to Apo and the DA receptor regulating PRL secretion.

Sixty insomniac patients participated in a controlled double-blind parallel group study designed to investigate the dose-response relationship of zopiclone. Following 1 day of treatment with placebo, patients were randomly assigned to 1 of 6 groups and received treatment for 7 days with either placebo, or flurazepam 30 mg, or zopiclone, 3.75 mg, 7.5 mg, 11.25 mg or 15 mg. Four patients were dropped from the study; two from the placebo group due to ineffectiveness and one each in zopiclone 11.25 mg and 15 mg groups due to side-effects. Flurazepam 30 mg significantly improved sleep induction and maintenance by comparison to placebo and was indistinguishable from zopiclone 7.5 mg or higher. Results of a self-administered sleep questionnaire found a predominantly linear relationship between the dose of zopiclone administered and the degree of sleep improvement. The greatest increment in improvement was generally obtained with 3.5 mg and 7.5 mg of zopiclone, with some additional benefit occurring with zopiclone 11.25 mg. Clinicians' global impressions showed that the severity of illness clearly decreased in a dose related manner up to zopiclone 11.25 mg. Although zopiclone was well tolerated at 3.75 mg and 7.5 mg, an increase in side-effects occurred at 11.25 mg and 15 mg, which favours the use of 7.5 mg zopiclone as the optimum dose for most patients, although certain patients may benefit from a higher dose of the drug when well tolerated.

Thyrotropin-releasing hormone (TRH) (200 μg iv) and 1-desamino-8-D-arginine vasopressin (DDAVP) (4 μg iv) antagonized the growth hormone (GH) response to apomorphine HC1 (Apo) (0.5 mg sc) in 10 normal men. Apo had no effect on basal prolactin (PRL) levels but antagonized the PRL response to TRH. DDAVP plus Apo decreased PRL compared to placebo or DDAVP alone. These observations are compatible with (a) an inhibitory effect of TRH on hypothalamic and pituitary lactotrophe dopamine (DA) function (b) a fa-cilitory effect of DDAVP on lactotrophe DA function and an inhibitory effect on hypothalamic DA function. Whether these are direct or indirect effects on DA mechanisms is unclear.

Alcohol is both a nutrient and a dangerous drug depending on the amount consumed and the duration of its consumption. Prolonged ingestion of large amounts of alcoholic beverages leads to the development of alcoholism. Presently, alcoholism may be considered as the most prevalent type of drug-addiction and is characterized by the development of tolerance and physical dependence, symptoms which are also found in other addictions including addiction to opiates. Furthermore, it is known that several behavioral and pharmacological effects of ethanol (E) are similar to those produced by opiates (Kalant, 1977), and cross-tolerance develops between E and morphine with respect to some of these effects (Khanna, Kalant & Leblanc, 1979; Ross, 1976). However, in contrast to opioids, which act through specific receptors, E is believed to have nonspecific effects on lipid components of cellular membranes (Goldstein, Chin & Lyon, 1982; Harris & Schroeder, 1981). The effects of E on membrane-lipids may in turn influence the activity of proteins which reside within the lipid environment of the membranes (receptors, enzymes) as well as the rate of release of certain cellular products (hormones, neurohormones and neurotransmitters). In fact, it has been proposed that E exerts its reinforcing effect by such interactions at neural and endocrine sites.

Eleven chronic schizophrenic patients with abnormal skin pigmentation associated with neuroleptic treatment were withdrawn from chlorpromazine (CPZ), which was replaced by levomepromazine (n = 4), trifluoperazine (n = 1) or thioproperazine (n = 1) as the sole neuroleptic, by a combination of these phenothiazines (n = 4) or with haloperidol plus pipotiazine (n = 1). Seven patients showed complete resolution of abnormal skin pigmentation over a period of 1-5 years and 4 markedly improved over 2.0-2.6 years of follow-up. Our observations suggest that neuroleptic-induced abnormal skin pigmentation is (i) predominantly, if not exclusively, a side effect of CPZ and (ii) reversible, providing that CPZ is withdrawn and sufficient time is allowed to elapse.

1. The erectile response to the short-acting dopamine (DA) receptor agonist, apomorphine (Apo) HCl (0.25, 0.5, 0.75 and 1.0 mg sc), and placebo was evaluated in 28 impotent patients and penile circumference monitored using a mercury strain gauge and strip chart recording. 2. A full erection (increment in penile circumference greater than 2 cm and lasting at least one minute) occurred in 17 patients with Apo; no erection developed after placebo. An erection occurred in 6/8 patients with impaired glucose tolerance, 2/6 patients with diabetes mellitus and in both patients on lithium. 3. Nine patients who responded to Apo were treated in an open trial with bromocriptine; 6 reported improvement in potency. 4. Impairment in DA function may play a role in idiopathic impotence and in impotence associated with impaired glucose tolerance and diabetes mellitus. 5. An erectile response to Apo may predict therapeutic response to bromocriptine or other long acting dopaminergic agents. 6. Lithium, which inhibits DA-sensitive adenylate cyclase, does not prevent Apo-induced erections. This provides further support indicating that Apo induces erections by an effect on D2 receptors. 7. The yawning response to placebo and four doses of Apo HC1 (3.5, 5.0, 7.0, and 10.5 ug/kg sc) was evaluated in five normal men using a polygraphic technique. The yawning response was also assessed in normal young (less than 30 yrs; N = 16) and elderly (greater than 60 yrs; N = 12) volunteers. 8. Under experimental conditions of study, placebo induced spontaneous yawning. This was antagonized by 3.5 and 5.0 ug/kg Apo HC1 but increased by 7.0 ug/kg Apo HC1. These observations are compatible with the view that Apo HC1 in doses of 3.5-5.0 ug/kg stimulates presynaptic DA receptors whereas 7.0 ug/kg stimulates postsynaptic DA receptors. 9. Spontaneous and Apo-induced yawning were significantly decreased in the elderly which suggests that D2 receptor function declines with normal aging.

– – Clonidine (0.15 mg intravenously), an alpha-adrenergic receptor agonist, was administered to 13 male chronic schizophrenics, who had been withdrawn from chronic neuroleptic therapy, and to 18 normal male controls. There was no significant difference in growth hormone (GH) response between the two groups. There was no significant correlation between duration of psychosis, duration of neuroleptic therapy or length of neuroleptic withdrawal and GH response. These results suggest that postsynaptic alpha-adrenergic receptor function in the hypothalamic-pituitary axis is unaltered in chronic schizophrenia or by prior chronic neuroleptic therapy.

We investigated the age-related changes in the circadian rhythm of plasma melatonin as a potential index of brain aging in man. The subjects were 5 young men aged 19-25 years, 11 older men aged 51-65 years, 6 elderly men aged 66-89 years, 7 young women aged 19-25 years, 5 premenopausal women aged 45-50 years, 8 postmenopausal women aged 51-65 years, and 5 elderly women aged 66-75 years. They were all physically and psychiatrically normal. Serial blood samples were drawn from 8:00 AM until 8:00 AM on the next day, with the indoor illumination set at 300 Lux from 7:00 AM until 4:00 PM and at 50 Lux thereafter. Plasma melatonin was estimated by radioimmunoassay. The results show that there is a significant negative correlation between age and 24-hr secretion of plasma melatonin (r = -0.952, p less than 0.0001), between age and peak levels of plasma melatonin (r = -0.937, p less than 0.00001), and between age and the lag in time from sunset to the onset of significant elevation of plasma melatonin over daytime values (r = 0.916, p less than 0.0001). It is concluded that study of the circadian rhythm of plasma melatonin may prove to be a useful index of the aging process.

The prolactin (PRL) response to placebo, sulpiride (2.5, 5, 10 and 20 mg im) and arginine HC1 infusion (0.33G/kg) was examined in young (18-25 yrs) and old (65-75 yrs) normal men. Analysis of variance for the sulpiride data showed no significant dose x age group interaction or dose X age group X period interaction. There was, however, a significant age group X period interaction (p less than 0.05). PRL concentrations were significantly lower in the old subjects (N = 9) compared with the young (N = 9) 15 min after 2.5, 5, or 10 mg but not significantly after 20 mg sulpiride or at any other time interval. The areas under the concentration-time curves and the mean individual peak PRL concentrations were not significantly different between the two groups. The pattern of findings suggests a delayed absorption of sulpiride in the elderly rather than a change in pituitary dopamine (DA) receptor sensitivity to account for the lower PRL concentrations at 15 min. Differences in magnitude of the PRL response between the four doses of sulpiride were small and results suggest that the 2.5 mg dose is close to that required to saturate DA receptors on the lactotrophe and that the 10 and 20 mg doses are sufficient to completely block pituitary DA receptors. There was no significant age effect on arginine-induced PRL secretion (N = 11 in each group).(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of the present studies was to investigate the activity of the adrenal gland and the pituitary beta-endorphin system in individuals from families with a 3 generation history of alcoholism, High Risk group, or from families without history of alcoholism, Low Risk group. All subjects had a medical examination, a drinking behavior personal interview and the Michigan Alcoholism Screening Test. Individuals with medical problems or excessive drinking were not included in the study. On the day of testing, a blood sample was taken at 9:00 a.m., then the subject drank a placebo drink or an ethanol solution (0.5 g ethanol/kg B.Wt.). Additional blood samples were taken at 15, 45 and 120 minutes post-drink. Results indicated that individuals of the High Risk group had lower basal levels of beta-endorphin like immunoreactivity (beta-EPLIR) than individuals of the Low Risk group. The dose of 0.5 g ethanol/kg B.Wt. induced an increase in the plasma content of beta-EPLIR of the High Risk group, but not of the Low Risk group. In the Low Risk group ethanol did not induce an increase above the 9:00 a.m. levels, however, it attenuated the beta-endorphin decrease overtime, observed following the placebo drink. Analysis of beta-endorphin-like peptides in the plasma of the High Risk group, with Sephadex G-75 chromatography indicated that the major component of the plasma beta-EPLIR was beta-lipotropin. Plasma cortisol levels, following ethanol intake, presented a small increase in the High Risk group but not in the Low Risk group. Both groups presented similar blood alcohol levels. The basal levels of immunoreactive cortisol and beta-endorphin in the plasma of individuals who were alcoholics, but had been abstinent for at least six months prior to testing were similar to the levels of the High Risk group. Thus there are differences both in the basal levels and in the response of the cortisol and the pituitary beta-endorphin system to an acute ethanol challenge between the two groups.

1. Apomorphine HC1 (Apo) (0.25 0.5 or 0.75 mg sc), a dopamine (DA) receptor agonist, induced penile erections (PEs) (monitored by mercury strain gauges and continuous recording on paper strip charts) in 7 out of 9 normal subjects and placebo in 1 of these 9 (p 2. Apo-induced PEs recurred in each of the 6 subjects retested. 3. Benztropine (2 mg iv) had no effect on Apo-induced penile tumescence (PT). 4. These data suggest (a) DA mechanisms play a role in normal erectile function (b) DA-mediated PT is not modulated by cholinergic systems (c) evaluation of the erectile response to Apo may provide a simple ancillary test to the investigation of impotence and a way of identifying a subpopulation of impotent subjects with impaired DA function who may respond to long-acting DA agents (d) Apo-induced PT may provide a novel way of studying DA 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.

Twenty-four hours sleep deprivation significantly decreased the growth hormone response to the dopamine receptor agonist, apomorphine HCl, in five normal men (0.5 mg s.c.) and one woman (0.75 mg s.c.) but had no effect on basal or post-apomorphine prolactin concentrations. These results suggest that sleep deprivation decreases the sensitivity of certain central dopamine receptors. The relevance of this finding to the antidepressant effect of sleep deprivation is unclear.

The growth hormone (GH) response to the dopamine (DA) receptor agonist, apomorphine HCl (Apo) (0.5 mg SC) was studied in young and elderly normal subjects as well as in patients with dementia of the Alzheimer type (DAT) and controls matched for age, gender and Quetelet index. The GH response was significantly decreased in normal elderly men (mean age 67.3 years; N=16) compared with young men (mean age 21.2 years; N=12) and in elderly women (mean age 65.4 years; N=9) compared with young women (mean age 25.5 years; N=6) in the luteal phase but not in the early follicular phase. Young men had a significantly greater GH response than young women in either phase of the menstrual cycle. The decline in GH response with normal aging may be related to a decrease in sex steroid activity. There was no significant difference in GH response between DAT patients (N=15) and paired controls. This suggests that hypothalamic D2 receptor function regulating GH secretion is not altered in DAT.

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 alpha-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.

Oral administration of choline (10 g) had no effect on basal serum growth hormone or prolactin concentrations in normal subjects (N = 5). Choline significantly enhanced the increase in growth hormone secretion induced by apomorphine HCl (0.5 mg s.c.). These data suggest that cholinergic mechanisms may enhance hypothalamic-pituitary dopaminergic function in man in contrast to their inhibitory effect on dopaminergic function in the basal ganglia.

1. 1. Apomorphine (Apo), a dopamine (DA) receptor agonist, induces yawning by stimulating central DA autoreceptors. Few data are available on Apo-induced yawning in man. 2. 2. A simple method for recording and measuring Apo-induced yawning by measuring the displacement of the lower jaw using a pair of lihearlized magnetometers with one sensor attached to the forehead just below the hairline and the other under the chin is described. The output of the magnetometers is fed into a DC amplifier and displayed on a strip chart recorder. Complete concordance between evaluators reading the tracings and between observed yawning and recorded yawns was found. 3. 3. Measuring Apo-induced yawning may provide a simple approach to evaluating DA autoreceptor function in normal subjects and in patients with psychiatric and neurological disorders. 4. 4. Preliminary data show that Apo-Induced yawning is more marked in women than in men. This is in contrast to spontaneous and drug-induced yawning in animals which is predominantly a male phenomenon. 5. 5. Sleep appears to inhibit Apo-Induced yawning.

Apomorphine (Apo), a short acting dopamine (DA) receptor agonist induces penile erections in normal subjects. The erectile response to one or more doses of Apo HCl (0.25, 0.5, 0.75, 1.0 mg sc) or placebo was investigated in eight impotent subjects and penile tumescence monitored using a mercury strain gauge and strip chart recording. Four patients showed a full erection with Apo and one a partial response. Distressing side effects (nausea, sweating) were associated with non-response or partial response. Three responders to Apo were treated with low doses of the long acting DA receptor agonist, bromocriptine (2.5-3.75 mg/d po); all three showed complete recovery of erectile function within two weeks. A subgroup of impotent patients may have impaired central DA function. Testing with Apo may provide a diagnostic and predictive test to identify such patients who may respond to treatment with low doses of bromocriptine or other DA receptor agonist.

Concurrent neuroleptic administration is a necessary factor in the therapeutic response to GABAergic agents. In contrast to their effect on the striatum, neither BAC nor NaV influences hypothalamic-pituitary DA function mediating PRL secretion.

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.