Long-lasting effects of (+/-)3,4-methylenedioxymethamphetamine (ecstasy) on serotonin system function in humans.

BACKGROUND: Fifteen (+/-)3,4-Methylenedioxymethamphetamine (MDMA) users, who did not show other drug dependencies or prolonged alcohol abuse, and 15 control subjects were included in the study. METHODS: Prolactin (PRL) and cortisol (CORT) responses to the serotonergic agonist d-fenfluramine (D-fen), clinical psychobehavioral changes, and psychometric measures were evaluated 3 weeks and then 12 months after MDMA discontinuation. RESULTS: MDMA users showed significantly reduced PRL and CORT responses in comparison with control subjects at 3 weeks (respectively, p < .001; p < .005). The responses of PRL to D-fen were unmodified at 12 months after prolonged abstinence and were significantly reduced in comparison with controls (p < .001). In contrast, CORT responses in MDMA users were restored after 12 months of abstinence, with significantly higher responses to D-fen, in comparison with 3-week responses (p < .05). MDMA users' high scores on the Novelty Seeking (NS) scale on the Tridimensional Personality Questionnaire (TPQ) appeared unchanged by long-term abstinence. In contrast, Buss Durkee Hostility Inventory (BDHI) (Buss and Durkee 1957) direct and guilt scores decreased significantly after 12 months of abstinence. PRL AUCs at 12 months were inversely correlated with the measures of MDMA exposure (r = -.538). CONCLUSIONS: Our data indicate long-lasting 5-HT system impairment in abstinent MDMA users although the hypothesis of serotonergic changes attributable to a premorbid condition cannot be excluded. CORT restored responses to D-fen at 12 months, and the correlation of neuroendocrine changes with MDMA exposure suggest that the neuroendocrine impairment may be due to a partially reversible neurotoxic action of MDMA on the human brain.

Neuroendocrine correlates of temperamental traits in humans.

Studies investigating temperament traits in humans and their biological correlates have found high levels of novelty seeking (NS) linked with dopaminergic system changes, and particularly a deficit of dopamine transporter. Harm avoidance and reward dependence, on the other hand, appeared to be associated, respectively with serotonin and noradrenaline changes. In the present study, we have investigated the dopaminergic (DA), serotonergic (5-HT), and noradrenergic (NE) functions in healthy volunteers by challenging the monoamine systems with the DA agonist bromocriptine, the 5-HT agonist D-fenfluramine, and the NE agonist clonidine, respectively. Parallel to this investigation, we examined the temperament traits of our subjects by measuring NS, harm avoidance (HA) and reward dependence (RD) using the 'Three-dimensional Personality Questionnaire' (TPQ). The aims of the study were to see whether or not the monoamine functions were correlated with temperament traits. Bromocriptine challenge induced a significant GH increase and a significant suppression of PRL. D-fenfluramine test significantly increased PRL and cortisol plasma levels and Clonidine test induced a significant rise in GH values. NS scores showed a significant direct correlation with brom-stimulated GH values (r=0.426, P<0.05) and a significant inverse correlation with brom-inhibited PRL values (r=-0.498, P<0.01). HA scores correlated significantly with D-fen-stimulated PRL and CORT AUCs, (PRL: r=0.424, P<0.05; CORT: r=0. 595, P<0.005). RD scores correlated positively with clon-stimulated GH values (r=0.55; F=8.6; P<0.01) and negatively with brom-inhibited-PRL AUCs (r=-0.439, P<0.05). Our data support Cloninger theory concerning the biological correlates of temperamental traits, and evidence the link between the neuroendocrine responses to dynamic challenges and stable temperament features.

Neuroendocrine responses to experimentally-induced psychological stress in healthy humans.

Previous studies of hormonal and neurophysiological changes in response to psychological stress in humans have produced contrasting findings due to differing experimental procedures and consistent individual variability. Habituation effects, which influence physiological coping in response to exposure to repeated stress, need to be investigated more extensively. In the present study, twenty healthy male subjects were each exposed twice to the same psychosocial stressor (Stroop Color Word Interference task, public speaking and mental arithmetic in front of an audience) during a first session (day 1) and a second session (day 8). Plasma concentrations of norepinephrine (NE), epinephrine (EPI), adrenocorticotropic hormone (ACTH), cortisol (CORT) and prolactin (PRL) were measured immediately before the beginning of the tests and at their end, 30 min later, on both experimental days. For the total group, NE, EPI, ACTH, and CORT levels were significantly elevated, and PRL levels were significantly decreased, after stress exposure on day 1. ACTH and CORT levels showed less significant increases after stress on day 8. In contrast, NE and EPI responses to stress were not significantly blunted, and PRL response was unchanged on day 8. Cluster analysis revealed two groups of subjects who showed different habituation patterns for ACTH and CORT. The first group (n=12) of subjects showed a reduction of ACTH and CORT responses to stress on day 8. The subjects of the second group (n=8) displayed a significant increase of ACTH and cortisol in response to stress on day 8, without any habituation effect. These results increase the evidence concerning the involvement of the HPA axis and catecholamines in response to psychological stress, and suggest that possible individual differences in the neuroendocrine coping mechanisms may affect mood regulation and the state of health.

Neuroendocrine correlates of depression in abstinent heroin-dependent subjects.

The functions of the central alpha-adrenergic, serotoninergic and dopaminergic systems were investigated in 28 heroin-dependent subjects 6-8 weeks after detoxification, and in 22 healthy control subjects (group C). Fourteen heroin-dependent subjects with depressive comorbidity (group A), and 14 heroin-dependent subjects without other Axis I and II pathologies (group B) were included among abstinent substance abusers. Norepinephrine (NE) function was evaluated by growth hormone (GH) responses to acute stimulation with clonidine (clon); serotonin (5-HT) function by prolactin (PRL) and cortisol (CORT) responses to acute stimulation with D-fenfluramine (D-fen) and dopamine (DA) function by GH and PRL responses to acute administration of bromocriptine (brom). Central NE activity, as measured by the GH-clon test, seems to be well preserved both in A and B subjects. PRL and CORT responses to D-fen were significantly blunted both in A subjects and in B subjects, in comparison with control subjects (C); the PRL response in A subjects was significantly lower than in B subjects. The DA system of B subjects was found unimpaired; in contrast, a significantly higher GH response to brom in A subjects (depressed) could express D2 post-synaptic receptor hypersensitivity and, therefore, decreased pre-synaptic DA release. In sum, the study of central monoamine function revealed an alteration only of the 5-HT system in detoxified heroin-dependent subjects without psychiatric comorbidity, which might be a trait character of these subjects, possibly involved in the pathogenesis of the disorder. A more significant impairment of 5-HT function and the hypersensitivity of post-synaptic DA receptors in A subjects suggests that specific biological correlates of psychiatric comorbidity may characterize substance abuser subtypes.

Rapid opiate detoxication in outpatient treatment: relationship with naltrexone compliance.

A variety of detoxification methods have been utilized for the treatment of heroin withdrawal before individuals begin long-term opiate-free and naltrexone programs. While methadone in decreasing doses is still widely used for detoxication procedures, rapid and ultrarapid protocols including clonidine and opiate receptors antagonists have been proposed. This study compares the efficacy of different detoxification methods and investigates possible changes in naltrexone compliance. Ninety-eight heroin-addicted individuals were studied to evaluate withdrawal symptoms, craving, mood, urine toxicologic screens, and drop-out rate during therapy with: Group A: clonidine only (5 days); Group B: clonidine, oxazepam, baclofen, and ketoprofene with naloxone and naltrexone (2 days); and Group C: methadone in decreasing doses (10 days). Naltrexone compliance and relapse rates were evaluated during a 6-month follow-up period. Rapid detoxification with opiate antagonists (Group B) induced slight and transient withdrawal symptoms, and resulted in a significantly lower percentage of heroin catabolites in urine controls during the detoxification procedure, lower negative and positive craving, less mood problems, and higher compliance in extended naltrexone treatment. In comparison with clonidine only (Group A) and methadone (Group C), the early use of naltrexone during detoxification in combination with benzodiazepines and clonidine facilitated extended naltrexone acceptance and improved the recovery outcome in outpatients.

Lofexidine versus clonidine in rapid opiate detoxification.

The aim of the present study is to evaluate lofexidine and clonidine, in an accelerated opiate detoxification procedure (3 days), without anaesthesia. Forty heroin-dependent individuals were detoxified, evaluating withdrawal symptoms, craving levels, mood changes, urine toxicologic screens, and dropout during therapy with either (1) clonidine, oxazepam, baclofen, and ketoprofene, with naloxone and naltrexone for 3 days (20 subjects) or (2) lofexidine, oxazepam, baclofen, and ketoprofene with naloxone and naltrexone for 3 days (20 subjects). Both clonidine and lofexidine rapid detoxifications were found effective. The subjects treated with lofexidine showed significantly lower levels of withdrawal symptoms, fewer mood problems, less sedation and hypotension. No significant differences in craving levels, morphine metabolites in urine, or dropout rate were evidenced between the two groups. The early use of naltrexone during detoxification in combination with either alpha-2-agonist facilitated the acceptance for long-term naltrexone treatment. Lofexidine appeared to be more useful than clonidine in a 3-day accelerated opiate detoxification, not only to counteract withdrawal symptoms, but also in the treatment of dysphoria and mood changes. Because lofexidine does not produce hypotension, safe outpatient treatment, without hospital support, could be possible.

Experimentally induced aggressiveness in adult children of alcoholics (ACOAs): preliminary behavioral and neuroendocrine findings.

OBJECTIVE: This study was conducted to determine the nature of the reaction of nonalcoholic adult children of alcoholic (ACOA) fathers to the experimental induction of aggression. Of particular interest was the relationship between biochemical factors and personality traits during a stressful event experienced by persons at risk for alcoholism. METHOD: Aggression was induced by a modified free-operant procedure in 14 ACOA and 14 non-ACOA subjects between 18 and 19 years of age with men and women represented in equal numbers. Neurotransmitter-hormonal assays from blood drawn immediately before, and 20 and 30 minutes after, starting the test included norepinephrine (NE), epinephrine (EPI), prolactin (PRL), growth hormone (GH) and cortisol (Cort). Personality traits were assessed by the Minnesota Multiphasic Personality Inventory (MMPI) Tridimensional Personality Questionnaire (TPQ) and the Buss-Durkee Hostility Inventory (BDHI). RESULTS: During the aggression induction session, ACOAs gained (F = 4.6, 1/13 df, p < .05) and subtracted (F = 9.2, 1/13 df, p < .005) significantly less money than non-ACOAs, evidence of lower outward-directed aggressiveness among ACOAs. Higher baseline plasma levels of Cort (F = 9.8, 1/13 df, p < .01) and PRL (F = 4.0, 1/13 df, p < .05) and decreased NE (F = 8.5, 1/13 df, p < .005) and GH (F = 10.9, 1/13 df, p < .001) responses during the experimental session were observed. On personality measures ACOAs scored higher than non-ACOAs on MMPI hysteria (F = 10.8, 1/13 df, p < .005), hypochondria (F = 20.1, 1/13 df, p < .001) and paranoia (F = 4.7, 1/13 df, p < 0.5) subscales, on the TPQ reward dependence (F = 10.9, 1/13 df, p < .005) subscale and on BDHI guilt (F = 15.7, 1/13 df, p < .001) and resentment (F = 6.4, 1/13 df, p < .05) subscales. CONCLUSION: These findings, preliminary in nature, support a hypothesis of inhibition of state and trait aggression in ACOAs in association with monoaminergic and endocrine changes.

Neuroendocrine responses to psychological stress in adolescents with anxiety disorder.

Neurotransmitter-neuroendocrine and cardiovascular responses to the administration of a psychologically stressful mixed-model test (Mental Arithmetic, Stroop Color Word Interference Task, Trier Social Stress Test) were examined in 20 male peripubertal subjects affected by anxiety disorder (group A: 14 with generalized anxiety disorder, 6 with generalized anxiety disorder and separation anxiety disorder) and 20 junior school adolescents, matched for age, without overt psychological disorders (group B). Plasma levels of norepinephrine (NE), epinephrine (EPI), adrenocorticotropic hormone (ACTH), beta-endorphin (beta-EP), cortisol (CORT), growth hormone (GH), prolactin (PRL) and testosterone (Te) were measured immediately before the beginning of the tests and 30 min later at their end. Mean prestress values of GH, PRL, beta-EP and ACTH were significantly higher in anxious subjects than in controls. There was no difference in NE, EPI, CORT and Te prestress levels in the two groups. After the psychological stress session NE, GH and Te concentrations increased significantly in anxious subjects (A), but not in controls. In contrast, beta-EP and PRL decreased significantly during the psychological stress session in anxious subjects, and were unaffected by stress in the subjects without anxiety. No significant changes were found in ACTH, CORT and EPI during the challenge either in anxious subjects or in controls, which may be attributed to the late time of poststress blood sampling. In contrast to controls, heart rate and systolic blood pressure increased significantly in anxious subjects after psychological stress testing. Our data support the hypothesis that the hyperactivity of the noradrenergic system in response to stress is associated with anxiety disorders in adolescents and might influence the responses of GH and Te. High prestress basal values of stress hormones seem to be induced in anxious subjects by the anticipation of the task or by a persistent hyperactivity of the noradrenergic system. Further studies are needed to investigate in more detail the involvement of the HPA axis in anxious adolescents by a more refined resolution of time points of blood sampling.

Neuroendocrine correlates of temperament traits in abstinent opiate addicts.

PURPOSE: Studies investigating temperament traits of drug abusers and their biological correlates have disclosed high rates of novelty seeking (NS) in opiate addicts, possibly based on dysfunctions of the dopaminergic (DA) system. The aims of the present study were to see whether or not the monoamine functions were impaired in detoxified addicts and whether or not these alterations were correlated with temperament traits, given the possibility that impairment of the biological and temperament parameters might be responsible for the development of addiction. METHODS: We have investigated the DA, serotonergic (5-HT), and noradrenergic (NE) functions in 22 abstinent heroin addicts and 22 healthy controls by challenging the monoamine systems with the DA agonist bromocriptine (brom), the 5-HT agonist D-fenfluramine (D-fen), and the NE agonist clonidine (clon), respectively. We examined the temperament traits by measuring NS, harm avoidance (HA), and reward dependence (RD) using the "Three-Dimensional Personality Questionnaire" (TPQ). RESULTS: Addicts showed higher than normal NS scores at TPQ blunted 5-HT function, and normal DA and NE activities, in response to the neuroendocrine challenges. NS correlated negatively with the DA function in both addicts and controls, and negatively with the 5-HT function only in addicts. HA correlated positively with 5-HT function in controls but not in addicts. IMPLICATIONS: The impairment in 5-HT function observed in heroin addicts and the changes in the biological correlates of temperamental traits could increase the proneness to addiction and possible comorbid psychiatric disorders.

Neurotransmitters, neuroendocrine correlates of sensation-seeking temperament in normal humans.

Correlations between sensation-seeking (SS) personality dimension and plasma concentrations of norepinephrine (NE), epinephrine, and NE-dependent testosterone (T), cortisol and prolactin (PRL) were studied in 74 physically and psychologically healthy male volunteers, in order to see whether or not the noradrenergic system is involved in the modulation of this personality trait. Novelty-seeking scores by the Temperament and Character Inventory and SS scores on a Visual Analog Scale were positively correlated with plasma NE, T and PRL levels, suggesting that NE and the downstream cascade of NE-dependent hormones, together with other monoaminergic changes, might be responsible for the development and the degree of this temperamental character.