Gilberto Gerra

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.

Serotonergic function after (±)3,4-methylene-dioxymethamphetamine ('Ecstasy') in humans

(±)3,4-Methylene-dioxymethamphetamine (MDMA, or ‘Ecstasy’) effects on serotonin system function and behaviour in humans are unclear. Fifteen MDMA users, who did not have other drug dependencies or alcohol abuse, and had not used other drugs for prolonged periods, and 15 control individuals were included in a study to assess the biological and psychological changes after chronic use of MDMA. Prolactin and cortisol responses to D-fenfluramine challenge, clinical psychobehavioural changes, personality characteristics, including mood, aggressiveness and temperamental aspects, were evaluated 3 weeks after MDMA discontinuation. MDMA users had significantly reduced prolactin and cortisol responses in comparison with control individuals (p < 0.001 and p < 0.005, respectively). Dysphoria and mood changes were exhibited in seven individuals, tiredness in five and sensation-seeking behaviour in twelve at the clinical evaluation. Significantly higher scores were found in MDMA individuals than in control individuals for Minnesota Multiphasic Personality Inventory subscale for Depression, for Buss Durkee Hostility Inventory direct and guilt subscales, for Hamilton Depression Rating Scale and for novelty-seeking Tridimensional Personality Questionnaire subscale. Prolactin responses to D-fenfluramine stimulation area under the curve among MDMA users were negatively correlated with direct aggressiveness scores for Buss Durkee Hostility Inventory; a negative correlation between prolactin responses and novelty-seeking scores was also evidenced among MDMA users. These data suggest an association between serotonin system impairment and MDMA use in humans; in interpretation of these results, the possibility that serotonin deficit in MDMA individuals was partially related to a premorbid condition, in relationship with novelty-seeking behaviour and mood disorders, can not be excluded.

Substance Use Among High-School Students: Relationships with Temperament, Personality Traits, and Parental Care Perception

Alcohol use, “alcohol abuse,” and illicit drug use were investigated in a representative sample of 1076 urban, northern Italian high school students aged 14 to 19 years in 2001. In addition to questions on substance use, the participants were asked about school achievements and perceived substance use among friends. All the students were submitted to Zuckerman Sensation Seeking Scale (SSS) scale, Eysenck Personality Questionnaire (EPQ), Buss-Durkee Hostility Inventory (BDHI), and Parental Bonding Instrument (PBI). Lifetime alcohol use was found in 80.5%, “alcohol abuse” in 37.7%, cannabis use in 26.2%, ecstasy in 2.8%, heroin in 3.8%, and cocaine in 8.3% of the students: gender differences were significant for alcohol use, “alcohol abuse” and ecstasy use, with male subjects outnumbering females, but not for reported cannabis, heroin, and cocaine use. Early substance use onset among adolescents aged 14–16 years was detected. Higher sensation seeking on SSS, social coping impairment on EPQ, direct aggressiveness on BDHI, poor school achievements, and lower parental care on PBI were found associated with illicit drug use and “alcohol abuse” (multiple drugs users). Increased levels of aggressiveness and sensation seeking were evidenced both in minimal experimenters (ME) and habitual users (HU), without any significant difference, in comparison with abstinent students. Similarly, ME scored higher than abstinent subjects on EPQ for social coping impairment, but lower than HU. Parental care perception was lower in HU, but not in ME with, respect to abstinent subjects. Pearson inverse correlation was demonstrated between PBI scores and EPQ maladaptation and BDHI aggressiveness. Data from this preliminary pilot study suggest that temperamental traits and personality changes may be associated to early substance use “proneness” and reduced perception of parental care.

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), β-endorphin (β-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, β-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, β-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.

Neurotransmitter-neuroendocrine responses to experimentally induced aggression in humans: influence of personality variable

Aggressiveness was experimentally induced in 30 psychophysically healthy male subjects, 18-19 years old, divided into 15 cases with low normal and 15 with high normal basal aggressivity. Plasma norepinephrine (NE), epinephrine (EPI), growth hormone (GH), prolactin (PRL), cortisol (CORT) and testosterone (Te) concentrations were measured in basal conditions and during experimentally induced aggressiveness. Basal Te and stimulated NE, GH and Cort levels were higher in subjects with high-normal than in those with low-normal aggressiveness, suggesting that the functional tonus of the NE system and of the NE-dependent hormonal axes might be a modulator of the behavioral parameter.

Clonidine and opiate receptor antagonists in the treatment of heroin addiction

Good results in detoxification methods have been reached using both together clonidine and opiate receptors antagonists. One hundred fifty-two heroin-abusing patients were studied evaluating withdrawal symptoms after therapy with (a) clonidine only, (b) clonidine and naltrexone, (c) clonidine and naloxone, and (d) placebos. Treatment results, emotional and behavioral changes, and involvement in psychosocial programs were evaluated after a 6-month follow-up. Although opiate antagonists were able to induce slight and transient withdrawal signs and symptoms, there was, in the group of patients treated with clonidine and naltrexone together, a low percentage of catabolites in urine and an improvement in mood and family relationships. Furthermore, the patients that underwent longer naltrexone treatment showed a stronger involvement in psychosocial programs, and even their relatives demonstrated more interest in the recovery program. A decrease in the difficulties of accepting an opiate antagonists treatment and a different evaluation of withdrawal syndrome were the results of an early use of naltrexone.

Neurotransmitter-hormonal responses to psychological stress in peripubertal subjects: Relationship to aggressive behavior

The relationship between different degrees of normal aggressiveness (low, medium, high) and neurotransmitter-neuroendocrine responses to the administration of psychologically stressful tests (Mental Arithmetic, Stroop Color Word Interference task, Trial Social Stress test) was examined in thirty male peripubertal junior school adolescents. Plasma concentrations of norepinephrine (NE), epinephrine (EPI), ACTH, cortisol (CORT), growth hormone (GH), prolactin (PRL) and testosterone (T) were measured immediately before the beginning of the tests and at their end, 30 min later. High-normal aggressiveness have been found associated with significantly higher basal concentrations of NE, ACTH, PRL, and T and with a significant increase of GH responses to the stressful stimuli.

Childhood neglect and parental care perception in cocaine addicts: relation with psychiatric symptoms and biological correlates.

UNLABELLED Childhood neglect and poor child-parent relationships have been reported to increase substance use disorders susceptibility. Stressful environmental factors, including emotional neglect, could affect individual personality traits and mental health, possibly inducing stable changes in hypothalamic-pituitary-adrenal (HPA) axis and brain mono-amine function, in turn involved in addictive behavior vulnerability. Therefore, we decided to investigate homovanillic (HVA) and prolactin (PRL) plasma levels, as expression of possible changes in dopamine function, ACTH and cortisol plasma levels, as measures of HPA axis function, and concomitant psychiatric symptoms profile in abstinent cocaine addicts, in relationship to their childhood history of neglect and poor parental care perception. METHODS Fifty abstinent cocaine dependent patients, and 44 normal controls, matched for age and sex, were submitted to a detailed psychiatric assessment (DSM IV criteria). All patients and controls completed the Symptoms Check List-90 (SCL-90) and the Buss Durkee Hostility Inventory (BDHI), to evaluate psychiatric symptoms frequency and aggressiveness levels. The Childhood Experience of Care and Abuse-Questionnaire (CECA-Q) and Parental Bonding Instrument (PBI) have been used to retrospectively investigate parent-child relationships. Blood samples were collected to determine HVA, PRL, ACTH and cortisol basal plasma levels. RESULTS Cocaine addicted individuals in general showed significantly lower HVA, and higher PRL, ACTH and cortisol basal levels respect to controls. In particular, neuroendocrine changes characterized cocaine addicts with childhood history of neglect and low perception of parental care. Obsessive-compulsive, depression and aggressiveness symptoms have been found related to poor parenting, inversely associated to HVA levels and directly associated to PRL, ACTH and cortisol levels. CONCLUSIONS These findings suggest the possibility that childhood experience of neglect and poor parent-child attachment may partially contribute to a complex neurobiological derangement including HPA axis and dopamine system dysfunctions, playing a crucial role in addictive and affective disorders susceptibility.

Regional cerebral blood flow and comorbid diagnosis in abstinent opioid addicts.

Studies using single photon emission computed tomography (SPECT) have found low cerebral blood flow (CBF) in frontal and parietal cortices in patients with chronic opiate dependence. In the present study, SPECT with 99mTc-HMPAO as tracer was used to compare 27 detoxified opiate addicts with nine healthy control subjects. All the subjects were evaluated with clinical psychiatric (DSM-IV), psychometric and neuropsychological measures. Compared with normal control subjects, the addicts showed a non-significant reduction of whole brain perfusion values. Significant hypoperfusion in the right frontal and left temporal lobes was found in addicts with comorbid depression, and a significant decrease in CBF in the right frontal lobe was observed in those with antisocial tendencies. A significant negative correlation emerged between Depression subscale scores on the Minnesota Multiphasic Personality Inventory and left temporal CBF in the patients. No significant correlations were found, however, between measures of cognition and CBF in opiate addicts. The asymmetrical findings in CBF that characterized the addicts relative to normal control subjects may be more closely related to mood and behavioral traits than to substance abuse, per se.

Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo‐controlled study

Flumazenil (FLU), a benzodiazepine (BZD) partial agonist with a weak intrinsic activity, was previously found unable to precipitate withdrawal in tolerant subjects submitted to long‐lasting BZD treatment. The potential use of FLU to treat BZD withdrawal symptoms has also been evaluated tentatively in clinical studies. In the present experiment, FLU (treatment A) was compared with oxazepam tapering (treatment B) and placebo (treatment C) in the control of BZD withdrawal symptoms in three groups of BZD dependent patients. Group A patients (20) received FLU 1 mg twice a day for 8 days, and oxazepam 30 mg in two divided doses (15 mg + 15 mg) during the first night, oxazepam 15 mg during the second night and oxazepam 7.5 mg during the third night. FLU was injected i.v. in saline for 4 hours in the morning and 4 hours in the afternoon, in association with placebo tablets. Group B patients (20) were treated by tapering of oxazepam dosage (from 120 mg) and with saline solution (as placebo) instead of FLU for 8 days. Group C patients (10) received saline instead of FLU and placebo tablets instead of oxazepam for 8 days. FLU immediately reversed BZD effects on balance task and significantly reduced withdrawal symptoms in comparison with oxazepam and placebo on both self‐reported and observer‐rated withdrawal scales. The partial agonist also reduced craving scores during the detoxification procedure. In addition, during oxazepam tapering, group B patients experienced paradoxical symptoms that were not apparent in FLU patients. Patients treated with FLU showed a significantly lower relapse rates on days 15, 23 and 30 after the detoxification week. Our data provide further evidence of FLUs ability to counteract BZD effects, control BZD withdrawal and normalize BZD receptor function. The effectiveness of FLU may reflect its capacity to upregulate BZD receptors and to reverse the uncoupling between the recognition sites of BZD and GABA, on the GABA A macromolecular complex, that has been reported in tolerant subjects.