PubMed · 13977268
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K SHICHIJO, S SAITO. 1962. [Thyroiditis].. https://pubmed.ncbi.nlm.nih.gov/13977268/
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Systemic adrenocorticotropic hormone (ACTH) administration is a first-line therapy for the treatment of infantile spasms, an age-specific seizure disorder of infancy. It is proposed that exogenous ACTH acts via negative feedback to suppress the synthesis of corticotropin-releasing hormone (CRH), a possible endogenous convulsant in infant brain tissue. The aim of this study was to determine whether systemic ACTH treatment in infant rats down-regulates the hippocampal CRH system, including CRH, CRH-binding protein (CRH-BP), and CRH receptors (CRH-R1 and CRH-R2). Daily i.p. injection of ACTH for 7 consecutive days (postnatal days 3-9) elevated serum corticosterone levels 20-fold measured on postnatal day 10, indicating systemic absorption and circulation of the ACTH. Semiquantitative reverse transcriptase-PCR demonstrated that both CRH and CRH-BP mRNA obtained from the hippocampi of ACTH-injected infant rats was significantly depressed relative to saline-injected animals. Comparable reductions in both CRH and CRH-BP synthesis were further demonstrated with radioimmunoassay. In contrast, neither CRH-R1 nor CRH-R2 mRNA was altered by ACTH treatment, relative to saline-injected rats. This latter finding was confirmed electrophysiologically by measuring the enhancement of hippocampal population spikes by exogenous CRH, also showing no differences between ACTH- and saline-injected rats. The results of this study support the proposal that systemic ACTH treatment down-regulates CRH expression in infant brain, perhaps contributing to the therapeutic efficacy observed during treatment of infantile spasms.
It is accepted that there are important individual differences in the vulnerability to stress-induced pathologies, most of them associated to the hypothalamic-pituitary and sympatho-medullo-adrenal axes, the two prototypical stress-responsive systems. However, there are few studies specifically aimed at characterising individual differences in the physiological response to daily repeated stress in rats. In the present work, male rats were submitted to repeated immobilisation (IMO) stress (1 h daily for 13 days) and several samples were taken at specific days and time points. Animals only subjected to blood sampling procedure served as controls. Daily adrenocorticotropic-hormone (ACTH), corticosterone and glucose responses to immobilisation (that included the post-immobilisation period) progressively declined over the days. In addition, repeated immobilisation resulted in decreased relative thymus weight, increased relative adrenal weight, elevated corticotropin-releasing factor (CRF) mRNA levels in the hypothalamic paraventricular nucleus (PVN), and down-regulation of glucocorticoid receptor gene transcription in hippocampus CA1. However, only CRF mRNA levels in the paraventricular nucleus correlated with the ACTH (on day 1) and corticosterone responses (from day 4-13) to immobilisation. When the animals were classified in three groups on the basis of their plasma ACTH levels immediately after the first immobilisation, individual differences in the ACTH response progressively disappeared on successive exposures to the stressor, whereas those in corticosterone and glucose were more sustained. The present results suggest that there are individual differences in the physiological response to stress that tend to be reduced rather than accentuated by repeated exposure to the stressor. Nevertheless, this buffering effect of repeated stress was dependent on the particular variable studied.
Objective measures of experimentally induced aggressiveness were evaluated in 20 abstinent heroin-dependent subjects, in comparison with 20 normal healthy male subjects. All the subjects were preliminarily submitted to DSM-IV interviews, Buss-Durkee Hostility Inventory (BDHI) and Minnesota Multiphasic Personality Inventory (MMPI II). During a laboratory task, the Point Subtraction Aggression Paradigm (PSAP), subjects earned monetary reinforcers with repeated button presses and were provoked by the subtraction of money, which was attributed to a fictitious other participant. Subjects could respond by ostensibly subtracting money from the fictitious subject (the aggressive response). Money-earning responses were not different in drug-free heroin addicts and controls during the first two sessions and significantly lower during the third session in heroin-dependent subjects (t=2.99, P<.01). Aggressive responses were significantly higher (F=4.9, P<.01) in heroin addicted individuals, in comparison with controls. During the experimentally induced aggressiveness, plasma adrenocorticotropic hormone (ACTH) and cortisol (CORT) concentrations increased less significantly, and norepinephrine (NE) and epinephrine (EPI) levels, together with heart rate (HR), increased more significantly in abstinent heroin-dependent subjects than in healthy subjects. PSAP aggressive responses positively correlated with catecholamine changes, BDHI "direct" and "irritability" scores, MMPI "psychopathic deviate" scores in heroin-dependent subjects and controls, and with CORT responses only in healthy subjects. No correlation was found between heroin-exposure extent (substance abuse history duration) and aggressiveness levels. The present findings suggest that heroin-dependent patients have higher outward-directed aggressiveness than healthy subjects, in relation with monoamine hyperreactivity, after long-term opiate discontinuation. Aggressiveness in heroin addicts seems to be related more to the personality traits than to drug effects. The impairment of hypothalamus-pituitary-adrenal (HPA) axis in abstinent addicted individuals could be due to a long-lasting action exerted by opiates on proopiomelanocortin (POMC) or to a premorbid psychobiological condition, in association with increased sympathetic arousal.