Michael S. Exton

Behavioral conditioning of immunosuppression is possible in humans

Behavioral conditioned immunosuppression has been described in rodents as the most impressive demonstration of brain‐to‐immune system interaction. To analyze whether behavioral conditioned immunosuppression is possible in humans, healthy subjects in this double‐blind, placebo‐controlled study were conditioned in four sessions over 3 consecutive days, receiving the immunosuppressive drug cyclosporin A as an unconditioned stimulus paired with a distinctively flavored drink (conditioned stimulus) each 12 h. In the next week, re‐exposure to the conditioned stimulus (drink), but now paired with placebo capsules, induced a suppression of immune functions as analyzed by the IL‐2 and IFN‐γ mRNA expression, intracellular production, and in vitro release of IL‐2 and IFN‐γ, as well as lymphocyte proliferation. These data demonstrate for the first time that immunosuppression can be behaviorally conditioned in humans.—Goebel, M. U., Trebst, A. E., Steiner, J., Xie, Y. F., Exton, M. S., Frede, S., Canbay, A., Michel, M. C., Heemann, U., Schedlowski, M. Behavioral conditioning of immunosuppression is possible in humans. FASEB J. 16, 1869–1873 (2002)

Infection-Induced Anorexia: Active Host Defence Strategy ☆

In association with fever production, decreased food consumption is the most common sign of infection. This effect is often regarded as an undesirable manifestation of sickness. However, evidence suggests that just as many behaviours have now been shown to modify immunocompetence, infection-induced anorexia is a behaviour systematically organised for pathogen elimination. That is, anorexia is an active defence mechanism that is beneficial for host defence. This review details the mechanism of infection-induced anorexia, placing it within the framework of the intricately organised acute phase response--the host response to infection. Furthermore, the evolutionary, behavioural, metabolic and immunological consequences of infection-induced anorexia are outlined, each providing evidence for the beneficial nature of this response. The evidence suggests that food restriction is one of the important behavioural strategies that organisms have evolved for the fight against pathogenic invasion. Nevertheless, such benefits require fine homeostatic control, as chronic undernutrition has deleterious consequences for host defence.

Cardiovascular and endocrine alterations after masturbation-induced orgasm in women.

OBJECTIVE The present study investigated the cardiovascular, genital, and endocrine changes in women after masturbation-induced orgasm because the neuroendocrine response to sexual arousal in humans is equivocal. METHODS Healthy women (N = 10) completed an experimental session, in which a documentary film was observed for 20 minutes, followed by a pornographic film for 20 minutes, and another documentary for an additional 20 minutes. Subjects also participated in a control session, in which participants watched a documentary film for 60 minutes. After subjects had watched the pornographic film for 10 minutes in the experimental session, they were asked to masturbate until orgasm. Cardiovascular (heart rate and blood pressure) and genital (vaginal pulse amplitude) parameters were monitored continuously throughout testing. Furthermore, blood was drawn continuously for analysis of plasma concentrations of adrenaline, noradrenaline, cortisol, prolactin, luteinizing hormone (LH), beta-endorphin, follicle-stimulating hormone (FSH), testosterone, progesterone, and estradiol. RESULTS Orgasm induced elevations in cardiovascular parameters and levels of plasma adrenaline and noradrenaline. Plasma prolactin substantially increased after orgasm, remained elevated over the remainder of the session, and was still raised 60 minutes after sexual arousal. In addition, sexual arousal also produced small increases in plasma LH and testosterone concentrations. In contrast, plasma concentrations of cortisol, FSH, beta-endorphin, progesterone, and estradiol were unaffected by orgasm. CONCLUSIONS Sexual arousal and orgasm produce a distinct pattern of neuroendocrine alterations in women, primarily inducing a long-lasting elevation in plasma prolactin concentrations. These results concur with those observed in men, suggesting that prolactin is an endocrine marker of sexual arousal and orgasm.

Orgasm-induced prolactin secretion: feedback control of sexual drive?

Recent studies from our laboratory have investigated the hormonal response to various forms of sexual stimulation, including film, masturbation, and coitus in both men and women. This series of studies clearly demonstrated that plasma prolactin (PRL) concentrations are substantially increased for over 1h following orgasm (masturbation and coitus conditions) in both men and women, but unchanged following sexual arousal without orgasm. Here we discuss evidence suggesting that the PRL response to orgasm may play an important role in the control of acute sexual arousal following orgasm. Supporting this position, chronic elevations of PRL (hyperprolactinemia) produce pronounced reductions in animal sexual activity, and significant reduction of libido and gonadal function in both men and women. These data suggest that PRL may represent a peripheral regulatory factor for reproductive function, and/or a feedback mechanism that signals CNS centres controlling sexual arousal and behaviour. Thus, we propose a theoretical model of the role of PRL as a neuroendocrine reproductive reflex.

NEUROENDOCRINE AND CARDIOVASCULAR RESPONSE TO SEXUAL AROUSAL AND ORGASM IN MEN

Data regarding the neuroendocrine response pattern to sexual arousal and orgasm in man are inconsistent. In this study, ten healthy male volunteers were continuously monitored for their cardiovascular and neuroendocrine response to sexual arousal and orgasm. Blood was continuously drawn before, during and after masturbation-induced orgasm and analyzed for plasma concentrations of adrenaline, noradrenaline, cortisol, luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, growth hormone (GH), beta-endorphin and testosterone. Orgasm induced transient increases in heart rate, blood pressure and noradrenaline plasma levels. Prolactin plasma levels increased during orgasm and remained elevated 30 min after orgasm. In contrast, none of the other endocrine variables were significantly affected by sexual arousal and orgasm.

Neuroendocrine response to film-induced sexual arousal in men and women

The psychoneuroendocrine responses to sexual arousal have not been clearly established in humans. However, we have demonstrated previously that masturbation-induced orgasm stimulates cardiovascular activity and induces increases in catecholamines and prolactin in blood of both males and females. We presently investigated the role of orgasm in producing these effects. Therefore, in this study parallel analysis of prolactin, adrenaline, noradrenaline, and cortisol concentrations, together with cardiovascular variables of systolic/diastolic blood pressure and heart rate were undertaken during film-induced sexual arousal in nine healthy adult men and nine healthy adult women. Blood was drawn continuously via an indwelling cannula and connected tubing system passed through a mini-pump. In parallel, the cardiovascular parameters were recorded continuously via a computerised finger-cuff sensor. Subjective sexual arousal increased significantly in both men and women during the erotic film, with sexual arousal eliciting an increase in blood pressure in both males and females, and plasma noradrenaline in females only. In contrast, adrenaline, cortisol and prolactin levels were unaffected by sexual arousal. These data further consolidate the role of sympathetic activation in sexual arousal processes. Furthermore, they demonstrate that increases in plasma prolactin during sexual stimulation are orgasm-dependent, suggesting that prolactin may regulate a negative-feedback sexual-satiation mechanism.

BEHAVIORALLY CONDITIONED IMMUNOSUPPRESSION USING CYCLOSPORINE A : CENTRAL NERVOUS SYSTEM REDUCES IL-2 PRODUCTION VIA SPLENIC INNERVATION

Bi-directional interactions between the central nervous system (CNS) and immune system are demonstrated by the modification of immune function using behavioral conditioning. However, the mechanisms by which the CNS achieves conditioned immunomodulation are still in question. Here, we report that the immunosuppressive effects of cyclosporine A (CsA) can be behaviorally conditioned in rats using saccharin as a gustatory conditioned stimulus. The conditioned effects were compared to control groups that received CsA paired with water (sham-conditioned), CsA injection on test days (CsA-treated), and unhandled rats (untreated). In conditioned animals, the mitogen-induced lymphocyte proliferation in the spleen is significantly suppressed, and the survival time of heterotopic heart allografts prolonged. These effects are paralleled by conditioned inhibition of IL-2 and IFN-gamma synthesis by splenocytes. Furthermore, the CNS-induced immunosuppression is mediated neuronally and not via the blood, since the conditioned reduction of proliferation and cytokine production is completely abrogated after surgical denervation of the spleen. Thus, during conditioning, the CNS learns to reinstate at demand a CsA-like immunosuppression via splenic innervation. This might be used as a supportive therapy for controlling immune functions.

Coitus-induced orgasm stimulates prolactin secretion in healthy subjects.

Previous data have indicated that orgasm produces marked alterations in plasma prolactin concentrations in men and women. Thus, the current study aimed to extend these data by examining prolactin response to coitus in healthy males and females. Ten pairs of healthy heterosexual couples participated in the study. Blood was drawn continuously for 20 min before, during, and until 60 min following sexual intercourse and orgasm. Plasma was subsequently analysed for prolactin concentrations. Coitus-induced orgasm produced a marked elevation of plasma prolactin in both males and females. Plasma prolactin concentrations remained elevated 1 h following orgasm. These data, together with previous evidence that masturbation-induced orgasm produces pronounced, long-lasting increases in plasma prolactin concentrations in both males and females, suggest a role for acute prolactin alterations in modifying human sexual desire following orgasm.

Adrenergic Modulation of Survival and Cellular Immune Functions during Polymicrobial Sepsis

Objective: An immunomodulatory effect of epinephrine has been reported that is supposed to be mediated via β-adrenergic receptors. The effect of epinephrine and/or β-adrenergic blockade on cellular immune functions during systemic inflammation has not yet been investigated. Methods: Male NMRI mice were treated with either an infusion of epinephrine (0.05 mg/kg/h i.p.), administration of the nonselective β-adrenoceptor antagonist propranolol (0.5 mg/kg s.c.), or a combination of epinephrine and propranolol after induction of a polymicrobial sepsis by cecal ligation and puncture. Forty-eight hours thereafter survival and cellular immune functions (splenocyte proliferation, splenocyte apoptosis and cytokine release, distribution of leukocyte subsets) were determined. Results: Infusion of epinephrine did not affect lethality of septic mice but induced alterations of splenocyte apoptosis, splenocyte proliferation and IL-2 release and was associated with profound changes of circulating immune cell subpopulations. Treatment with propranolol augmented the epinephrine-induced increase of splenocyte apoptosis, did not affect the decrease of splenocyte proliferation and IL-2 release, augmented the release of IL-6 and antagonized the mobilization of natural killer cells observed in epinephrine-treated animals. Furthermore, these immunologic alterations were accompanied by a significant increase of sepsis-induced mortality. Coadministration of propranolol and epinephrine augmented the propranolol-induced changes of splenocyte apoptosis and IL-6 release and was associated with the highest mortality of septic mice. Conclusion: Epinephrine infusion modulated cellular immune functions during systemic inflammation without an impact on survival. A pharmacologic β-adrenergic blockade partly augmented the epinephrine-induced immune alterations and was associated with a pronounced increase of mortality. This effect was further augmented by a combination of epinephrine infusion and β-adrenergic blockade. These data indicate that adrenergic mechanisms modulate cellular immune functions and survival during sepsis, with these effects being mediated via α- and β-adrenergic pathways.

Migration of naive, effector and memory T cells: implications for the regulation of immune responses

Summary: T cells play an important role in protective immune responses and in the pathogenesis of many diseases. Understanding the mechanisms regulating their distribution in vivo may therefore be of therapeutic value. Reviewing studies that have followed the migration of labelled naive, effector and memory T cells in healthy animals reveals that all T‐cell subsets enter all organs investigated. Within the tissue, two principally different migration patterns can be identified. First, naive and memory T cells accumulate in lymphoid organs for about 48 h after injection, as the time needed for migration through lymphoid organs is longer than through non‐lymphoid organs. During this time, surface molecule expression is temporarily modified. These changes are reversed before leaving the lymphoid organs and entering the blood to start a new cycle of migration. Second, effector T cells are evenly distributed throughout the body, and most die in the tissues within 24 h. However, depending on the presence of cytokines, some are able to survive and to proliferate, and thereby accumulate in defined microenvironments of the body. Analysing the principles regulating T‐cell migration and survival within the tissue may lead to the development of new options for the treatment of disease.