Jonathan D. Karp

ALTERATIONS IN INTERLEUKIN-4 AND ANTIBODY PRODUCTION FOLLOWING PHEROMONE EXPOSURE : ROLE OF GLUCOCORTICOIDS

We have previously shown that exposure to pheromones from footshock-stressed mice suppresses cell-mediated immunity and enhances humoral immunity. Here we show that stress odor exposure is associated with enhanced antigen-specific antibody production and interleukin (IL)-4 production in BALB/c, but not C57Bl/6, mice. Glucocorticoid receptor antagonism blocks the enhancement of IL-4, but not antibody titers. There is an apparent differential sensitivity of BALB/c and C57Bl/6 spleen cells to in vitro incubation with the synthetic glucocorticoid dexamethasone; IL-2 production by BALB/c spleen cells is more sensitive to the effects of steroid. These data suggest that C57Bl/6 mice may not respond to stress pheromones due to their relative insensitivity to endogenous steroids.

Immune deviation following stress odor exposure: role of endogenous opioids

Olfactory cues can alter immune function. BALB/c mice exposed to odors produced by footshock stressed donor mice have increased antibody responses and increased splenic interleukin (IL)-4 production following immunization relative to recipients of odors from unstressed animals. Here we document that exposure to stress odors results in analgesia that is blocked by the non-selective opioid receptor antagonist naltrexone. The stress odor-induced increase in antigen-driven IL-4 and antibody is also blocked by oral administration of naltrexone. Thus, we provide evidence that immune deviation can occur following a psychosocial stressor, and that the deviation appears to be mediated by endogenous opioid production.

Restraint stress augments antibody production in cyclophosphamide-treated mice.

These studies evaluated the effects of a psychological stressor (restraint, RST) on antibody production in male BALB/cByJ mice. In Experiment 1, mice were immunized with keyhole limpet hemocyanin (KLH, 100 microg i.p.) 8 h prior to 15 h of RST or food and water deprivation (FWD). RST mice exhibited higher serum anti-KLH IgM and IgG antibodies than FWD mice. In Experiment 2, mice were given either cyclophosphamide (CY, 15 mg/kg) or saline (SAL) prior to immunization with KLH and RST or FWD. ANOVA revealed serum anti-KLH IgG antibody titers in CY+RST animals to be significantly higher than in CY+FWD, SAL+FWD, and SAL+RST mice. Anti-KLH IgM titers of CY+RST mice were higher than those of other groups before and after a second immunization with KLH. In Experiment 3, we show that these changes in antibody production are not likely to be mediated via CY-induced alterations in the reactivity of the hypothalamo-pituitary-adrenal axis to RST. Together, these results indicate two potentially immunomodulatory parameters (RST and CY) can interact to alter a humoral immune response. In addition, these data support the hypothesis that humoral immune response of mice can be more reactive to stress when the mice are given a low dose of an immunomodulatory drug prior to stressor exposure.

Systemic lipopolysaccharide plus MPTP as a model of dopamine loss and gait instability in C57Bl/6J mice

In most environmental models of Parkinsons disease (PD), a single neurodegenerative agent is introduced to cause nigrostriatal dopamine depletion. However, cell loss in human PD often might derive, at least in part, from multiple toxins or vulnerabilities, any one of which alone does not inevitably lead to chronic dopamine depletion. In the present research, male C57BL/6J mice were systemically administered the inflammatory bacterial endotoxin, lipopolysaccharide (LPS) and the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) alone or in combination and the behavior as well as striatal dopamine levels were compared to saline-treated mice. Mice in the combination (LPS+MPTP) group, but not in the single-factor groups, showed both dopamine depletion and parkinsonian symptoms, i.e., reduced stride length, at 4 months post-injection. MPTP alone acutely reduced striatal dopamine levels but this effect was transient as striatal dopamine recovered to normal levels after time (4 months). The LPS-only group showed no dopamine depletion or reduced stride length. These data are consistent with the view that nigrostriatal dopamine neurons might succumb after time to multiple toxic agents that independently may have only a transient, adverse effect.

Quantitative differences in interleukin-2 and interleukin-4 production by antigen-stimulated splenocytes from individually- and group-housed mice

The effects of differential housing on T-helper (TH) cell activation were investigated. BALB/c and C57Bl/6 male mice housed 1 or 4 per cage were administered three i.p. injections of keyhole limpet hemocyanin (KLH) over several weeks. Effects of differential housing on in vitro antigen-specific interleukin (IL)-2 (a TH1 cell derived cytokine) and IL-4 (a TH2 cell derived cytokine) production were observed. BALB/c mice housed alone produced significantly more IL-4 than BALB/c mice housed in groups. C57Bl/6 mice housed alone produced significantly more IL-2 than C57Bl/6 mice housed in groups. Differential housing did not influence either IL-2 production among BALB/c mice or IL-4 production among C57Bl/6 mice. These data demonstrate that environmental conditions can influence cytokine production by both TH-1 dominant (C57Bl/6) and TH-2 dominant (BALB/c) mice.

Photoperiodic and pineal influences on estrogen-stimulated behaviors in female Syrian hamsters.

Three experiments investigated the effects of short photoperiod exposure on the estrogenic facilitation of locomotor activity and lordosis. In Experiment 1, ovariectomized female hamsters were administered exogenous estrogen to stimulate locomotor activity in running wheels. Estrogen was effective in the long photoperiod group but did not stimulate running-wheel activity in the short photoperiod group. In Experiment 2, the role of the pineal gland in mediating photoperiodic influences on female hamster behavior was examined. Both estrogen-induced locomotor activity and estrogen+progesterone-stimulated lordosis behavior were significantly reduced in short photoperiod females. Both these photoperiodic effects were absent in pinealectomized hamsters. Sham-pinealectomized, short photoperiod females expressed behavioral deficits; pinealectomized hamsters in the short photoperiod did not. Experiment 3 investigated lordosis only and used hormone injections rather than silastic implants to administer estrogen. The photoperiodic and pineal effects observed in Experiment 2 were replicated in Experiment 3. Additionally, the suppression of lordosis responsiveness by short photoperiod exposure was estrogen dose dependent. Photoperiodic effects were present when 2 micrograms estradiol cypionate was used but absent when higher estrogen doses were used. These findings are discussed in the context of other results that suggested photoperiodic effects on hamster lordosis were pineal independent.

Corticosterone Modulates Auditory Gating in Mouse

Previous studies suggest that circulating glucocorticoids may influence the encoding and processing of sensory stimuli. The current study investigated this hypothesis by measuring the generation (amplitude), gating (recovery cycle), and sensitivity (intensity function) of auditory evoked responses in C57BL/6 mice treated with chronic corticosterone (0, 1, 5, 15, or 30 mg/kg/day for 14 days). We found that low-dose corticosterone (5 but not 1 mg/kg/day) enhanced the amplitude and improved gating of evoked potentials without affecting the intensity function. In comparison, higher doses (15 and 30 mg/kg/day) decreased the amplitude and impaired gating of evoked potentials, also without altering the stimulus intensity function. At all doses, lower amplitudes of evoked potentials were significantly correlated with higher circulating corticosterone levels. These data highlight the need to consider serum glucocorticoid levels when assessing human disease states associated with aberrations of information processing such as schizophrenia and depression.

Stress-Induced Modulation of Immune Function in Mice

Publisher Summary Stress, which is the response of an organism to stimulation or change, is characterized by activation of the autonomic nervous system and the hypothalamo-pituitary-adrenal (HPA) axis. The resulting neurochemical changes have been demonstrated to affect immune function directly and indirectly. Direct effects are possible because lymphocytes bear receptors on their surfaces for many neurohormones and transmitters, and lymphocytes are exposed to neurochemicals in lymphoid organs and in peripheral blood. More indirect mechanisms for neural-immune interactions might involve changes in lymphocyte trafficking resulting from changes in sympathetic vascular tone. The elucidation of pathways of communication between the central nervous system and the immune system has advanced, to a large extent, from studies utilizing stressor administration in animal models. Application of stressor in animals results in diverse changes in specific humoral and cell-mediated immune parameters, and in non-specific natural killer (NK) cell number and/or activity.

Pinealectomy prevents short photoperiod inhibition of male hamster sexual behavior.

The role of the pineal gland in mediating photoperiodic influences on copulatory behavior (CB) of male hamsters (Mesocricetus auratus) was assessed in the presence and absence of testosterone (T). The results demonstrate that the pineal gland is necessary for short photoperiod exposure to alter CB. Sexually experienced males were exposed to either long (14L:10D; LP) or short (8L:16D; SP) photoperiods for 13 weeks; after the first 2 weeks of exposure, all animals were castrated and then either pinealectomized (PINX) or sham operated (SHAM PINX). CB tests over an 8-week period following surgery indicated that copulatory impairments developed in all animals, but deficits occurred more rapidly among short photoperiod males with intact pineal glands (SP-SHAM PINX), compared to pinealectomized males housed in either the long (LP-PINX) or short photoperiod (SP-PINX). LP-PINX and SP-PINX animals were not statistically different on any of the CB measures examined. Nine weeks after castration (11 weeks of photoperiod exposure), all hamsters were given a T-filled Silastic capsule to restore CB. Restoration of sexual behavior was less rapid and less complete among SP-SHAM PINX hamsters. Additionally, males in this group took longer to initiate copulation relative to the pinealectomized hamsters. These findings are compared to other reports suggesting that photoperiodic effects on the sexual behavior of female hamsters do not require an intact pineal gland.

Melatonin and the coding of day length in male Syrian hamsters

Abstract: Two experiments investigated the response of the pituitary‐gonadal axis of pinealectomized male Syrian hamsters to programmed systemic administration of melatonin. In the first experiment, castrated male Syrian hamsters were housed in a short photoperiod (8L:16D) and maintained on subcutaneous testosterone implants for 7 weeks. These males were then pinealectomized or sham‐pinealectomized and their testosterone capsules removed. Daily infusions of melatonin 250 ng/infusion) or its vehicle were administered for 3 weeks; infusion duration was long (11 or 12 hr) or short (6 hr). Measurement of serum luteinizing hormone (LH) following this 3‐week period indicated that long‐duration melatonin infusions mimicked short‐day conditions (LH levels were low), but short‐duration infusions did not (LH levels were significantly elevated). In the second experiment, pinealectomized, gonadally intact males were housed in a 12L:12D photoperiod and injected once daily with melatonin or its vehicle, either 3 or 5 hr after dark onset for 11 weeks. These times were chosen to coincide with the light: dark cycle phase that according to published reports is optimally responsive to exogenous melatonin for the induction of short‐photoperiodic effects. Melatonin injections did not induce gonadal regression in pinealectomized hamsters. Melatonin and vehicle‐treated males responded similarly; their testis widths and serum testosterone levels were not significantly different at the end of the experiment. These results support the hypothesis that the duration of melatonin secretion each night is an important variable in conveying photoperiodic information, but that the circadian phase during which melatonin is present is not.