Effects of peptides on animal and human behavior: a review of studies published in the first twenty years of the journal Peptides.

This review catalogs effects of peptides on various aspects of animal and human behavior as published in the journal Peptides in its first twenty years. Topics covered include: activity levels, addiction behavior, ingestive behaviors, learning and memory-based behaviors, nociceptive behaviors, social and sexual behavior, and stereotyped and other behaviors. There are separate tables for these behaviors and a short introduction for each section.

Administration of FGF-1 through transfected cells alleviates MPTP toxicity in mice.

The use of genetically modified cells to deliver growth factors has been proposed as a possible treatment for neurodegeneration, including Parkinson's disease. Here we demonstrate that the implantation of fibroblasts genetically modified to secrete fibroblast growth factor-1 (FGF) increased striatal dopamine concentrations in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson's disease.

Passage of interleukin-1-beta across the blood-brain barrier is reduced in aged mice: a possible mechanism for diminished fever in aging.

OBJECTIVE: Cytokine signaling is the key to fighting infection. Fever is elicited by the production of inflammatory cytokines, particularly interleukin-1beta (IL-1beta), and the subsequent action of cytokines in the hypothalamus. In old age, the ability to produce fever in response to infection or to peripheral injections of IL-1beta is diminished. Intracerebroventricular injections of IL-1beta can still produce a normal fever response in the aged. A logical hypothesis to explain this discrepancy is that passage of IL-1beta across the blood-brain barrier (BBB) is altered. METHOD: We used a quantitative in vivo technique, which previously showed a saturable system transporting IL-1beta across the BBB, to investigate the speed at which radiolabeled IL-1beta crosses from blood to brain in mice of widely different ages. RESULTS: We found that passage of IL-1beta across the BBB was significantly decreased in old (23-month) mice as compared with young (2-month) or middle-aged (12-month) animals. Passage of IL-1beta across the blood-testis barrier was not significantly different among the groups. The passage of radiolabeled albumin across the BBB was not increased in any group, ruling out any disruption of the BBB by IL-1beta. CONCLUSION: These results provide a mechanism that could help explain why fever production is reduced in old age and suggest an important role for the BBB in regulating immune changes.

Kind strangers? Physicians through the eyes of Tennessee Williams.

In Louisiana, Tennessee Williams is usually thought of as a famous denizen of the French Quarter or perhaps as our greatest playwright. Medicine rarely enters into it. Illness, however, particularly mental illness, shaped much of Williams' life and his work. The playwright had mixed feelings about physicians and their effect on his life and that of his close relations. These feelings worked their way into his plays. Through it all Williams gives a vivid, humorous, and deeply truthful image of the doctor-patient relationship in the first half of the twentieth century. Here we give a brief review of medicine in Williams' work.

Veterans have less age-related cognitive decline.

Military service involves exposure to a number of stresses, both psychological and physical. On the other hand, military personnel generally maintain excellent fitness, and veterans have increased access to education and health care. The overall effect on age-related cognitive decline, whether for good or ill, of having served in the armed forces has not been investigated previously. In this study, we examined a diverse population of 208 veterans and 1,216 civilians followed as part of the Epidemiologic Catchment Area Study in 1981, 1982, and 1993 to 1996. We examined change in Mini-Mental State Examination (MMSE) score after a median of 11.5 years. Veterans were found to have significantly less decrease in MMSE scores at follow-up even after sex, race, and education were taken into account. These results suggest an overall positive effect of military service on the rate of age-related cognitive decline.

Passage of leptin across the blood-testis barrier.

Leptin is a 17-kDa protein, secreted by fat, that controls adiposity and has been proposed to have numerous effects on reproduction in the mouse. To assess whether the effects of leptin on testicular function are direct, we determined whether leptin can cross the murine blood-testis barrier. Multiple time regression analysis showed that a small amount of blood-borne leptin is able to enter the testis but does so by a nonsaturable process. In addition, no significant expression of leptin receptors was found at the Leydig cells or Sertoli cells of the testis. This compares with the presence of a saturable transport system for leptin at the blood-brain barrier and abundant receptors for leptin at the leptomeninges, neurons, and choroid plexus of the central nervous system (CNS). These results support the hypothesis that the effects of leptin on reproductive function are not mediated at the level of the testis but indirectly, probably through the CNS.

Tests used to assess the cognitive abilities of aged rats: their relation to each other and to hippocampal morphology and neurotrophin expression.

BACKGROUND: Aged rodents have proven to be a useful tool in studying age-related cognitive decline, particularly with regard to hippocampal function. A number of maze tests have been developed to evaluate hippocampal function in aged rodents, including the eight-arm radial maze, Barnes circular platform maze and Morris water maze. To some extent, these mazes have been used interchangeably to evaluate aged animals. Few researchers, however, have examined how performance of individual, aged animals compares in these three mazes. OBJECTIVE: The purpose of this study was to compare the performances in the three mazes and to examine how such performances are related to each other, to hippocampal morphology and to neurotrophin gene expression. METHODS: We screened groups of young and old Fisher 344 x Brown Norway rats for general health and physical abilities, tested the animals in the three mazes and examined correlations among performances in the mazes and in screening tests. Hippocampal neuron density and expression of hippocampal neurotrophin mRNAs were also examined and compared with behavior in the three mazes. RESULTS: Aged animals were found to be impaired in all three mazes and to have lower hippocampal neuron densities compared with young animals, with poor learning behavior significantly correlating with reduced hippocampal neuron density. Differences were observed between performance in the different mazes, but in general the Morris water maze and Barnes circular platform maze were found to give similar results.

Chronic corticosterone impairs memory performance in the Barnes maze.

Chronic stress has been reported to impair spatial memory and cause hippocampal impairment in rodents. Glucocorticoids are believed to be the active agent in this impairment. Studies have demonstrated that chronic glucocorticoid administration results in animals being impaired in the Morris water maze (MWM) or eight-arm radial maze. Although both of these methods are well established means of testing spatial memory, neither might be considered optimal for studying the behavioral effects of stress. The Morris maze is itself highly stressful to the animals. The eight-arm maze relies on a food reward to motivate the animals, and glucocorticoids have profound effects on hunger and satiety. We therefore investigated behavioral deficits of corticosterone-treated animals in the two previously used mazes and the Barnes circular platform maze (BCM), a test similar in design to the Morris maze, but one that does not require the animal to perform a highly stressful swim. Consistent with results in other tests, we found that animals that had been treated for 3 months with stress-equivalent concentrations of glucocorticoids showed significantly impaired behavior in the Barnes maze.

Granulocyte-macrophage colony-stimulating factor crosses the blood--brain and blood--spinal cord barriers.

Granulocyte-macrophage colony-stimulating factor (GM-CSF), a glycoprotein with hormonal properties, is produced by several cell types, most of which exist outside the CNS. GM-CSF, however, affects the CNS. If capable of crossing from blood to CNS, GM-CSF might be an important signalling molecule between the CNS and periphery. We used an established in vivo method in mice and rats to study passage of radioactively labelled GM-CSF from blood to CNS. We found that GM-CSF crossed the blood-brain barrier and blood-spinal cord barrier significantly faster than the control substance, albumin. Labelled GM-CSF was recovered in intact form by high performance liquid chromatography from brain after peripheral injection, and passage was not significantly reduced by simultaneous injection of unlabelled L-tryptophan. Both findings indicate that the observed passage of radioactivity was intact protein. Capillary depletion experiments showed that most of the GM-CSF was deposited in brain parenchyma rather than cerebral capillary endothelium. Co-injection of unlabelled GM-CSF significantly reduced the passage rate of labelled cytokine across the blood-brain and blood-spinal cord barriers, demonstrating that passage was mediated by a saturable system. In summary, a saturable mechanism transports GM-CSF intact from blood to CNS.

Interactions of beta-amyloids with the blood-brain barrier.

Blood-borne beta-amyloids (A beta s) could affect brain function by (1) crossing the BBB to directly interact with brain tissues or (2) altering BBB function by interacting with the brain capillaries that make up the BBB. Several radioactively labeled A beta s have been examined for such interactions. Blood-borne A beta 1-28 is hindered from accumulating in brain by a slow rate of passage across the BBB and by robust enzymatic degradation. A beta 1-40, but not A beta 40-1 or A beta 1-42, is sequestered by brain capillaries, raising the possibility that it could affect BBB function. Small amounts of circulating A beta 1-40 are recovered intact from CSF and brain. A beta 1-40 is degraded by aluminum-sensitive, calcium-dependent intracellular enzymes. Apo-J, which can bind A beta, has been shown with an in situ method to be transported by a saturable system across the BBB. However, our recent work has shown that this system is not operable in vivo, probably because the transporter is saturated at physiological blood levels. In conclusion, A beta s have been shown to interact with and to cross the BBB.

Aging in the hippocampus: interrelated actions of neurotrophins and glucocorticoids.

Over the past two decades, evidence has been accumulating that diffusible molecules, such as growth factors and steroids hormones, play an important part in neural senescence, particularly in the hippocampus. There is also evidence that these molecules do not act as independent signals, but show interrelated regulation and cooperative control over the aging process. Here, we review some of the changes that occur in the hippocampus with age, and the influence of two classes of signaling substances: glucocorticoids and neurotrophins. We also examine the interactions between these substances and how this could influence the aging process.

Granulocyte macrophage-colony stimulating factor crosses the blood-testis barrier in mice.

Granulocyte macrophage-colony stimulating factor (GM-CSF) has hormone-like effects on female reproductive systems. Recent evidence has suggested that GM-CSF also might be important to male testicular function. It is possible, however, that most sources of GM-CSF might not be able to reach the testis, since testes are shielded from contact with the general circulation by vascular and Sertoli cell barriers, which together comprise the blood-testis barrier (BTB). We used a sensitive in vivo method to determine whether blood-borne GM-CSF crossed the BTB in mice. 125I-GM-CSF was found to cross the BTB, showing a unidirectional influx constant (Ki) of 1.45 x 10(-3) ml/g-min, nine times faster than the influx rate of the control substance, 99mTc-albumin. HPLC analysis confirmed the presence of intact 125I-GM-CSF in the testis after peripheral injection. More 125I-GMCSF than 99mTc-albumin crossed both the vascular barrier, to enter the testicular interstitial fluid, and the Sertoli cell barrier, to enter the seminiferous tubule fluid. Coinjection of unlabeled GM-CSF significantly reduced the passage rate of labeled cytokine across the BTB, demonstrating that passage was mediated by a saturable system and suggesting the presence of a transport or facilitated diffusion system for GM-CSF. In summary, GM-CSF passes intact from blood to testis by means of a saturable mechanism.

The putative blood-brain barrier transporter for the beta-amyloid binding protein apolipoprotein j is saturated at physiological concentrations.

beta-amyloid (A beta), the major component of the amyloid deposited in the brains of patients with Alzheimer's disease, is found in blood and can cross the blood-brain barrier (BBB). This suggests that the circulation could be a source of A beta in brain. The passage of unbound A beta across the BBB is slow. Most of the A beta in blood, however, is likely to be bound to apolipoprotein J (ApoJ). ApoJ and A beta bound to ApoJ have been shown to rapidly cross the BBB of the guinea pig when studied in situ with a blood-free brain perfusion model. ApoJ in blood, however, is found in a concentration 28 times higher than that needed to saturate the ApoJ transporter in situ. This suggests that the putative ApoJ transporter may not be functional in vivo. We found here that when measured in a murine in situ brain perfusion model, 125I-ApoJ crossed the BBB with a unidirectional influx rate constant (Ki) of 3.75 x 10(-3) ml/g-min, which is similar to that found in the guinea pig. After intravenous injection, however, no penetration of ApoJ across the BBB was measured in either the mouse or guinea pig. These results suggest that ApoJ is unlikely to provide a significant route for the transport of A beta across the BBB in vivo.