Neuroendocrine aspects of the serotonergic hypothesis of depression

This review examines the role of serotonin (5-HT) in depression. Dysfunction of serotonergic neurons has been implicated as one of the causes of endogenous depression. Since serotonergic neurons innervate the hypothalamus and these neurons send collaterals to several other brain areas, it is possible that hypothalamic sites which control hormone secretion receive the same serotonergic afferents that innervate other limbic areas in the brain. Several investigators have devised neuroendocrine challenge tests measuring the effect of 5-HT agonists on plasma cortisol and prolactin in depressed patients. These tests help to identify dysfunctional 5-HT neurons, and are a "window into the brain." The secretion of cortisol and prolactin is increased predominantly by 5-HT1 receptors. However, changes in 5-HT2 receptors have also been implicated in depression. Results from our laboratory and by others suggest that brain serotonergic neurons stimulate renin and vasopressin secretion by activation of 5-HT2 receptors. Therefore, the renin and vasopressin response to 5-HT agonists should be included in neuroendocrine tests of serotonergic function in affective disorders. Since antidepressants produce a decrease in the density of 5-HT2 receptors, renin and vasopressin could be used to evaluate the antidepressant potential of new drugs.     

Gaucher disease: in vivo evidence for allele dose leading to neuronopathic and nonneuronopathic phenotypes

Gaucher disease, a common lysosomal storage disorder, is associated with mutations at the acid beta-glucosidase (GCase) locus. Two affected individuals are described to share a common mutant allele, but manifest different clinical categorical phenotypes. A 57-year-old female, with Gaucher disease type 1 and Cherokee ancestry, was homozygous for a rare mutant allele encoding Lys79Asn (K79N). A 2-year-old Caucasian male, with Gaucher disease type 3 and Cherokee ancestry, was a heteroallelic homozygote for this same allele (K79N) and a novel complex mutation (null allele). The shared alleles were identical as determined by complete gene sequencing, suggesting a founder effect. The discrepant phenotypes (types 1 and 3) in these two patients provide support for a threshold of residual activity necessary to "protect" the central nervous system (CNS) from the pathogenic effects of Gaucher disease, indicating an allele dose-effect. Designation of genotype associations with specific phenotypes must be assessed with this perspective.     

Studies on Chinese hamster ovary mutants showing multiple cross-resistance to oxidative phosphorylation inhibitors

Several stable Chinese hamster ovary (CHO) mutants were selected after ethylmethane sulfonate mutagenesis for resistance to oligomycin, rutamycin, venturicidin, or antimycin. These mutants shared a number of common properties. They exhibited cross-resistance to those drugs which act on oxidative phosphorylation, irrespective of the structure and site of action of the drug. All the mutants showed a reduced ability to grow in suspension and to reach high saturation densities. They were also unable to use galactose as a carbon source. The short lag period required for selection (10–15 days), the similarity of the mutation rates for resistance to each of the four drugs, the high variance/mean ratios in fluctuation tests, and the recessive behavior of the resistance marker in hybrids suggest that the mutations responsible for resistance to oxidative phosphorylation inhibitors in CHO cells are coded by nuclear DNA. Segregation experiments indicated no linkage between the oligomycin-resistant marker (Olg^r) and Thg^r (thioguanine resistance). Oxidative phosphorylation, as measured by the rate of respiration coupled to phosphorylation in whole cells remained as sensitive to the drugs in the mutants as in the parental cell line. Glucose transport and the overall Krebs' cycle activities also appeared similar in the mutants and the wild type. All the mutants had an increased rate of lactic acid production (up to twofold), associated with increased specific activities for several glycolytic enzymes when assayed in cell-free extracts.We wish to dedicate this paper to Dr. Boris Ephrussi one of the founders of the field of somatic cell genetics. Many of the techniques, and more important, the concepts which prevail in this field can be laid to his seminal thinking on the subject. One of us (L.S.) in particular, owes a great deal to his personal stimulation and encouragement over a large number of years.     

Managing pain: The Challenge in Underserved Populations: Appropriate Use Versus Abuse and Diversion

ISSUE: Inadequate pain management is a serious public health problem that affects a wide cross-section of Americans. Patients are often denied sufficient medication, because physicians lack training and fear scrutiny from federal and state regulatory agencies. In addition, even the state-financed system of care, Medicaid, has been increasingly denying payment for the best treatment for pain management. These factors are complicated by physician bias about various subgroups and poor physician-patient communication. Comprehensive patient assessment plays a crucial role in determining appropriate treatment and identifying potential abuse problems. Physicians must routinely document medications analgesic effects and screen for potential ill effects and drug abuse. OBJECTIVE: To examine the prevalence of the undertreatment of pain, particularly among African Americans, and to recommend relevant proactive policy and practice changes to aid in eliminating this health problem. CONSENSUS PROCESS: In July 2002, the NMA convened the "Managing Pain: The Challenge in Underserved Populations: Appropriate Use versus Abuse and Diversion" Consensus Meeting in Washington, DC. The country's most renowned experts in the area of pain management and substance abuse reviewed substantial information regarding pain management and substance abuse including the following: --A draft summary paper on pain management and substance abuse that served as briefing material for consensus members; --Annotated bibliographies; --Articles on pain management and substance abuse; and --Key presentations on pain management and substance abuse.     

Influence of Malaria Infection on the Elaboration of Soluble Mediators by Adherent Mononuclear Cells

MALARIA RESULTS IN TWO SEEMINGLY PARADOXICAL PERTURBATIONS OF THE IMMUNE RESPONSE: polyclonal B-cell activation and immunosuppression. To determine what immunoregulatory role mediators secreted by adherent cells might play in these alterations, we cultured adherent cells from uninfected mice and from mice at different times during infection with Plasmodium berghei or P. yoelii. Culture supernatants obtained from these cells were tested for their ability to enhance the in vitro proliferative responses of thymocytes to suboptimal concentrations of concanavalin A or to inhibit the mitogen-stimulated proliferation of normal spleen cells. Supernatants obtained from adherent cells of mice early in infection (days 1 to 3) contained significantly elevated levels of enhancing activity which on Bio-Gel P-100 chromatography resembled lymphocyte-activating factor. Later in infection (days 4 and 5), these supernatants contained inhibitory activity. Normal adherent cells, when cocultivated in vitro with parasitized erythrocytes, ingested parasite debris and were stimulated to produce the enhancing factor. At high parasite/adherent-cell ratios, cells elaborated an inhibitory factor. These findings suggest that during malaria, adherent cells are converted from a nonspecific helper role to a nonspecific suppressor role. This modulation in function may be due to the direct interaction between adherent cells and parasitized erythrocytes.     

The dependence of the latency relaxation on sarcomere length and other characteristics of isolated muscle fibres

1. The latency relaxation has been examined in single fibres from frog striated muscle with particular attention given to its possible relation to Ca(2+) release during excitation-contraction coupling.2. Latency relaxations were recorded at 19-23 degrees C from massively stimulated (0.2 msec pulses) single fibres using two selected RCA 5734 transducer tubes in a bridge circuit.3. The depth of the latency relaxation has its full value when stimulus strength is between 40 and 400% above twitch threshold. Stronger stimuli reversibly diminish the latency relaxation.4. The variation in depth of latency relaxation with sarcomere length was found similar to that reported previously for multifibre preparations but in single fibres the peak of the curve consists of a plateau between sarcomere lengths of 2.8 mu and 3.2 mu.5. Sucrose hypertonicity increases the depth of the latency relaxation at sarcomere lengths below 2.8 mu but above this length it has either no effect or a depressant effect depending on the degree of hypertonicity.6. The maximal depth of the latency relaxation (measured at 3 mu) averaged 0.23% of the maximal tetanus tension (measured at 2.2 mu) and was strongly correlated (r = 0.87) with the latter in forty-five single fibres.7. The maximal depth of the latency relaxation is not correlated with the number of sarcomeres in series in a fibre.8. The results of this study are shown to fully support and extend Sandow's (1966) hypothesis that the latency relaxation is caused by release of activator Ca(2+) from the sarcoplasmic reticulum.     

Amyloidosis and the serum amyloid A protein response to muramyl dipeptide analogs and different mycobacterial species.

Serum amyloid A protein (SAA) elevation accompanies induction of secondary amyloidosis in mice given Mycobacterium butyricum in Freund adjuvant. The synthesis of SAA by cultured hepatocytes is induced by a macrophage-derived mediator, which has been identified as interleukin 1. In these studies, SAA synthesis has been used as an index of macrophage activation to examine the in vivo response of mice to challenge with seven different mycobacteria and with synthetic analogs of the immunoadjuvant N-acetylmuramyl-L-alanyl-D-isoglutamine [MDP(L-D)]. SAA synthesis was stimulated by administration (by the intraperitoneal route) of the mycobacteria dissolved in saline, with Mycobacterium vaccae being the most active and Mycobacterium leprae being the least stimulatory. MDP(L-D), which is the minimal structure (molecular weight, 492) able to substitute for mycobacteria in Freund adjuvant, stimulated SAA synthesis, whereas the MDP(D-D) isomer was inactive. The butyl ester of MDP, which induces no detectable pyrogenicity but retains adjuvanticity, required a 100-fold greater dosage than MDP(L-D) in stimulating SAA synthesis. Amyloidosis was detected histologically only when active SAA inducers MDP(L-D), M. vaccae, and M. butyricum, were administered in incomplete Freund adjuvant, with amyloid-enhancing factor. These studies demonstrated that SAA elevation was a sensitive in vivo marker of the capacity of antigens to stimulate macrophages to produce interleukin 1. A point of considerable relevance to the human use of MDP was the observation that repeated injections of the adjuvant MDP in saline did not induce secondary amyloidosis.