Effect of methysergide, a blocker of serotonin receptors, on plasma prolactin levels in lactating and ovariectomized rats.

The effect of methysergide (MES, 2.5 mg/100 g body wt), a serotonin antagonist, on prolactin release has been studied in lactating and ovariectomized rats. MES caused significant increases in prolactin release in both animals. Studies in ovariectomized, hypophysectomized rats indicate that this effect is not due to a decrease in the peripheral metabolism of prolactin. In vitro incubations of anterior pituitary fragments with MES failed to demonstrate any increase in prolactin release, suggesting that MES does not act directly on the anterior pituitary. Parachlorophenylalanine (PCPA; 32 mg/100 g body wt) decreased brain serotonin levels in ovariectomized rats 5, 24, and 70 h after its administration, yet did not alter plasma prolactin levels. L-tryptophan (6.3 mg/100 g body wt) given 1 and 1 1/2 h prior to sacrifice increased brain serotonin levels, yet did not affect plasma prolactin levels. Neither PCPA nor L-tryptophan altered MES-induced prolactin release. In lactating rats, suckling caused marked increases in plasma prolactin levels, an effect completely abolished by the administration of MES to the mother rats 3 1/4 h prior to suckling. However, MES-induced prolactin release was not altered by prior treatment with MES, either in lactating or ovariectomized rats. Others have shown that suckling releases prolactin through an excitatory serotonergic mechanism. Therefore, the failure of suckling to release prolactin in MES-pretreated rats suggests that MES can block brain serotonin receptors. However, the ability of methysergide to release prolactin in rats with serotonin receptors presumably blocked, suggests that the serotonin receptor-blocking and the prolactin-releasing actions of MES are not related.     

Vaccination with tat toxoid attenuates disease in simian/HIV-challenged macaques

The Tat protein is essential for HIV type 1 (HIV-1) replication and may be an important virulence factor in vivo. We studied the role of Tat in viral pathogenesis by immunizing rhesus macaques with chemically inactivated Tat toxoid and challenging these animals by intrarectal inoculation with the simian/human immunodeficiency virus 89.6PD. Immune animals had significantly attenuated disease with lowered viral RNA, interferon-alpha, and chemokine receptor expression (CXCR4 and CCR5) on CD4(+) T cells; these features of infection have been linked to in vitro effects of Tat and respond similarly to extracellular Tat protein produced during infection. Immunization with Tat toxoid inhibits key steps in viral pathogenesis and should be included in therapeutic or preventive HIV-1 vaccines.     

Adolescent Exposure to WIN 55212-2 Render the Nigrostriatal Dopaminergic Pathway Activated During Adulthood

BackgroundDuring adolescence, neuronal circuits exhibit plasticity in response to physiological changes and to adapt to environmental events. Nigrostriatal dopaminergic pathways are in constant flux during development. Evidence suggests a relationship between early use of cannabinoids and psychiatric disorders characterized by altered dopaminergic systems, such as schizophrenia and addiction. However, the impact of adolescent exposure to cannabinoids on nigrostriatal dopaminergic pathways in adulthood remains unclear. The aim of this research was to determine the effects of repeated activation of cannabinoid receptors during adolescence on dopaminergic activity of nigrostriatal pathways and the mechanisms underlying this impact during adulthood.MethodsMale Sprague-Dawley rats were treated with 1.2 mg/kg WIN 55212-2 daily from postnatal day 40 to 65. Then no-net flux microdialysis of dopamine in the dorsolateral striatum, electrophysiological recording of dopaminergic neuronal activity, and microdialysis measures of gamma-aminobutyric acid (GABA) and glutamate in substantia nigra par compacta were carried out during adulthood (postnatal days 72–78).ResultsRepeated activation of cannabinoid receptors during adolescence increased the release of dopamine in dorsolateral striatum accompanied by increased population activity of dopamine neurons and decreased extracellular GABA levels in substantia nigra par compacta in adulthood. Furthermore, perfusion of bicuculline, a GABAa antagonist, into the ventral pallidum reversed the increased dopamine neuron population activity in substantia nigra par compacta induced by adolescent cannabinoid exposure.ConclusionsThese results suggest that adolescent exposure to cannabinoid agonists produces disinhibition of nigrostriatal dopamine transmission during adulthood mediated by decreased GABAergic input from the ventral pallidum.     

Processing of the structural proteins of human immunodeficiency virus type 1 in the presence of monensin and cerulenin.

The synthesis and processing of structural proteins of human immunodeficiency virus type 1 (HIV-1) were studied in infected cells treated with monensin and cerulenin. In MOLT-3 cells chronically infected with HTLV-IIIB, monensin inhibited the proteolytic cleavage of the env-coded polyprotein gp160 to gp120, leading to the accumulation of the precursor gp160. The formation of syncytia normally observed when CEM cells are cocultivated with HIV-1-infected MOLT-3 cells was significantly inhibited in the presence of monensin. The effect of the ionophore on the culture was reversible, as withdrawal of monensin from the medium restored the ability of the cells to form syncytia with CEM cells and led to the resumption of the processing of gp160 to gp120. Monensin did not affect the synthesis and processing of gag-coded proteins and regulatory proteins. Cerulenin, an inhibitor of de novo fatty acid biosynthesis, inhibited the myristoylation and the proteolytic cleavage of the gag-coded polyprotein Pr53gag to p24 but did not affect the processing of gp160. However, use for monensin and cerulenin as antiviral agents for treatment of HIV-1 infection cannot be foreseen because of the pronounced in vitro toxicity observed.     

Human herpesvirus 7 is a T-lymphotropic virus and is related to, but significantly different from, human herpesvirus 6 and human cytomegalovirus.

An independent strain (JI) of human herpesvirus 7 (HHV-7) was isolated from a patient with chronic fatigue syndrome (CFS). No significant association could be established by seroepidemiology between HHV-7 and CFS. HHV-7 is a T-lymphotropic virus, infecting CD4+ and CD8+ primary lymphocytes. HHV-7 can also infect SUP-T1, an immature T-cell line, with variable success. Southern blot analysis with DNA probes scanning 58.8% of the human herpesvirus 6 (HHV-6) genome and hybridizing to all HHV-6 strains tested so far revealed homology to HHV-7 with only 37.4% of the total probe length. HHV-7 contains the GGGTTA repetitive sequence, as do HHV-6 and Marek's disease chicken herpesvirus. DNA sequencing of a 186-base-pair fragment of HHV-7(JI) revealed an identity with HHV-6 and human cytomegalovirus of 57.5% and 36%, respectively. Oligonucleotide primers derived from this sequence (HV7/HV8, HV10/HV11) amplified HHV-7 DNA only and did not amplify DNA from other human herpesviruses, including 12 different HHV-6 strains. Southern blot analysis with the p43L3 probe containing the 186-base-pair HHV-7 DNA fragment hybridized to HHV-7 DNA only. The molecular divergence between human cytomegalovirus, on the one hand, and HHV-6 and HHV-7, on the other, is greater than between HHV-6 and HHV-7, which, in turn, is greater than the difference between HHV-6 strains. This study supports the classification of HHV-7 as an additional member of the human beta-herpesviruses.     

Intestinal microbial metabolism of phosphatidylcholine: a novel insight in the cardiovascular risk scenario

Intestinal microbiota is a “dynamic organ” influencing host metabolism, nutrition, physiology and immune system. Among its several interactions, the role of a phosphatidylcholine metabolite derived by gut flora activity, i.e., trimethylamine-N-oxide (TMAO), allows perceiving a novel insight in the cardiovascular risk scenario, being a strong predictor of this condition. Based on current reports, including the paper of Tang et al., we describe here: the possible role of intestinal microbiota in cardiovascular risk as well as potential interventions to reduce gut flora TMAO production by diet, probiotics and antibiotics. Finally, we highlight the possibility of evaluating, monitoring and modulating TMAO in order to use its serum levels as a marker of cardiovascular risk in the next future, when the need of controlled studies on large series will be satisfied.