Synaptic Vesicle Recycling Pathway Determines Neurotransmitter Content and Release Properties.

In contrast to temporal coding by synaptically acting neurotransmitters such as glutamate, neuromodulators such as monoamines signal changes in firing rate. The two modes of signaling have been thought to reflect differences in release by different cells. We now find that midbrain dopamine neurons release glutamate and dopamine with different properties that reflect storage in different synaptic vesicles. The vesicles differ in release probability, coupling to presynaptic Ca2+ channels and frequency dependence. Although previous work has attributed variation in these properties to differences in location or cytoskeletal association of synaptic vesicles, the release of different transmitters shows that intrinsic differences in vesicle identity drive different modes of release. Indeed, dopamine but not glutamate vesicles depend on the adaptor protein AP-3, revealing an unrecognized linkage between the pathway of synaptic vesicle recycling and the properties of exocytosis. Storage of the two transmitters in different vesicles enables the transmission of distinct signals.

Regional Heterogeneity of D2-Receptor Signaling in the Dorsal Striatum and Nucleus Accumbens.

Dopamine input to the dorsal and ventral striatum originates from separate populations of midbrain neurons. Despite differences in afferent inputs and behavioral output, little is known about how dopamine release is encoded by dopamine receptors on medium spiny neurons (MSNs) across striatal subregions. Here we examined the activation of D2 receptors following the synaptic release of dopamine in the dorsal striatum (DStr) and nucleus accumbens (NAc) shell. We found that D2 receptor-mediated synaptic currents were slower in the NAc and this difference occurred at the level of D2-receptor signaling. As a result of preferential coupling to Gαo, we also found that D2 receptors in MSNs demonstrated higher sensitivity for dopamine in the NAc. The higher sensitivity in the NAc was eliminated following cocaine exposure. These results identify differences in the sensitivity and timing of D2-receptor signaling across the striatum that influence how nigrostriatal and mesolimbic signals are encoded across these circuits.

Phasic dopamine release drives rapid activation of striatal D2-receptors.

Striatal dopamine transmission underlies numerous goal-directed behaviors. Medium spiny neurons (MSNs) are a major target of dopamine in the striatum. However, as dopamine does not directly evoke a synaptic event in MSNs, the time course of dopamine signaling in these cells remains unclear. To examine how dopamine release activates D2-receptors on MSNs, G protein activated inwardly rectifying potassium (GIRK2; Kir 3.2) channels were virally overexpressed in the striatum, and the resulting outward currents were used as a sensor of D2-receptor activation. Electrical and optogenetic stimulation of dopamine terminals evoked robust D2-receptor inhibitory postsynaptic currents (IPSCs) in GIRK2-expressing MSNs that occurred in under a second. Evoked D2-IPSCs could be driven by repetitive stimulation and were not occluded by background dopamine tone. Together, the results indicate that D2-receptors on MSNs exhibit functional low affinity and suggest that striatal D2-receptors can encode both tonic and phasic dopamine signals.

Incidence of colorectal cancer and influence of dietary habits in fifteen European countries from 1971 to 2002.

OBJECTIVE: This study aimed to analyze the incidence of colorectal cancer in 15 European countries in recent decades and the relationship between the incidence found and changes in dietary habits. METHODS: Pearson's or Spearman's correlation coefficients were calculated by comparing incidence rates obtained from the International Agency for Research on Cancer for 1971-2002 with data on per capita consumption obtained from the Food and Agriculture Organization of the United Nations using 10-year delay intervals. RESULTS: Incidence rates increased in all countries except France in men and except Austria, Denmark, England and France in women. Of the dietary variables considered, there were marked increasing trends (linear regression coefficient, R ≥0.5) in red meat consumption in Germany (R = 0.9), Austria (R = 0.7), Finland (R = 0.8), Italy (R = 0.9), Poland (R = 0.5), Spain (R = 2.1), Sweden (R = 0.6), and the Netherlands (R = 0.7). CONCLUSIONS: Changes in dietary habits may be consistent with the observed trends in the incidence of colorectal cancer in the distinct European countries.

Effects of changes in dietary habits on colorectal cancer incidence in twenty countries from four continents during the period 1971-2002.

INTRODUCTION: the incidence of colorectal cancer is one of the highest on a global level. Many epidemiological studies have identified risk and protective factors, many of which have a behavioral component and, therefore, are potentially avoidable or subject to modification. This study investigated the incidence rates of colorectal cancer by gender in twenty different countries, taking into account the dietary habits of the habitants of each country. MATERIAL AND METHODS: adjusted incidence rates, according to gender, were obtained for each country from the International Agency for Research on Cancer during the period 1971-2002.Annual per capita consumption data of the different dietary variables were obtained for the period 1961-2007 from the Food and Agriculture Organization of the United Nations. Pearson's correlation coefficients were calculated comparing incidence rates according to gender with different dietary variable using ten-year delay intervals. RESULTS: there is an important variation in trends of colorectal cancer incidence worldwide which were found to be related with the dietary habits of each country. DISCUSSION: based on the trends observed, each country was classified into one of four different situations based on the range of values of their incidence rates and linear trends observed. Due to the potential of primary prevention programs for colorectal cancer and to the delay between changes in the exposure to risk and protective factors and the effects on the incidence of this tumor, the application of legislative and educational measures promoting a healthy diet has become an urgent issue to stop the increasing tendency of colorectal cancer reported worldwide.