The role of N-glycan trimming in glycoprotein fate and function is unclear. We have recently shown that hepatitis B virus (HBV) DNA is not efficiently secreted from cells in which ␣-glucosidase mediated N-glycan trimming is inhibited. Here it is shown that, in cells in glucosidaseinhibited cells, viral DNA, accompanied by envelope and core proteins, most likely accumulate within lysosomal compartments. Pulse-chase experiments show that although the viral glycoproteins (L, M, and S) are dysfunctional, in the sense that they do not mediate virion egress and are not efficiently secreted from the cell, they all still leave the endoplasmic reticulum (ER). Surprisingly, however, the glycoproteins retained within the cell were not rapidly degraded, appearing as aggregates, enriched for L and M, with intracellular half-lives exceeding 20 h. Moreover, by 24 h after synthesis, a substantial fraction of the detained glycoproteins appeared to return to the ER, although a considerable amount was also found in the lysosomes. To our knowledge, this is the first report that shows, as a consequence of inhibiting glycosylation processing, certain glycoproteins (i) become dysfunctional and aggregate, yet still depart from the ER, and (ii) have extended rather than shortened half-lives. Taken together, these data suggest that proper intracellular routing of HBV glycoproteins requires ER glucosidase function. It is hypothesized that failure to process N-glycan causes HBV glycoproteins to aggregate and that impaired protein-protein interactions and trafficking are the result of misfolding.
The 2-bottle free-choice method was used to study the voluntary consumption of nicotine by rats. Rats consumed nicotine voluntarily at different, albeit quite consistent, amounts. Voluntary intakes were higher in younger than older rats, but were not affected by gender. A previously forced nicotine intake had no effect on a subsequent voluntary intake of nicotine in older but increased it in younger rats. Forced exposure to nicotine of pregnant and lactating rats did not increase the voluntary intake by their offsprings. Established free-choice drinking patterns of nicotine were not affected by a temporary forced intake of this substance. The 2-bottle choice proved to be a reliable method to study the voluntary intake of nicotine, and results suggest that nicotine is not ‘addictive’ per se, but that its use is apparently determined by the response of an individual rat to this substance.
Self-administration of either nicotine (NIC) or ethanol (ETH) has been extensively studied. This study addressed for the first time the self-administration of both substances when offered together. Male and female rats of different ages were offered NIC and ETH using the two- or three-bottle free-choice method. When NIC and ETH were offered together at different concentrations to young male rats (about 45 days old), intake of NIC increased with increasing NIC concentrations, and intake of ETH increased with decreasing ETH concentrations, but these effects were independent of the presence of the second drug. These rats also consumed the same amounts of NIC or ETH regardless of whether offered individually or together. A prior choice of only NIC or ETH did not affect a subsequent intake of both drugs offered together. A choice of both drugs for 24 h for several days followed by a choice for only 2 h for several days showed the same intake of NIC but a decreased intake of ETH for the shorter period. Young female rats (about 45 days old) and older male rats (about 75 days old) consumed the same amounts of NIC but less ETH than did the young male rats. These results show that young male rats voluntarily consume NIC and ETH independently of each other and that preexposure to one drug does not affect the subsequent intake of both drugs in combination. The data also suggest that these drugs act on different reward centers which have to be ‘satisfied’ independently of each other.
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