Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation

Altered mesolimbic dopamine signaling has been widely implicated in addictive behavior. For the most part, this work has focused on dopamine within the striatum, but there is emerging evidence for a role of the auto-inhibitory, somatodendritic dopamine D2 receptor (D2R) in the ventral tegmental area (VTA) in addiction. Thus, decreased midbrain D2R expression has been implicated in addiction in humans. Moreover, knockout of the gene encoding the D2R receptor (Drd2) in dopamine neurons has been shown to enhance the locomotor response to cocaine in mice. Therefore, we here tested the hypothesis that decreasing D2R expression in the VTA of adult rats, using shRNA knockdown, promotes addiction-like behavior in rats responding for cocaine or palatable food. Rats with decreased VTA D2R expression showed markedly increased motivation for both sucrose and cocaine under a progressive ratio schedule of reinforcement, but the acquisition or maintenance of cocaine self-administration were not affected. They also displayed enhanced cocaine-induced locomotor activity, but no change in basal locomotion. This robust increase in incentive motivation was behaviorally specific, as we did not observe any differences in fixed ratio responding, extinction responding, reinstatement or conditioned suppression of cocaine, and sucrose seeking. We conclude that VTA D2R knockdown results in increased incentive motivation, but does not directly promote other aspects of addiction-like behavior.     

Gastric epithelial cell turnover, mucus production, and healing of gastric ulcers with carbenoxolone.

Nineteen healthy subjects were studied and 17 patients with gastric ulcer before and after ulcer healing with carbenoxolone. Gastric deoxytibonucleic acid (DNA) loss was measured as an index of epithelial cell turnover, and N-acetylneuraminic acid (NANA) content of gastric juice as an index of mucus secretion. In normal subjects there was a negative correlation (p less that 0-025) between gastric DNA loss and NANA secretion; the lower the cell turnover the higher the NANA production. In gastric ulcer patients DNA loss or turnover was significantly (p less than 0-01) higher than normal, and fell significantly (p less than 0-01) after four weeks' treatment with carbenoxolone when 16 of the 17 ulcers had healed. At the same time NANA output increased significantly (p less than 0-01). It is suggested that patients with gastric ulcer lose cells at a high rate, a state of affairs which is returned towards normal by carbenoxolone, thus allowing the epithelial cells to mature within the mucosa and produce more mucus.     

Gastric cytoprotection by antacids and papaverine in rats

Prostaglandin E2 (PGE2) prevented hemorrhagic ulceration of rat stomach mucosa induced by various procedures when given orally at a non-antisecretory dose. This effect of PGE2 is called gastric cytoprotection. We used absolute ethanol, 0.6 N hydrochloric acid and 0.2 N sodium hydroxide as damaging agents. Ranitidine at an antisecretory dose did not exhibit any cytoprotective effect. However, the poorly absorbable antacids, magnesium hydroxide plus aluminium hydroxide and aluminium phosphate inhibited the development of hemorrhagic lesions significantly. A similar protective effect was seen after intragastric administration of papaverine, which is known to stimulate endogenous prostaglandin synthesis. However, the question as to whether or not stimulation of endogenous prostaglandin synthesis is the mode of action of the cytoprotective effect of papaverine and poorly absorbable antacids, cannot yet be answered.     

Human intestinal M cells exhibit enterocyte-like intermediate filaments

Background—The derivation and ultrastructuralcomposition of M cells covering the lymphoid follicles of Peyer'spatches is still unknown. Results from different animal models haveshown that there are species specific differences in the composition ofintermediate filaments between M cells and neighbouring enterocytes. Little is known, however, about intermediate filaments of human M cells.
Aims—To compare components of the cytoskeleton ofhuman M cells with those of adjacent absorptive enterocytes.
Methods—The expression and localisation ofdifferent cytokeratins, vimentin, and desmin in M cells was determinedon follicle associated epithelia of human appendix usingimmunohistochemistry and immunogold electron microscopy.
Results—Cytokeratins specific for humanintestinal epithelial cells such as cytokeratins 8, 18, 19, and 20 wereexpressed in both absorptive enterocytes and M cells with nodifferences in intensity and cellular distribution between both celltypes. Vimentin and desmin, tissue specific markers of eithermesenchymal or myogenic cells, as well as other cytokeratins were notdetectable in enterocytes or M cells.
Conclusion—This is the first study on thestructure of intermediate filaments in human intestinal M cells. Ourresults show that in contrast to several animal models, human M cellsapparently do not differ from adjacent enterocytes in the compositionof their intermediate filament cytoskeleton. The presence of enterocyte like cytokeratins and the absence of other cytokeratins as well as ofvimentin and desmin supports the hypothesis of an epithelial origin ofhuman intestinal M cells and suggests that M cells may derive fromdifferentiated enterocytes.

Keywords:human intestinal M cells; appendix; cytokeratin; intermediate filaments; follicle associated epithelium