2A Receptor Levels Research Articles

P.188 Long-term effects of psilocybin on cerebral serotonin 2A receptor levels and personality

P.188 Long-term effects of psilocybin on cerebral serotonin 2A receptor levels and personality

BDNF downregulates 5-HT 2A receptor protein levels in hippocampal cultures

Both brain-derived neurotrophic factor (BDNF) and the serotonin receptor 2A (5-HT 2A) have been related to depression pathology. Specific 5-HT 2A receptor changes seen in BDNF conditional mutant mice suggest that BDNF regulates the 5-HT 2A receptor level. Here we show a direct effect of BDNF on 5-HT 2A receptor protein levels in primary hippocampal neuronal and mature hippocampal organotypic cultures exposed to different BDNF concentrations for either 1, 3, 5 or 7 days. In vivo effects of BDNF on hippocampal 5-HT 2A receptor levels were further corroborated in (BDNF +/−) mice with reduced BDNF levels. In primary neuronal cultures, 7 days exposure to 25 and 50 ng/mL BDNF resulted in downregulation of 5-HT 2A, but not of 5-HT 1A, receptor protein levels. The BDNF-associated downregulation of 5-HT 2A receptor levels was also observed in mature hippocampal organotypic cultures, excluding confounding effects of BDNF on immature tissue. BDNF +/− mice showed significant increased 5-HT 2A receptor levels in hippocampus confirming the association between 5-HT 2A receptor and BDNF levels in vivo. In conclusion, our results point to a regulatory role of BDNF on 5-HT2A receptor levels. This interaction may be an important mechanism in the role of BDNF in affective disorders emphasizing the need for further elucidating the specificity and the mechanism behind this regulation.

Activation of glucocorticoid receptors increases 5-HT 2A receptor levels

Major depression is associated with both dysregulation of the hypothalamic pituitary adrenal axis and serotonergic deficiency, not the least of the 5-HT 2A receptor. However, how these phenomena are linked to each other, and whether a low 5-HT 2A receptor level is a state or a trait marker of depression is unknown. In mice with altered glucocorticoid receptor (GR) expression we investigated 5-HT 2A receptor levels by Western blot and 3H-MDL100907 receptor binding. Serotonin fibre density was analyzed by stereological quantification of serotonin transporter immunopositive fibers. To establish an effect of GR activation on 5-HT 2A levels, mature organotypic hippocampal cultures were exposed to corticosterone with or without GR antagonist mifepristone and mineralocorticoid receptor (MR) antagonist spironolactone. In GR under-expressing mice, hippocampal 5-HT 2A receptor protein levels were decreased (26.3 ± 1.6%, p < 0.05) and frontal 5-HT 2A receptor binding was decreased (20 ± 15%, p < 0.01) as compared to wild-type mice. Conversely, in over-expressing GR mice hippocampal 5-HT 2A receptor protein levels were increased (60.8 ± 4.0%, p = 0.0001) and 5-HT 2A receptor binding was increased in dorsal hippocampus (77 ± 35%, p < 0.05) as compared to wild-type mice. No difference in serotonin fibre density was observed in the GR over-expressing mice, while the GR under-expressing mice showed lower serotonergic innervation in the frontal cortex area. An effect of GR activation on 5-HT 2A receptor levels was further corroborated by the culture studies as long-term exposure of 3 μM corticosterone to organotypic hippocampal cultures increased 5-HT 2A receptor levels ( p < 0.05). The corticosterone-induced 5-HT 2A receptor up-regulation was blocked by addition of either spironolactone or mifepristone.

Diminished iron concentrations increase adenosine A 2A receptor levels in mouse striatum and cultured human neuroblastoma cells

Brain iron insufficiency has been implicated in several neurological disorders. The dopamine system is consistently altered in studies of iron deficiency in rodent models. Changes in striatal dopamine D 2 receptors are directly proportional to the degree of iron deficiency. In light of the unknown mechanism for the iron deficiency-dopamine connection and because of the known interplay between adenosinergic and dopaminergic systems in the striatum we examined the effects of iron deficiency on the adenosine system. We first attempted to assess whether there is a functional change in the levels of adenosine receptors in response to this low iron. Mice made iron-deficient by diet had an increase in the density of striatal adenosine A 2A (A 2AR) but not A 1 receptor (A 1R) compared to mice on a normal diet. Between two inbred murine strains, which had 2-fold differences in their striatal iron concentrations under normal dietary conditions, the strain with the lower striatal iron had the highest striatal A 2AR density. Treatment of SH-SY5Y (human neuroblastoma) cells with an iron chelator resulted in increased density of A 2AR. In these cells, A 2AR agonist-induced cyclic AMP production was enhanced in response to iron chelation, also demonstrating a functional upregulation of A 2AR. A significant correlation ( r 2 = 0.79) was found between a primary marker of cellular iron status (transferrin receptor (TfR)) and A 2AR protein density. In conclusion, the A 2AR is increased across different iron-insufficient conditions. The relation between A 2AR and cellular iron status may be an important pathway by which adenosine may alter the function of the dopaminergic system.

Aβ (1–42) injection causes memory impairment, lowered cortical and serum BDNF levels, and decreased hippocampal 5-HT 2A levels

Aggregation of the beta-amyloid protein (Aβ) is a hallmark of Alzheimer's disease (AD) and is believed to be causally involved in a neurodegenerative cascade. In patients with AD, reduced levels of serum Brain Derived Neurotrophic Factor (BDNF) and cortical 5-HT 2A receptor binding has recently been reported but it is unknown how these changes are related to beta-amyloid accumulation. In this study we examined in rats the effect of intrahippocampal injections of aggregated Aβ (1–42) (1 μg/μl) on serum and brain BDNF or 5-HT 2A receptor levels. A social recognition test paradigm was used to monitor Aβ (1–42) induced memory impairment. Memory impairment was seen 22 days after injection of Aβ (1–42) in the experimental group and until termination of the experiments. In the Aβ (1–42) injected animals we saw an abolished increase in serum BDNF levels that was accompanied by significant lower BDNF levels in frontal cortex and by an 8.5% reduction in hippocampal 5-HT 2A receptor levels. A tendency towards lowered cortical 5-HT 2A was also observed. These results indicate that the Aβ (1–42) associated memory deficit is associated with an impaired BDNF regulation, which is reflected in lower cortical BDNF levels, and changes in hippocampal 5-HT 2A receptor levels. This suggests that the BDNF and 5-HT2A changes observed in AD are related to the presence of Aβ (1–42) deposits.