Cocaine decreases expression of neurogranin via alterations in thyroid receptor/retinoid X receptor signaling.
Mounting evidence suggests a potential link between cocaine abuse, disruptions in hypothalamic-pituitary-thyroid axis signaling, and neuroplasticity, but molecular mechanisms remain unknown. Neurogranin (Ng) is a gene containing a thyroid hormone-responsive element within its first intron that is involved in synaptic plasticity. Transcriptional activation requires heterodimerization of thyroid hormone receptor (TR) and retinoid X receptor (RXR) bound by their respective ligands, tri-iodothryonine and 9-cis-retinoic acid (9-cis-RA), and subsequent binding of this complex to the thyroid hormone-responsive element of the Ng gene. In this study, the effects of chronic cocaine abuse on Ng expression in euthyroid and hypothyroid mice were assessed. In cocaine-treated mice, decreased Ng expression was observed in the absence of changes in levels of thyroid hormones or other hypothalamic-pituitary-thyroid signaling factors. Therefore, we hypothesized that cocaine decreases Ng expression via alterations in 9-cis-RA availability and TR/RXR signaling. In support of this hypothesis, RXR-γ was significantly decreased in brains of cocaine-treated mice while CYP26A1, the main enzyme responsible for neuronal RA degradation, was significantly increased. Results from this study provide the first evidence for a direct effect of cocaine abuse on TR/RXR signaling, RA metabolism, and transcriptional regulation of Ng, a gene essential for adult neuroplasticity.
Department of Neuroscience, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Jane
J
Kovalevich
Gladys
G
Corley
William
W
Yen
Jae
J
Kim
Scott M
SM
Rawls
Dianne
D
Langford
D000818:Animals; D013956:Antithyroid Agents; D015153:Blotting, Western; D003042:Cocaine / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D003864:Depression, Chemical; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D007037:Hypothyroidism / Q000139:chemically induced / Q000503:physiopathology / Q000523:psychology; D007453:Iodide Peroxidase / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051579:Neurogranin / Q000096:biosynthesis*; D011441:Propylthiouracil; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D011988:Receptors, Thyroid Hormone / Q000187:drug effects*; D000072516:Retinoic Acid 4-Hydroxylase; D047488:Retinoid X Receptors / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013239:Stereotyped Behavior / Q000187:drug effects; D013963:Thyroid Hormones / Q000097:blood; D014212:Tretinoin / Q000378:metabolism
D013956:Antithyroid Agents; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D013963:Thyroid Hormones; D051579:Neurogranin; D014212:Tretinoin; D012313:RNA; D011441:Propylthiouracil; D003577:Cytochrome P-450 Enzyme System; D007453:Iodide Peroxidase; C000607080:Cyp26a1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase; D003042:Cocaine