tretinoin and Mood-Disorders

Current models of affective disorders implicate alterations in norepinephrine, serotonin, dopamine, and CRF/cortisol; however treatments targeted at these neurotransmitters or hormones have led to imperfect resolution of symptoms, suggesting that the neurobiology of affective disorders is incompletely understood. Until now retinoids have not been considered as possible contributors to affective disorders. Retinoids represent a family of compounds derived from vitamin A that perform a large number of functions, many via the vitamin A product, retinoic acid. This signaling molecule binds to specific retinoic acid receptors in the brain which, like the glucocorticoid and thyroid hormone receptors, are part of the nuclear receptor superfamily and regulate gene transcription. Research in the field of retinoic acid in the CNS has focused on the developing brain, in part stimulated by the observation that isotretinoin (13-cis retinoic acid), an isomer of retinoic acid used in the treatment of acne, is highly teratogenic for the CNS. More recent work has suggested that retinoic acid may influence the adult brain; animal studies indicated that the administration of isotretinoin is associated with alterations in behavior as well as inhibition of neurogenesis in the hippocampus. Clinical evidence for an association between retinoids and depression includes case reports in the literature, studies of health care databases, and other sources. A preliminary PET study in human subjects showed that isotretinoin was associated with a decrease in orbitofrontal metabolism. Several studies have shown that the molecular components required for retinoic acid signaling are expressed in the adult brain; the overlap of brain areas implicated in retinoic acid function and stress and depression suggest that retinoids could play a role in affective disorders. This report reviews the evidence in this area and describes several systems that may be targets of retinoic acid and which contribute to the pathophysiology of depression.

Topics: Adult; Animals; Brain; Corpus Striatum; Depressive Disorder, Major; Disease Models, Animal; Hippocampus; Humans; Isotretinoin; Mice; Mood Disorders; Neurotransmitter Agents; Prefrontal Cortex; Retrospective Studies; Signal Transduction; Suicide; Tretinoin

Corticotropin-releasing hormone (CRH) is considered the central driving force in the stress response and plays a key role in the pathogenesis of depression. Retinoic acid (RA) has been suggested by clinical studies to be associated with affective disorders.. First, hypothalamic tissues of 12 patients with affective disorders and 12 matched control subjects were studied by double-label immunofluorescence to analyze the expression of CRH and retinoic acid receptor-alpha (RAR-alpha). Second, critical genes involved in the RA signaling pathways were analyzed in a rat model of depression. Finally, the regulatory effect of RAR-alpha on CRH gene expression was studied in vitro.. We found that the expression of RAR-alpha was colocalized with CRH neurons in human hypothalamic paraventricular nucleus (PVN). The density of RAR-alpha-immunoreactive neurons and CRH-RAR-alpha double-staining neurons was significantly increased in the PVN of patients with affective disorders. The ratio of the CRH-RAR-alpha double-staining neurons to the CRH-immunoreactive neurons in affective disorder patients was also increased. Recruitment of RAR-alpha by the CRH promoter was observed in the rat hypothalamus. A dysregulated RA metabolism and signaling was also found in the hypothalamus of a rat model for depression. Finally, in vitro studies demonstrated that RAR-alpha mediated an upregulation of CRH gene expression.. These results suggest that RAR-alpha might contribute to regulating the activity of CRH neurons in vivo, and the vulnerable character of the critical proteins in RA signaling pathways might provide novel targets for therapeutic strategies for depression.

Topics: Adult; Aged; Aged, 80 and over; Aldehyde Dehydrogenase 1 Family; Animals; Arginine Vasopressin; Cell Line, Tumor; Corticotropin-Releasing Hormone; Female; Humans; Hypothalamus; Male; Middle Aged; Mood Disorders; Neurons; Rats; Receptors, Retinoic Acid; Retinal Dehydrogenase; Retinoic Acid Receptor alpha; Signal Transduction; Stress, Physiological; Tretinoin; Up-Regulation

Variable number tandem repeats (VNTR) within non-coding regions of a number of genes have been correlated with susceptibility to various disease states. In particular, a VNTR polymorphism of a 16 or 17 bp element within intron 2 of the human serotonin transporter gene has been correlated with a predisposition to affective disorders. We have demonstrated that this region will support differential levels of reporter gene expression in differentiating embryonic stem cells, this being dependent on the presence of 10 or 12 copies of the repeat. The VNTR domain can therefore act as a transcriptional regulator, a property which potentially contributes to disease susceptibility.

Topics: Alleles; Carrier Proteins; Cell Line; Cloning, Molecular; Embryo, Mammalian; Enhancer Elements, Genetic; Gene Dosage; Gene Expression Regulation; Genes, Reporter; Genetic Predisposition to Disease; HeLa Cells; Humans; Introns; Membrane Glycoproteins; Membrane Transport Proteins; Minisatellite Repeats; Mood Disorders; Nerve Tissue Proteins; Polymorphism, Genetic; Serotonin Plasma Membrane Transport Proteins; Stem Cells; Transfection; Tretinoin