Accutane's effect on the hippocampus.

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      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC387382/

      “This report demonstrates that a clinical dose (1 mg/kg/day) of 13-cis-RA in mice significantly reduces cell proliferation in the hippocampus and the subventricular zone, suppresses hippocampal neurogenesis, and severely disrupts capacity to learn a spatial radial maze task.

      This study is probably well-known to people who have been researching the long-term effects of Accutane for any amount of time. However, this always caught my attention since the hippocampus is not only associated with memory functions, but also depression. Depressed patients show smaller hippocampi than healthy patients. In the past, studies have been done which show that the antidepressant effect of many SSRIs are negated when the neurogenic effects of these drugs are blocked. In fact, novel antidepressants which serve to do nothing more than promote neurogenesis in the hippocampus are undergoing clinical trials as we speak. Accutane does, literally, the opposite.

      In any case, this study may partially explain some of the cognitive issues and depressive issues some people experience.

    • #1932
      dubya_b
      Keymaster

      Thanks. Noticed Prof. Peter McCaffrey was one of the authors. Pretty certain he spoke at one of the congressional hearings regarding Accutane and performed that study you posted with funding provided by Liam Grant of the Roaccutane action group. May be a bit of a conflict of interest, but that never seems to come into question when an industry-funded study is provided to the FDA or published in a dermatology journal.

       

      Two more studies showing that Accutane causes a “functional dissociation” between serotogenic cells in the raphe nuclei and the hippocampus without altering the number of hippocampal cells:

       

      K. C. O’Reilly, J. Shumake, S. J. Bailey, F. Gonzalez-Lima, and M. A. Lane, “Chronic 13-cis-retinoic acid administration disrupts network interactions between the raphe nuclei and the hippocampal system in young adult mice,” European Journal of Pharmacology, vol. 605, no. 1–3, pp. 68–77, Mar. 2009.

       

      Abstract

      Previously, we showed that chronic administration of 13-cis-retinoic acid (13-cis-RA) induces depression-related behaviors in mice and that 13-cis-RA alters components of the serotonergic system in vitro. Work by others has shown that 13-cis-RA reduces hippocampal neurogenesis in mice and orbitofrontal cortex metabolism in humans. In the current study, we measured cytochrome oxidase activity, a metabolic marker that reflects steady state neuronal energy demand, in various regions of the brain to determine the effects of 13-cis-RA on neuronal metabolic activity and network interactions between the raphe nuclei and the hippocampal system. Brain cytochrome oxidase activity in young adult male mice was analyzed following 6 weeks of daily 13-cis-RA (1 mg/kg) or vehicle injection and behavioral testing. Chronic 13-cis-RA administration significantly decreased cytochrome oxidase activity only in the inferior rostral linear nucleus of the raphe. However, covariance analysis of interregional correlations in cytochrome oxidase activity revealed that 13-cis-RA treatment caused a functional uncoupling between the dorsal raphe nuclei and the hippocampus. Furthermore, a path analysis indicated that a network comprising lateral habenula to dorsal raphe to hippocampus was effectively uncoupled in 13-cis-RA treated animals. Finally, cytochrome oxidase activity in the dentate gyrus of 13-cis-RA treated mice was inversely correlated with depression-related behavior. Taken together, these data show that 13-cis-RA alters raphe metabolism and disrupts functional connectivity between the raphe nuclei and the hippocampal formation, which may contribute to the observed increase in depression-related behaviors.

       
      The following by the same team of authors appears to contradict some of the statements in the first study
       

       

      These data show that apoptotic actions of 13-cis-RA do not occur in vivo at drug concentrations that induce changes in depression-related behaviour and functional uncoupling of the DRN and hippocampus. The potential pro-depressant behavioural and molecular effects associated with chronic administration of 13-cis-RA may result from changes in serotoninergic activity rather than changes in the number of serotoninergic neurons.

       
      Another study in that series:
       

       

      Abstract

      In addition to their established role in nervous system development, vitamin A and related retinoids are emerging as regulators of adult brain function. Accutane (13-cis-retinoic acid, isotretinoin) treatment has been reported to increase depression in humans. Recently, we showed that chronic administration of 13-cis-retinoic acid (13-cis-RA) to adolescent male mice increased depression-related behaviors. Here, we have examined whether 13-cis-RA regulates components involved in serotonergic neurotransmission in vitro. We used the RN46A-B14 cell line, derived from rat embryonic raphe nuclei. This cell line synthesizes serotonin (5-hydroxytryptamine, 5-HT) and expresses the 5-HT1A receptor and the serotonin reuptake transporter (SERT). Cells were treated with 0, 2.5, or 10 μM 13-cis-RA for 48 or 96 hrs, and the levels of 5-HT; its metabolite, 5-hydroxyindoleacetic acid (5HIAA); 5-HT1A receptor; and SERT were determined. Treatment with 13-cis-RA for 96 hrs increased the intracellular levels of 5-HT and tended to increase intra-cellular 5HIAA levels. Furthermore, 48 hrs of treatment with 2.5 and 10 μM 13-cis-RA significantly increased 5-HT1A protein to 168.5 ± 20.0% and 148.7 ± 2.2% of control respectively. SERT protein levels were significantly increased to 142.5 ± 11.1% and 119.2 ± 3.6% of control by 48 hrs of treatment with 2.5 and 10 μM of 13-cis-RA respectively. Increases in both 5-HT1A receptor and SERT proteins may lead to decreased serotonin availability at synapses. Such an effect of 13-cis-RA could contribute to the increased depression-related behaviors we have shown in mice.

       

       
      There is some more info on how neurosteroids may be involved in this but that can wait for another day/post.

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