Long-term inhibition of ethanol intake by the administration of an aldehyde dehydrogenase-2 (ALDH2)-coding lentiviral vector into the ventral tegmental area of rats

2014 ◽  
Vol 20 (2) ◽  
pp. 336-344 ◽  
Author(s):  
Eduardo Karahanian ◽  
Mario Rivera-Meza ◽  
Lutske Tampier ◽  
María Elena Quintanilla ◽  
Mario Herrera-Marschitz ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Aldehyde Dehydrogenase ◽  
Lentiviral Vector ◽  
Ethanol Intake ◽  
Aldehyde Dehydrogenase 2 ◽  
Ventral Tegmental

Acute cocaine exposure alters spine density and long-term potentiation in the ventral tegmental area

2007 ◽  
Vol 26 (3) ◽  
pp. 749-756 ◽  
Author(s):  
Federica Sarti ◽  
Stephanie L. Borgland ◽  
Viktor N. Kharazia ◽  
Antonello Bonci
Keyword(s):  
Ventral Tegmental Area ◽  
Long Term Potentiation ◽  
Spine Density ◽  
Cocaine Exposure ◽  
Term Potentiation ◽  
Ventral Tegmental

scholarly journals Pharmacologic Activation of Aldehyde Metabolism to Protect Hematopoietic Stem Cells (HSC) in Murine Models of Fanconi Anemia (FA)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 105-105
Author(s):  
Jennifer Tsai ◽  
Kelsey R. Logas ◽  
Lauren D. Van Wassenhove ◽  
Beruh Dejene ◽  
Che-Hong Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Aldehyde Dehydrogenase ◽  
Principal Component ◽  
Patent Office ◽  
Aldehyde Dehydrogenase 2 ◽  
Short Term ◽  
Hematopoietic Stem

HSC loss in FA is due to failure to resolve DNA inter-strand crosslinks (ICL), which can be induced by reactive aldehydes, radiation, or other clastogenic agents. Aldehyde exposure may occur through environmental sources, e.g. ingestion, absorption, and inhalation, or endogenously as a byproduct of cellular metabolism. The ALDH2*2 genotype, a dominant-negative point mutation in the aldehyde dehydrogenase 2 (ALDH2) gene, causes the "Asian flushing syndrome" when ethanol (EtOH) is ingested, due to decreased metabolism of small aldehydes, particularly acetaldehyde. ALDH2*2 is a disease modifier in FA, causing more rapid bone marrow failure and earlier leukemia onset in doubly affected children. Similarly, mice experimentally doubly knocked out for FANCD2 and ALDH2 demonstrate increased HSC loss, which is accelerated by EtOH exposure. To reduce aldehyde exposure, we developed a small molecule ALDH activator, Alda-1, which increases the enzymatic activity of both wild type (WT) and mutant ALDH2. We hypothesized that DNA damage and HSC loss in FA would be prevented by reduction of the aldehyde load. To test the effects of Alda-1 mediated ALDH2 activation, we generated a novel murine FA model with FANCD2 KO and knock-in of the ALDH2*2 mutation into the murine locus. The FANCD2-/- ALDH2*1/*2 genetic model and parental controls were then tested after exogenous aldehydic challenge and/or therapeutic intervention with Alda-1. Increased aldehydic load was experimentally induced by EtOH administration 10 mg/kg/day IP, while Alda-1 10 ug/kg/day was continuously administered via osmotic pump. For each of these conditions, marrow was analyzed for HSC and progenitor cell (HSPC) number, HSC gene expression, and function. The importance of the altered aldehyde metabolism due to ALDH2*2 genotype was demonstrated by progressive loss of HSPC in ALDH2*2/*2 and FANCD2-/- ALDH2*1/*2 mice, e.g., 5-fold and 2-fold decline in long-term HSC (LT-HSC), respectively, by 36 weeks. Experimental EtOH challenge to increase the aldehyde load precipitously decreased HSC numbers of all genotypes. After 5 weeks of EtOH challenge, LT-HSC decreased 35-fold in FANCD2-/- ALDH2*1/*2, 12.5-fold in FANCD2-/-ALDH2*1/*1, and 10.5-fold in WT mice. Long-term Alda-1 treatment to decrease aldehydic load rescued FA mice from HSC loss. After 7 months of Alda-1 treatment, LT-HSC numbers in FANCD2-/-ALDH2*1/*2 and FANCD2-/-ALDH2*1/*1 were approximately 10-fold higher than untreated controls. There were no clinically observed adverse effects. Aldehyde exposure and Alda-1 treatment altered gene expression of HSC. Principal component analysis and clustering of HSC gene expression showed that the first principal component representing 40% of the variation in gene expression could be attributed to increased aldehydic load, either genetically (ALDH2*2 genotype) or environmentally (EtOH administration) induced, while Alda-1 treatment obviated these effects. HSC from Alda-1 treated mice clustered with those from control WT mice. To test whether Alda-1 improved HSC function as well as phenotypic number, engraftment potential was assessed with competitive repopulation assays of sorted HSC from congenic untreated donors vs short-term (3 weeks) Alda-1 treated donors. HSC from Alda-1 treated mice had 2-4 fold greater granulocyte repopulating capacity than those from the untreated donors. Our results demonstrate that Alda-1 treatment rescues HSC from aldehyde induced loss, whether from genetic variation (FANCD2- and/or ALDH2*2) or experimental challenge (EtOH administration). Furthermore, Alda-1 treatment prevents the abnormal HSC gene expression induced by increased aldehydic load. HSC function is improved by Alda-1 with greater repopulating capacity observed even after short-term treatment. These preclinical experiments provide compelling proof-of-concept that sustained activation of ALDH2 can prevent HSC loss in FA. Potential applications include long-term administration to prevent the development of marrow failure or leukemia, and HSC expansion to increase the number of cells available for gene therapy with autologous HSC. Our results suggest that a clinical trial of ALDH2 activation in FA patients to prevent marrow failure is warranted. Disclosures Van Wassenhove: U.S. Patent Office: Patents & Royalties: patent pending - submitted for ALDH2 activators to expand hematopoietic stem cells. Chen:Foresee Pharmaceuticals: Patents & Royalties: patents licensed to Foresee related to compounds that activate aldehyde dehydrogenase 2 (ALDH2) and correct the dysfunction in ALDH2*2; U.S. Patent Office: Patents & Royalties: patent pending - submitted for aldehyde dehydrogenase 2 (ALDH2) activators to expand hematopoietic stem cells. Mochly-Rosen:Foresee Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: patents licensed to Foresee related to compounds that activate aldehyde dehydrogenase 2 (ALDH2) and correct the dysfunction in ALDH2*2; U.S. Patent Office: Patents & Royalties: patent pending - submitted for aldehyde dehydrogenase 2 (ALDH2) activators to expand hematopoietic stem cells. Weinberg:U.S. Patent Office: Patents & Royalties: patent pending - submitted for aldehyde dehydrogenase 2 (ALDH2) activators to expand hematopoietic stem cells.

scholarly journals Chronic methylphenidate treatment during adolescence has long-term effects on monoaminergic function

2018 ◽  
Vol 33 (1) ◽  
pp. 109-121 ◽  
Author(s):  
Mathieu Di Miceli ◽  
Adesina Omoloye ◽  
Benjamin Gronier
Keyword(s):  
Ventral Tegmental Area ◽  
Dorsal Raphe Nucleus ◽  
Late Adolescence ◽  
Dorsal Raphe ◽  
Raphe Nucleus ◽  
Late Adolescent ◽  
Serotonin Neurons ◽  
Ventral Tegmental ◽  
Dorsal Raphé

Background: Psychostimulants like methylphenidate or D-amphetamine are often prescribed for attention deficit and hyperactivity disorders in children. Whether such drugs can be administered into a developing brain without consequences in adulthood is still an open question. Methods: Here, using in vivo extracellular electrophysiology in anesthetised preparations, combined with behavioural assays, we have examined the long-term consequences in adulthood of a chronic methylphenidate oral administration (5 mg/kg/day, 15 days) in early adolescent (post-natal day 28) and late adolescent (post-natal day 42) rats, by evaluating body weight change, sucrose preference (indicator of anhedonia), locomotor sensitivity to D-amphetamine and electrical activities of ventral tegmental area dopamine and dorsal raphe nucleus serotonin neurons. Results: Chronic methylphenidate treatment during early or late adolescence did not induce weight deficiencies and anhedonia-like behaviours at adulthood. However, it increased bursting activities of dorsal raphe nucleus serotonin neurons. Furthermore, chronic methylphenidate treatment during early but not during late adolescence enhanced D-amphetamine-induced rearing activity, as well as ventral tegmental area dopamine cell excitability (firing, burst and population activity), associated with a partial desensitisation of dopamine D2 auto-receptors. Conclusions: We have demonstrated here that early, but not late, adolescent exposure to oral methylphenidate may induce long-lasting effects on monoamine neurotransmission. The possible clinical implication of these data will be discussed.

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