D-578, an orally active triple monoamine reuptake inhibitor, displays antidepressant and anti-PTSD like effects in rats. 2019

Aloke K Dutta, and Soumava Santra, and Arman Harutyunyan, and Banibrata Das, and Michael J Lisieski, and Liping Xu, and Tamara Antonio, and Maarten E A Reith, and Shane A Perrine
Wayne State University, Department of Pharmaceutical Sciences, Detroit, MI, 48202, USA. Electronic address: adutta@wayne.edu.

Significant unmet needs exist for development of better pharmacotherapeutic agents for major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) as the current drugs are inadequate. Our goal in this study is to investigate behavioral pharmacological characterization of a novel triple reuptake inhibitor (TRI) D-578 which exhibits nanomolar potency at all three monoamine transporters (Ki; 16.2. 16.2, 3.23 nM, and 29.6, 20.6, 6.10 nM for the rat brain and cloned human dopamine, serotonin and norepinephrine transporters, respectively) and exhibited little to no affinity for other off-target CNS receptors. In a rat forced swim test, compound D-578 upon oral administration displayed high efficacy and not stimulating in locomotor behavior. The effects of D-578 and paroxetine were next evaluated in a rat model for traumatic stress exposure - the single prolonged stress (SPS) model - which has been shown to have construct, predictive, and behavioral validity in modeling aspects of PTSD. Our results show that SPS had no effect on the acquisition of conditioned fear, but impaired extinction learning and extinction retention of fear behavior compared to sham treatment. D-578, but not paroxetine, attenuated the extinction and extinction-retention deficit induced by SPS. These findings suggest that D-578 has greater efficacy in normalizing traumatic stress-induced extinction-retention learning in a model for PTSD compared to paroxetine. Overall these results suggest that D-578, in addition to producing a robust and efficacious antidepressant effect, may attenuate maladaptive retention of fearful memories and support further testing of this agent for the pharmacotherapy of depression and PTSD.

UI MeSH Term Description Entries
D008297 Male Males
D012153 Retention, Psychology The persistence to perform a learned behavior (facts or experiences) after an interval has elapsed in which there has been no performance or practice of the behavior. Psychological Retention,Retention (Psychology),Psychology Retention,Retention, Psychological
D003865 Depressive Disorder, Major Disorder in which five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Symptoms include: depressed mood most of the day, nearly every daily; markedly diminished interest or pleasure in activities most of the day, nearly every day; significant weight loss when not dieting or weight gain; Insomnia or hypersomnia nearly every day; psychomotor agitation or retardation nearly every day; fatigue or loss of energy nearly every day; feelings of worthlessness or excessive or inappropriate guilt; diminished ability to think or concentrate, or indecisiveness, nearly every day; or recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt. (DSM-5) Depression, Involutional,Major Depressive Disorder,Melancholia, Involutional,Paraphrenia, Involutional,Psychosis, Involutional,Depressive Disorders, Major,Involutional Depression,Involutional Melancholia,Involutional Paraphrenia,Involutional Paraphrenias,Involutional Psychoses,Involutional Psychosis,Major Depressive Disorders,Paraphrenias, Involutional,Psychoses, Involutional
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004353 Drug Evaluation, Preclinical Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000067289 Behavior Observation Techniques A wide range of formal and informal techniques used to document behavior. Behavior Observation,Behavioral Observation,Behavioral Observation Techniques,Behavior Observation Technique,Behavior Observations,Behavioral Observation Technique,Behavioral Observations,Observation Technique, Behavior,Observation Technique, Behavioral,Observation Techniques, Behavior,Observation Techniques, Behavioral,Observation, Behavior,Observation, Behavioral,Observations, Behavior,Observations, Behavioral
D000284 Administration, Oral The giving of drugs, chemicals, or other substances by mouth. Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000928 Antidepressive Agents Mood-stimulating drugs used primarily in the treatment of affective disorders and related conditions. Several MONOAMINE OXIDASE INHIBITORS are useful as antidepressants apparently as a long-term consequence of their modulation of catecholamine levels. The tricyclic compounds useful as antidepressive agents (ANTIDEPRESSIVE AGENTS, TRICYCLIC) also appear to act through brain catecholamine systems. A third group (ANTIDEPRESSIVE AGENTS, SECOND-GENERATION) is a diverse group of drugs including some that act specifically on serotonergic systems. Antidepressant,Antidepressant Drug,Antidepressant Medication,Antidepressants,Antidepressive Agent,Thymoanaleptic,Thymoanaleptics,Thymoleptic,Thymoleptics,Antidepressant Drugs,Agent, Antidepressive,Drug, Antidepressant,Medication, Antidepressant

Related Publications

Aloke K Dutta, and Soumava Santra, and Arman Harutyunyan, and Banibrata Das, and Michael J Lisieski, and Liping Xu, and Tamara Antonio, and Maarten E A Reith, and Shane A Perrine
April 2016, Scientific reports,
Aloke K Dutta, and Soumava Santra, and Arman Harutyunyan, and Banibrata Das, and Michael J Lisieski, and Liping Xu, and Tamara Antonio, and Maarten E A Reith, and Shane A Perrine
February 2003, European journal of pharmacology,
Aloke K Dutta, and Soumava Santra, and Arman Harutyunyan, and Banibrata Das, and Michael J Lisieski, and Liping Xu, and Tamara Antonio, and Maarten E A Reith, and Shane A Perrine
August 2014, European journal of pharmacology,
Aloke K Dutta, and Soumava Santra, and Arman Harutyunyan, and Banibrata Das, and Michael J Lisieski, and Liping Xu, and Tamara Antonio, and Maarten E A Reith, and Shane A Perrine
May 2015, Journal of psychopharmacology (Oxford, England),
Aloke K Dutta, and Soumava Santra, and Arman Harutyunyan, and Banibrata Das, and Michael J Lisieski, and Liping Xu, and Tamara Antonio, and Maarten E A Reith, and Shane A Perrine
January 2007, European journal of pharmacology,
Aloke K Dutta, and Soumava Santra, and Arman Harutyunyan, and Banibrata Das, and Michael J Lisieski, and Liping Xu, and Tamara Antonio, and Maarten E A Reith, and Shane A Perrine
December 2011, European journal of pharmacology,
Aloke K Dutta, and Soumava Santra, and Arman Harutyunyan, and Banibrata Das, and Michael J Lisieski, and Liping Xu, and Tamara Antonio, and Maarten E A Reith, and Shane A Perrine
May 2010, European journal of pharmacology,
Aloke K Dutta, and Soumava Santra, and Arman Harutyunyan, and Banibrata Das, and Michael J Lisieski, and Liping Xu, and Tamara Antonio, and Maarten E A Reith, and Shane A Perrine
June 1958, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.),
Aloke K Dutta, and Soumava Santra, and Arman Harutyunyan, and Banibrata Das, and Michael J Lisieski, and Liping Xu, and Tamara Antonio, and Maarten E A Reith, and Shane A Perrine
July 2013, European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology,
Aloke K Dutta, and Soumava Santra, and Arman Harutyunyan, and Banibrata Das, and Michael J Lisieski, and Liping Xu, and Tamara Antonio, and Maarten E A Reith, and Shane A Perrine
August 2016, CNS neuroscience & therapeutics,
Copied contents to your clipboard!