Abstract
ABSTRACTThe research domain criteria (RDoC) matrix has been developed to reorient psychiatric research towards measurable behavioral dimensions and underlying mechanisms. Here, we used a new genetic rat model with a loss-of-function point mutation in the dopamine transporter (DAT) gene (Slc6a3_N157K) to systematically study the RDoC matrix. First, we examined the impact of the Slc6a3_N157K mutation on monoaminergic signaling. We then performed behavioral tests representing each of the five RDoC domains: negative and positive valence systems, cognitive, social and arousal/regulatory systems. The use of RDoC may be particularly helpful for drug development. We studied the effects of a novel pharmacological approach metabotropic glutamate receptor mGluR2/3 antagonism, in DAT mutants in a comparative way with standard medications. Loss of DAT functionality in mutant rats not only elevated subcortical extracellular dopamine concentration but also altered the balance of monoaminergic transmission. DAT mutant rats showed deficits in all five RDoC domains. Thus, mutant rats failed to show conditioned fear responses, were anhedonic, were unable to learn stimulus-reward associations, showed impaired cognition and social behavior, and were hyperactive. Hyperactivity in mutant rats was reduced by amphetamine and atomoxetine, which are well-established medications to reduce hyperactivity in humans. The mGluR2/3 antagonist LY341495 also normalized hyperactivity in DAT mutant rats without affecting extracellular dopamine levels. We systematically characterized an altered dopamine system within the context of the RDoC matrix and studied mGluR2/3 antagonism as a new pharmacological strategy to treat mental disorders with underlying subcortical dopaminergic hyperactivity.
Highlights
It has long been noticed that a number of different psychiatric diagnoses largely overlap in terms of their symptoms, their underlying molecular alterations and their genetic risk factors
On the genetic and molecular level, dopamine transporter (DAT) is an essential element of the research domain criteria (RDoC) matrix
We generated a novel genetic rat model with a loss of function of DAT in order to systematically study the consequences of innate imbalance of the dopaminergic system within the RDoC matrix
Summary
It has long been noticed that a number of different psychiatric diagnoses largely overlap in terms of their symptoms, their underlying molecular alterations and their genetic risk factors. High rates of comorbidity among different diagnostic groupings are seen, and several psychiatric disorders can be treated by the same medications. This highlights the ambiguities associated with the classification of mental disorders using DSM5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) or ICD10 (10th revision of the International Statistical Classification of Diseases and Related Health Problems). During the past few years an attempt has been made to fundamentally change the classification principles of psychiatric diagnoses This new approach, the research domain criteria (RDoC) project developed by the National Institute of Mental Health (NIMH), aims for a re-categorization of psychiatric disorders based solely on measurable behavioral dimensions and underlying mechanisms (Insel et al, 2010; www.nimh.nih.gov/researchpriorities/rdoc). An imbalanced dopaminergic system is one of the underlying neurobiological pathomechanisms for several psychiatric conditions, such as schizophrenia (Laruelle et al, 1999; Weinstein et al, 2016), attention deficit hyperactivity disorder (ADHD) (Ohno, 2003), obsessive compulsive disorder (OCD) (Pauls et al, 2014), and alcoholism (Tupala et al, 2001; Hirth et al, 2016)
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