S.23.04 Targeting the dopamine system with chemogenetics to treat psychiatric disease

Abstract

Hyperdopaminergic states in mental disorders (which include ADHD, Addiction and eating disorders) are associated with impulsivity, impaired attention, hyperactivity and deficits in decision-making. However, the precise contribution of topographically distinct mesencephalic dopamine projections to these processes remains elusive. Chemogenetics is a novel tool which revolutionizes neuroscience since it enables us to bring specific neuronal circuits under control of a drug that acts on a designed (usually G protein-coupled) receptor. We investigated the effects of chemogenetic activation of different populations of dopamine neurons in the ventral tegmental area (VTA) or substantia nigra pars compacta (SN) on performance of a variety of tasks that quantify behaviors related to psychiatric traits. The results suggest that enhanced midbrain dopamine neuronal activity underlies deficits in attentional performance, but is not sufficient to provoke impulsive actions (in the 5-CSRTT). Furthermore, our results suggest that impaired attention caused by VTA dopamine activation is tightly linked to behavioral activation, whilst SN dopamine activation disrupts attention and performance accuracy at a more cognitive level [1,2]. Activation of VTA neurons projecting to the accumbens decreased performance on a reversal learning paradigm because rats did not learn from losses efficiently [3]. These findings support that chemogenetic targeting of VTA dopamine neurons is an innovative approach for the treatment of motivational deficits in psychiatric disorders. Chemogenetics has the potential to become a novel brain-directed treatment strategy for psychiatric disease such as major depression and anorexia nervosa.Copyright © 2018