Measurement of psychostimulant-induced reward in zebrafish and validation for the detection of dominant mutations affecting D-amphetamine addiction

J. Ninkovic^1,2, A. Folchert^1,2, Y. V. Makhankov³, S. C.F. Neuhauss³, I. Sillaber⁴, U. Straehle⁵ and L. Bally-Cuif^1,2

¹Zebrafish Neurogenetics Junior Research group, Institute of Virology, Technical University-Munich, Munich, Germany
²GSF-National Research Center for Environment and Health, Department Zebra.sh Neurogenetics, Institute of Developmental Genetics, Neuherberg, Germany
³Brain Research Institute, University of Zurich and ETH Zurich, Switzerland
⁴Affectis Pharmaceuticals AG, Munich, Germany
⁵University of Heidelberg and Institute of Toxicology and Genetics, Forschungszentrum Karlsruhe, Karlsruhe, Germany

Addiction is a complex maladaptive behavior involving long-lasting alterations in a number of neurotransmitter networks. In mammals, psychostimulants lead to elevated extracellular levels of dopamine, which can be modulated by experimental perturbations of central cholinergic transmission. Which elements of the cholinergic system might be targeted for efficient drug addiction therapies remains unknown. The rewarding properties of drugs of abuse are central for the development of addictive behavior and are most commonly measured by means of the conditioned place preference (CPP) paradigm. We will report here the development of a reliable CPP test in adult zebra.sh, and demonstrate that adult zebra.sh show robust conditioned place preference induced by the psychostimulant D-amphetamine. We further will show that this behavior is dramatically reduced upon genetic impairment of acetylcholinesterase (AChE) function in ache/+ heterozygotes, a reduction that cannot be accounted for by concomitant defects in exploratory activity, learning and visual performance. Our observations demonstrate that the cholinergic system is a modulator of drug-induced reward in zebrafish, and thereby validate the zebrafish as a model to study the molecular neurobiology of addiction in vertebrates. Our results also identify genetically AChE as a promising target for systemic therapies against addiction to psychostimulants, and open the way to screening for dominant mutations affecting psychostimulant-induced reward in zebrafish.

Paper presented at Measuring Behavior 2005 , 5^th International Conference on Methods and Techniques in Behavioral Research, 30 August - 2 September 2005, Wageningen, The Netherlands.

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