Netrin-1 receptor-deficient mice show enhanced mesocortical dopamine transmission and blunted behavioural responses to amphetamine.
The mesocorticolimbic dopamine (DA) system is implicated in neurodevelopmental psychiatric disorders including schizophrenia but it is unknown how disruptions in brain development modify this system and increase predisposition to cognitive and behavioural abnormalities in adulthood. Netrins are guidance cues involved in the proper organization of neuronal connectivity during development. We have hypothesized that variations in the function of DCC (deleted in colorectal cancer), a netrin-1 receptor highly expressed by DA neurones, may result in altered development and organization of mesocorticolimbic DA circuitry, and influence DA function in the adult. To test this hypothesis, we assessed the effects of reduced DCC on several indicators of DA function. Using in-vivo microdialysis, we showed that adult mice that develop with reduced DCC display increased basal DA levels in the medial prefrontal cortex and exaggerated DA release in response to the indirect DA agonist amphetamine. In contrast, these mice exhibit normal levels of DA in the nucleus accumbens but significantly blunted amphetamine-induced DA release. Concomitantly, using conditioned place preference, locomotor activity and prepulse inhibition paradigms, we found that reduced DCC diminishes the rewarding and behavioural-activating effects of amphetamine and protects against amphetamine-induced deficits in sensorimotor gating. Furthermore, we found that adult DCC-deficient mice exhibit altered dendritic spine density in layer V medial prefrontal cortex pyramidal neurones but not in nucleus accumbens medium spiny neurones. These findings demonstrate that reduced DCC during development results in a behavioural phenotype opposite to that observed in developmental models of schizophrenia and identify DCC as a critical factor in the development of DA function.
Grant
Alanna
A
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, 6875 LaSalle Boulevard, Verdun, Quebec, Canada, H4H 1R3.
Hoops
Daniel
D
Labelle-Dumais
Cassandre
C
Prévost
Michael
M
Rajabi
Heshmat
H
Kolb
Bryan
B
Stewart
Jane
J
Arvanitogiannis
Andreas
A
Flores
Cecilia
C
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D000075389:DCC Receptor; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis / Q000379:methods; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency*; D012737:Sex Factors; D016622:Silver Staining / Q000379:methods; D025521:Tumor Suppressor Proteins / Q000172:deficiency*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000075389:DCC Receptor; C501910:Dcc protein, mouse; D018765:Dopamine Uptake Inhibitors; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine