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Changes in apical dendritic structure correlate with sustained ERK1/2 phosphorylation in medial prefrontal cortex of a rat model of dopamine D 1 receptor agonist sensitization
Author(s) -
Papadeas Sophia T.,
Halloran Christopher,
McCown Thomas J.,
Breese George R.,
Blake Bonita L.
Publication year - 2008
Publication title -
journal of comparative neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.855
H-Index - 209
eISSN - 1096-9861
pISSN - 0021-9967
DOI - 10.1002/cne.21835
Subject(s) - prefrontal cortex , infralimbic cortex , dopamine , neurochemical , agonist , neuroscience , dendrite (mathematics) , sensitization , latent inhibition , medicine , psychology , endocrinology , stimulation , dopamine receptor d1 , dopamine receptor d2 , receptor , biology , conditioning , classical conditioning , cognition , statistics , geometry , mathematics
Abstract Rats lesioned with 6‐hydroxydopamine (6‐OHDA) as neonates exhibit behavioral and neurochemical abnormalities in adulthood that mimic Lesch–Nyhan disease, schizophrenia, and other developmental disorders of frontostriatal circuit dysfunction. In these animals a latent sensitivity to D 1 agonists is maximally exposed by repeated administration of dopamine agonists in the postpubertal period (D 1 priming). In neonate‐lesioned, adult rats primed with SKF‐38393, we found selective, persistent alterations in the morphology of pyramidal neuron apical dendrites in the prelimbic area of the medial prefrontal cortex (mPFC). In these animals, dendrite bundling patterns and the typically straight trajectories of primary dendritic shafts were disrupted, whereas the diameter of higher‐order oblique branches was increased. Although not present in neonate‐lesioned rats treated with saline, these morphological changes persisted at least 21 days after repeated dosing with SKF‐38393, and were not accompanied by markers of neurodegenerative change. A sustained increase in phospho‐ERK immunoreactivity in wavy dendritic shafts over the same period suggested a relationship between prolonged ERK phosphorylation and dendritic remodeling in D 1 ‐primed rats. In support of this hypothesis, pretreatment with the MEK1/2‐ERK1/2 pathway inhibitors PD98059 or SL327, prior to each priming dose of SKF‐38393, prevented the morphological changes associated with D 1 priming. Together, these findings demonstrate that repeated stimulation of D 1 receptors in adulthood interacts with the developmental loss of dopamine to profoundly and persistently modify neuronal signaling and dendrite morphology in the mature prefrontal cortex. Furthermore, sustained elevation of ERK activity in mPFC pyramidal neurons may play a role in guiding these morphological changes in vivo. J. Comp. Neurol. 511:271–285, 2008. © 2008 Wiley‐Liss, Inc.