title: Mechanisms of initiation and reversal of drug-seeking behavior induced by prenatal exposure to glucocorticoids.
abstract: Stress and exposure to glucocorticoids (GC) during early life render individuals vulnerable to brain disorders by inducing structural and chemical alterations in specific neural substrates. Here we show that adult rats that had been exposed to in utero GCs (iuGC) display increased preference for opiates and ethanol, and are more responsive to the psychostimulatory actions of morphine. These animals presented prominent changes in the nucleus accumbens (NAcc), a key component of the mesolimbic reward circuitry; specifically, cell numbers and dopamine (DA) levels were significantly reduced, whereas DA receptor 2 (Drd2) mRNA expression levels were markedly upregulated in the NAcc. Interestingly, repeated morphine exposure significantly downregulated Drd2 expression in iuGC-exposed animals, in parallel with increased DNA methylation of the Drd2 gene. Administration of a therapeutic dose of L-dopa reverted the hypodopaminergic state in the NAcc of iuGC animals, normalized Drd2 expression and prevented morphine-induced hypermethylation of the Drd2 promoter. In addition, L-dopa treatment promoted dendritic and synaptic plasticity in the NAcc and, importantly, reversed drug-seeking behavior. These results reveal a new mechanism through which drug-seeking behaviors may emerge and suggest that a brief and simple pharmacological intervention can restrain these behaviors in vulnerable individuals.
authors.affiliation: Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal.
authors.forename: A J
authors.initials: AJ
authors.lastname: Rodrigues
authors.forename: P
authors.initials: P
authors.lastname: Leão
authors.forename: J M
authors.initials: JM
authors.lastname: Pêgo
authors.forename: D
authors.initials: D
authors.lastname: Cardona
authors.forename: M M
authors.initials: MM
authors.lastname: Carvalho
authors.forename: M
authors.initials: M
authors.lastname: Oliveira
authors.forename: B M
authors.initials: BM
authors.lastname: Costa
authors.forename: A F
authors.initials: AF
authors.lastname: Carvalho
authors.forename: P
authors.initials: P
authors.lastname: Morgado
authors.forename: D
authors.initials: D
authors.lastname: Araújo
authors.forename: J A
authors.initials: JA
authors.lastname: Palha
authors.forename: O F X
authors.initials: OF
authors.lastname: Almeida
authors.forename: N
authors.initials: N
authors.lastname: Sousa
mesh_terms: D000818:Animals; D002452:Cell Count / Q000706:statistics & numerical data; D019175:DNA Methylation / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000009:adverse effects*; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000523:psychology*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis
chemical_list: D005938:Glucocorticoids; D017448:Receptors, Dopamine D2; D007980:Levodopa; D009020:Morphine; D004298:Dopamine