Mu-opioid receptor activation induces transcriptional plasticity in the central extended amygdala.
Addiction develops from the gradual adaptation of the brain to chronic drug exposure, and involves genetic reprogramming of neuronal function. The central extended amygdala (EAc) is a network formed by the central amygdala and the bed nucleus of the stria terminalis. This key site controls drug craving and seeking behaviors, and has not been investigated at the gene regulation level. We used Affymetrix microarrays to analyze transcriptional activity in the murine EAc, with a focus on mu-opioid receptor-associated events because these receptors mediate drug reward and dependence. We identified 132 genes whose expression is regulated by a chronic escalating morphine regimen in the EAc from wild-type but not mu-opioid receptor knockout mice. These modifications are mostly EAc-specific. Gene ontology analysis reveals an overrepresentation of neurogenesis, cell growth and signaling protein categories. A separate quantitative PCR analysis of genes in the last of these groups confirms the dysregulation of both orphan (Gpr88) and known (DrD1A, Adora2A, Cnr1, Grm5, Gpr6) G protein-coupled receptors, scaffolding (PSD95, Homer1) and signaling (Sgk, Cap1) proteins, and neuropeptides (CCK, galanin). These transcriptional modifications do not occur following a single morphine injection, and hence result from long-term adaptation to excessive mu receptor activation. Proteins encoded by these genes are classically associated with spine modules function in other brain areas, and therefore our data suggest a remodeling of EAc circuits at sites where glutamatergic and monoaminergic afferences interact. Together, mu receptor-dependent genes identified in this study potentially contribute to drug-induced neural plasticity, and provide a unique molecular repertoire towards understanding drug craving and relapse.
Befort
K
K
IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Département Neurobiologie et Génétique, Illkirch, F-67400 France. befort@igbmc.u-strasbg.fr
Filliol
D
D
Ghate
A
A
Darcq
E
E
Matifas
A
A
Muller
J
J
Lardenois
A
A
Thibault
C
C
Dembele
D
D
Le Merrer
J
J
Becker
J A J
JA
Poch
O
O
Kieffer
B L
BL
D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D009293:Opioid-Related Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D012686:Septal Nuclei / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects* / Q000235:genetics
D000701:Analgesics, Opioid; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D017450:Receptors, Opioid, mu; D009020:Morphine