Role of corticotropin-releasing factor (CRF) receptor-1 on the catecholaminergic response to morphine withdrawal in the nucleus accumbens (NAc).
Stress induces the release of the peptide corticotropin-releasing factor (CRF) into the ventral tegmental area (VTA), and also increases dopamine (DA) levels in brain regions receiving dense VTA input. Since the role of stress in drug addiction is well established, the present study examined the possible involvement of CRF1 receptor in the interaction between morphine withdrawal and catecholaminergic pathways in the reward system. The effects of naloxone-precipitated morphine withdrawal on signs of withdrawal, hypothalamo-pituitary-adrenocortical (HPA) axis activity, dopamine (DA) and noradrenaline (NA) turnover in the nucleus accumbens (NAc) and activation of VTA dopaminergic neurons, were investigated in rats pretreated with vehicle or CP-154,526 (selective CRF1R antagonist). CP-154,526 attenuated the increases in body weight loss and suppressed some of withdrawal signs. Pretreatment with CRF1 receptor antagonist resulted in no significant modification of the increased NA turnover at NAc or plasma corticosterone levels that were seen during morphine withdrawal. However, blockade of CRF1 receptor significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropin (ACTH) levels, DA turnover and TH phosphorylation at Ser40 in the NAc. In addition, CP-154,526 reduced the number of TH containing neurons expressing c-Fos in the VTA after naloxone-precipitated morphine withdrawal. Altogether, these results support the idea that VTA dopaminergic neurons are activated in response to naloxone-precipitated morphine withdrawal and suggest that CRF1 receptors are involved in the activation of dopaminergic pathways which project to NAc.
Departamento de Farmacología, Facultad de Medicina, Universidad de Murcia, Murcia, Spain.
Pilar
P
Almela
Javier
J
Navarro-Zaragoza
Juan-Antonio
JA
García-Carmona
Lucía
L
Mora
Juana
J
Hidalgo
María-Victoria
MV
Milanés
María-Luisa
ML
Laorden
D000818:Animals; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009021:Morphine Dependence / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000378:metabolism; D000099052:CRF Receptor, Type 1
C101628:CP 154526; D016760:Proto-Oncogene Proteins c-fos; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D009270:Naloxone; D012694:Serine; D000099052:CRF Receptor, Type 1; D009020:Morphine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D003345:Corticosterone; D009638:Norepinephrine