Accumbal dopamine, noradrenaline and serotonin activity after naloxone-conditioned place aversion in morphine-dependent mice.
Dopamine (DA) neurons not only show a pattern signaling the magnitude, delay and probability of rewards but also code negative motivation and aversive events. Beside DA, other systems such as noradrenaline (NA) and serotonin (5-HT) may also be implicated in naloxone-induced conditioned place aversion (CPA; an index of the aversive consequences of withdrawal). The purpose of the present study was to evaluate: (i) the turnover of DA, NA and 5-HT in the nucleus accumbens (NAc), one of the most important substrates for aversive states, (ii) the changes in tyrosine hydroxylase (TH) gene expression in the ventral tegmental area, and (iii) total TH protein levels and TH phosphorylation in the NAc after naloxone-induced morphine withdrawal. DA, NA and 5-HT turnover was evaluated by high-performance liquid chromatography (HPLC). TH gene expression was determined by real time quantitative PCR (RT-PCR) and total TH and TH phosphorylated at Ser31 and Ser40 were analyzed by Western blot. Present results show that the aversion for environmental cues paired with opioid withdrawal was higher than that observed in the saline group treated with naloxone, which indicates that morphine pretreatment potentiated the ability of naloxone to produce place aversion. In addition, present data show that naloxone-induced CPA positively correlated with an increase of DA and NA turnover in the NAc, which paralleled an increase in TH gene expression in the VTA and TH phosphorylation and enhanced TH protein levels in the NAc. Thus, the present study indicates that naloxone-induced aversion in morphine-dependent mice enhances DA and NA activity in the NAc and suggests that transcriptional and post-transcriptional regulation of TH could be involved in the hyperactivity of mesolimbic dopaminergic system observed in morphine-withdrawn mice.
Department of Pharmacology, Faculty of Medicine, Campus de Espinardo, 30100 Murcia, Spain.
Iván
I
Gómez-Milanés
Pilar
P
Almela
Juan-Antonio
JA
García-Carmona
M Salud
MS
García-Gutiérrez
Auxiliadora
A
Aracil-Fernández
Jorge
J
Manzanares
María Victoria
MV
Milanés Maquilón
M Luisa
ML
Laorden
D000818:Animals; D001362:Avoidance Learning; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D003216:Conditioning, Operant; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage*; D009270:Naloxone / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000378:metabolism*; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D012701:Serotonin / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
D012701:Serotonin; D009270:Naloxone; D009020:Morphine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D009638:Norepinephrine