Differential regulation of neurotrophin and trk receptor mRNAs in catecholaminergic nuclei during chronic opiate treatment and withdrawal.
The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and their receptors trkB and trkC, respectively, are expressed in the locus coeruleus (LC) and ventral tegmental area (VTA), brain regions known to be involved in opiate addiction. Previously, administration of exogenous neurotrophins has been shown to oppose effects of chronic morphine treatment on LC and VTA neurons. However, the response of endogenous neurotrophins in LC and VTA to opiate treatment is unknown. In this study, BDNF, NT-3, trkB, and trkC mRNAs were analyzed in these regions after chronic morphine treatment and during antagonist precipitated withdrawal. Although chronic morphine exposure resulted in only modest increases in BDNF and NT-3 mRNA expression in LC, precipitated withdrawal led to a marked, rapid, and prolonged increase in BDNF mRNA and a delayed decrease in NT-3 mRNA. Levels of trkB and trkC mRNAs, which were unchanged by chronic morphine treatment, were elevated in LC at 2 and 6 hr of withdrawal. By 20 hr, trkB mRNA levels in LC had returned to control, whereas trkC mRNA levels fell below control values. In contrast to the substantial alterations observed in LC, there was no regulation of the neurotrophins or trk mRNAs within the VTA during chronic opiate treatment or withdrawal, with the exception of an increase in trkB mRNA at 6 hr of withdrawal. These results suggest that neurotrophins and their receptors per se may be involved in opiate-induced plasticity of the LC, whereas other mechanisms would appear to be involved in the VTA.
Numan
S
S
Laboratory of Molecular Psychiatry, Yale University School of Medicine and Connecticut Mental Health Center, New Haven, Connecticut 06508, USA.
Lane-Ladd
S B
SB
Zhang
L
L
Lundgren
K H
KH
Russell
D S
DS
Seroogy
K B
KB
Nestler
E J
EJ
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D004334:Drug Administration Schedule; D004343:Drug Implants; D005786:Gene Expression Regulation / Q000187:drug effects*; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism*; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D020933:Neurotrophin 3; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020801:Receptor, Ciliary Neurotrophic Factor; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D004343:Drug Implants; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D012333:RNA, Messenger; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D009020:Morphine; D020794:Receptor Protein-Tyrosine Kinases; D020812:Receptor, trkC