Differential Regulation of Neurotrophin andtrkReceptor mRNAs in Catecholaminergic Nuclei during Chronic Opiate Treatment and Withdrawal

Abstract

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.

Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal

“…In rat A6 neurons, NT-3 expression was increased after chronic morphine exposure but fell below baseline levels after acute withdrawal. 5 The high affinity receptor for NT-3, trkC, also shows dynamic changes in expression during chronic opiate exposure and withdrawal. 5 These studies suggested indirectly that NT-3, by affecting noradrenergic neuronal function, modulates opiate addiction and withdrawal behaviors.…”

“…Molecules of the nerve growth factor family may influence neuronal health and plasticity both in the developing and in the adult brain, including the reward and addiction circuitry. 4 Brainstem noradrenergic neurons of the adult rodent and primate brain express the neurotrophin-3 (NT-3) high affinity receptor, TrkC, [5][6][7] as well as the brain derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5) receptor TrkB. In selected neuronal populations, NT-3 may promote growth and survival by binding to TrkB or TrkA, the high affinitity receptor for nerve growth factor (NGF).…”

“…In selected neuronal populations, NT-3 may promote growth and survival by binding to TrkB or TrkA, the high affinitity receptor for nerve growth factor (NGF). [8][9][10] Although levels of NT-3 and TrkC mRNA are altered in several brain areas during opiate withdrawal, 5 in vivo evidence of a role for NT-3 in opiate withdrawal and noradrenergic neuron function is still lacking. The perinatal lethality of conventional NT-3 knock-out mice, 11,12 due to major cardiovascular malformations, 13 prevented the use of these mice to study NT-3 in the adult brain.…”

Transgenic mice overexpressing the full-length neurotrophin receptor TrkC exhibit increased catecholaminergic neuron density in specific brain areas and increased anxiety-like behavior and panic reaction

“…However, some authors have specifically questioned the involvement of NT3 in prenatal LC development since Nt3-or double Gdnf/Nt3-null mutant mice (Ernfors et al, 1994;Fariñas et al, 1994;Holm et al, 2003) do not display clear developmental abnormalities in this region. Neurons of the LC, express high levels of neurotrophin type-2 TrkB (NTRK2-Mouse Genome Informatics) and neurotrophin type-3 receptor TrkC (NTRK3-Mouse Genome Informatics) (Numan et al, 1998;King et al, 1999). However, it remains to be determined whether TrkC ligands regulate the development of LC NA neurons in vivo and if developmental alterations in LC may facilitate an anxiety prone phenotype and predispose to the development of panic disorder.…”

Neurotrophin-4 is required for tolerance to morphine in the mouse

“…For morphine tolerance, NT4 may be acting in regions relevant to addiction, such as the nucleus accumbens and locus coeruleus. Interestingly, BDNF and NT3, as well as their receptors trkB and trkC, show expression changes in the locus coeruleus as a result of both morphine withdrawal and chronic administration [11].…”