Regulation of Tyrosine Hydroxylase Promoter Activity by Chronic Morphine in TH9.0-LacZ Transgenic Mice

Boundy, Virginia A.; Gold, Stephen J.; Messer, Chad J.; Chen, Jingshan; Son, Jin H.; Joh, Tong H.; Nestler, Eric J.

doi:10.1523/jneurosci.18-23-09989.1998

Cited by 60 publications

(65 citation statements)

References 36 publications

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“…18 This transcriptional regulation is mediated, in part, by cAMP-dependent transcription factors and repressors. 19 Western blot analysis of microdissected A6 from wild-type mice that received morphine (total of 500 mg over 60 h) showed increased TH immunoreactivity in comparison to drug-free animals.…”

Section: Nt-3 Modulates Expression Of Tyrosine Hydroxylase But Is Notmentioning

confidence: 99%

“…18,23 While the functional significance of TH upregulation is not clear, the fact that it is diminished in NT-3 deficient mice suggests impaired capacity to adapt to chronic opiate exposure. Alterations in neuronal activity, including a hypoactive cAMP signaling cascade under drug-free conditions, an abnormal elevation in baseline firing rate after chronic morphine exposure, provide additional evidence that noradrenergic neurons are dysfunctional in NT-3 conditional mutants.…”

Section: Reduced Opiate Withdrawal In Conditional Mutants Is Accompanmentioning

confidence: 99%

“…18 Samples were homogenized in 2% SDS and aliquots of A6 containing 20 g of protein were loaded on 7.5% SDS polyacrylamide gels, electrophoresed and transferred to nitrocellulose (Schleicher and Schuell, Keene, NH, USA). Blots were immunolabeleled for TH exactly as described.…”

Section: Western Blot Analysismentioning

confidence: 99%

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Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal

et al. 2001

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Ongoing drug use in an opiate-addicted individual could be reinforced by withdrawal reactions that occur when drug use is halted abruptly. 1 Overactivity and disinhibition of brainstem noradrenergic neurons is thought to be a key mechanism for the hyperautonomic state and for many of the somatic symptoms that occur during acute withdrawal 2 and also for the acquisition of avoidance behaviors after occurrence of withdrawal reactions. 3 Little is known about endogenous factors that regulate noradrenergic neuron function and opiate withdrawal-related 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, 5-7 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). [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. Using a conditional knock-out strategy with Cre/loxP mediated NT-3 gene deletion that results in complete loss of NT-3 in the central nervous system in mice with normal viability, fertility and lifespan, 14 we show here for the first time that NT-3 modulates electrophysiological responses and neurochemistry of brainstem noradrenergic neurons and that NT-3 is essential both for opiate withdrawal-induced avoidance behavior and for the somatic symptoms that occur during acute withdrawal. NT-3 modulates expression of tyrosine hydroxylase but is not essential for survival of noradrenergic neuronsWe used two transgenic lines, a conditional NT3 mutant 14 and a transgenic line carrying an NT3 transgene under the control of the DBH promoter to examine the consequences of NT3 deficiency as well as NT3 overexpression in opiate withdrawal reactions and in noradrenergic neuron function in vivo. Expression of the recombinase cre under control of the nestin promoter results in complete deletion of NT-3 during prenatal development of the brain and spinal cord. 14 To ascertain ubiquitous nestin-cre expression, a reporter line that expressed beta-galactosidase in all tissues upon cre-mediated removal of a stop translation sequence 15 was crossed with the nestin-cre transgenic line. The results shown in Figure 1a-c indicate that cre-mediated recombination is complete throughout the brain, consistent with previous Northern blot results. 14 In adult brain, NT-3 has been implicated in survival of noradrenergic neuron...

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Section: Nt-3 Modulates Expression Of Tyrosine Hydroxylase But Is Notmentioning

confidence: 99%

Section: Reduced Opiate Withdrawal In Conditional Mutants Is Accompanmentioning

confidence: 99%

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Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal

et al. 2001

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“…Upregulation of the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines, has been suggested to lead to changes in noradrenergic transmission that contribute to behavioral, cognitive, emotional and physiological manifestations of depression and anxiety (Persson et al 1997;Sands et al 2000;Van Bockstaele et al 1999). Levels of TH are known to be upregulated in specific brain regions by chronic administration of drugs of abuse (Boundy et al 1998;Shishido et al 1997). However, the effects of chronic cannabinoid administration on TH expression have been relatively unexplored in adult rat or human.…”

Section: Introductionmentioning

confidence: 99%

Repeated cannabinoid administration increases indices of noradrenergic activity in rats

Page

Oropeza

Sparks

et al. 2007

Pharmacology Biochemistry and Behavior

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SummaryThe present study examined the impact of repeated administration of a synthetic cannabinoid agonist, WIN 55,212-2 on the coeruleo-cortical pathway, a circuit implicated in anxiety. Male SpragueDawley rats received repeated systemic injections of WIN 55,212-2 (3.0 mg/kg). A separate group of rats received repeated WIN 55,212-2 injections followed by a period of abstinence. Control animals received vehicle injections. Ninety minutes following the last injection on day 8, anxietyrelated behavior was assessed using the elevated plus maze. The abstinent group was tested after another 8 days. Following behavioral testing, brain tissue was extracted from the locus coeruleus (LC) and probed for tyrosine hydroxylase (TH) expression. In a separate group of animals, in vivo microdialysis was used to monitor extracellular norepinephrine efflux in the frontal cortex following repeated WIN 55,212-2 administration and following a period of abstinence.Repeated administration of WIN 55,212-2 evoked an anxiogenic-like response that was accompanied by an increase in TH protein expression in the LC. A similar neurochemical profile was observed using in vivo microdialysis where an augmented increase in cortical norepinephrine efflux was identified in response to a systemic injection of WIN 55,212-2 on day 8. Anxiety-like behavior, catecholamine synthesizing enzyme levels and NE efflux returned to control values after eight days of abstinence.The present findings indicate that repeated administration of a synthetic cannabinoid receptor agonist induces transient anxiety-like behaviors that correlate with increases in catecholamine synthesizing enzyme expression in the LC and augmented norepinephrine efflux in response to a challenge injection of WIN 55,212-2.

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“…TH expression could be upregulated by increase of Ca 2 + entry into dopamine VTA neurons, that activate enzymes such as calcium-calmodulin-dependent-kinase II (CaMKII), or after activation of other kinases such as protein kinase C Williams et al, 2001). Post-transcriptional mechanisms based on regulation of TH mRNA stability have also been proposed for explaining TH upregulation after opiates (Kumer and Vrana, 1996;Boundy et al, 1998). These facts deserve further investigation.…”

Section: Thmentioning

confidence: 99%

Role for Dopamine Neurons of the Rostral Linear Nucleus and Periaqueductal Gray in the Rewarding and Sensitizing Properties of Heroin

Flores

Galan-Rodriguez

Ramiro-Fuentes

et al. 2005

Neuropsychopharmacol

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There is a mesencephalic dopaminergic network outside the ventral tegmental area (VTA), including structures such as the rostral linear nucleus (RLi) and periaqueductal gray (PAG). These nuclei project to neural areas implicated in reinforcing effects of drugs, indicating that they could participate in opiate reward. The objectives were to study the morphological characteristics of the dopamine network of the RLi/PAG region, and to discern its role on rewarding and sensitizing effects of heroin in rats, following dopamine depletion or local injection of dopaminergic antagonists. The findings indicated that this network is composed of small cells in the RLi/ventral PAG, large multipolar dopamine PAG neurons, and periaqueductal PAG neurons. Following repeated heroin, large PAG neurons and small RLi/ ventral PAG cells (not periaqueductal neurons) were activated, since tyrosine-hydroxylase was adaptively induced, without changes in protein kinase Aa. After dopamine depletion, small RLi/ventral PAG neurons and large cells of the PAG (not periaqueductal ones) were selectively affected by the neurotoxin. Dopamine neurons of the nearby VTA and dorsal raphe were not affected, as revealed by cell counting. After lesion, 'anxiety-like' responses and basal locomotion were not altered. However, conditioned place preference to heroin was found to be abolished, as well as heroin-induced motor sensitization. Following infusions of dopaminergic antagonists into RLi/PAG, D 2 (not D 1 ) receptor blocking dose-dependently abolished heroin-induced reward. The present study provides evidence that dopamine neurons of the RLi/PAG region (excluding PAG periaqueductal cells) show adaptive biochemical changes after heroin, and mediate the rewarding and sensitizing effects of this drug. D 2 dopamine receptors within the RLi/PAG region participate in these effects.

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Regulation of Tyrosine Hydroxylase Promoter Activity by Chronic Morphine in TH9.0-LacZ Transgenic Mice

Cited by 60 publications

References 36 publications

Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal

Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal

Repeated cannabinoid administration increases indices of noradrenergic activity in rats

Role for Dopamine Neurons of the Rostral Linear Nucleus and Periaqueductal Gray in the Rewarding and Sensitizing Properties of Heroin

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