Increases in tyrosine hydroxylase messenger RNA in the locus coeruleus after a single dose of nicotine are followed by time-dependent increases in enzyme activity and noradrenaline release

doi:10.1016/0306-4522(93)90145-6

Neuroscience

Volume 56, Issue 4, October 1993, Pages 989-997

https://doi.org/10.1016/0306-4522(93)90145-6 Get rights and content

Abstract

We have utilized biochemical, molecular biological, and functional neurochemical measurements to investigate the integrated and long-term effects of a single dose of nicotine on the noradrenergic system in the central nervous system of the rat, from enzyme induction to transmitter release. We have found that a single systemic injection of nicotine (0.8 mg/kg) increases messenger RNA for the rate-limiting enzyme in the synthesis of catecholamines, tyrosine hydroxylase, two to six days later in the noradrenergic cell body region, the locus coeruleus (and not in the dopaminergic cell body regions, substantia nigra and ventral tegmental area). This was then followed by a time-dependent increase in enzyme activity, measured in vitro, in terminal regions of the ascending dorsal noradrenergic bundle up to four weeks later. Functionally, the increase in tyrosine hydroxylase activity in the terminals four weeks after a single administration was associated with an increase in the capacity to release noradrenaline in the hippocampus, measured using in vivo microdialysis in freely moving animals. This occurred in response to an acute systemic nicotine injection (0.4 mg/kg) but not to a local, intrahippocampal, challenge with 250/gmM nicotine.

These experiments have revealed a long-term effect of nicotine on noradrenergic activity in the central nervous system, associated with induction of tyrosine hydroxylase. This is accompanied by a time-dependent increase in terminal tyrosine hydroxylase activity and an increase in noradrenaline release.

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Acute administration of clozapine has been reported to activate the locus coeruleus (LC) and beta-adrenoceptor-dependent Fos immunoreactivity in the medial prefrontal cortex (mPFC) in rodents. Haloperidol is reported to exhibit a similar acute effect on LC firing and beta-adrenoceptor dependent Fos immunoreactivity in the mPFC but only at high doses. We compared the effects of chronic 4-week treatment with risperidone (1 mg/kg/day s.c.), clozapine (10 mg/kg/day s.c.) or a high dose of haloperidol (4 mg/kg/day s.c.) on immediate-early gene protein (c-Fos, Egr-1 and Egr-2) and tyrosine hydroxylase (TH) expression. In the mPFC, haloperidol decreased, whereas clozapine increased, c-Fos immunoreactivity. Only haloperidol increased Egr-1 immunoreactivity. There was no significant effect on Egr-2 immunoreactivity. In the LC, both Egr-1 and Egr-2 expression was down regulated by all three antipsychotics. Clozapine and risperidone increased TH immunoreactivity in both mPFC and LC. Haloperidol caused a smaller increase in TH expression in the LC, but did not alter expression in the mPFC. In conclusion, despite qualitatively similar effects in the LC, chronic treatment with haloperidol had different effects to clozapine and risperidone in the mPFC. This may relate to the reported advantage of clozapine and risperidone over haloperidol against prefrontal cortical-dependent cognitive and negative symptoms.
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^†: Present address: Department of Biochemistry and Physiology, AMS Building, University of Reading, Whiteknights, P.O. Box 228, Reading RG6 2AJ, U.K.

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Increases in tyrosine hydroxylase messenger RNA in the locus coeruleus after a single dose of nicotine are followed by time-dependent increases in enzyme activity and noradrenaline release

Abstract

Biochem. Pharmac.

Eur. J. Pharmac.

Brain Res.

Neuropharmacology

Brain Res.

Analyt. Biochem.

Neuropharmacology

Biochem. Pharmac.

Brain Res.

Neurochem. Int.

Eur. J. Pharmac.

Eur. J. Pharmac.

Eur. J. Pharmac.

Biochem. Pharmac.

Neuroscience

Brain Res.

Short- and long-term changes in tyrosine hydroxylase activity in rat brain after subtotal destruction of central noradrenergic neurons

J. Neurosci.

Effects of synaptic and antidromic stimulation on tyrosine hydroxylase activity in the rat superior cervical ganglion

J. Physiol., Lond.

Time course for the changes in tyrosine hydroxylase mRNA in rat brain and adrenal medulla after a single injection of reserpine

Eur. molec. Biol. Org. J.

Noradrenergic Neurons

Complete coding sequence of rat TH mRNA