Elsevier

Brain Research

Volume 799, Issue 2, 20 July 1998, Pages 257-263
Brain Research

Research report
Effect of nicotine use and withdrawal on brain preproenkephalin A mRNA

https://doi.org/10.1016/S0006-8993(98)00454-5Get rights and content

Abstract

Although the effect of nicotine on brain neurotransmitters and behavior has been studied, the mechanism(s) by which nicotine contributes to tobacco use remains unclear. One transmitter that may relate to long-term nicotine use and its withdrawal is enkephalin, a five-amino acid opioid peptide derived from the proenkephalin A family. In the present study we determined the effect of acute and chronic nicotine treatment and its withdrawal on preproenkephalin A mRNA levels (PPE mRNA) in specific rat brain regions using Northern blot analysis. Acute treatment with nicotine produced a significant increase in PPE mRNA in striatum and hippocampus. Chronic treatment with nicotine caused a significant decrease in PPE mRNA in these brain regions. In both striatum and hippocampus there was a rebound increase in PPE mRNA 24 h after nicotine cessation which approached the saline level 7 days later. Nicotine withdrawal 24 h following nicotine cessation, caused a significant increase in PPE mRNA in both brain regions. These effects of nicotine were blocked by pretreating rats with the nicotinic antagonist, mecamylamine. These data strongly suggest that brain opioid system(s) are involved in mediating nicotinic responses and its withdrawal and may have clinical implications in treating nicotine addiction.

Introduction

Nicotine is critical in the maintenance of tobacco use 30, 43. The extensive health problems associated with tobacco use are exacerbated by the addictive properties of cigarette smoking and the limited success of smoking cessation programs [24]. Although the effect of acute nicotine in the central nervous system has been extensively studied, the mechanism(s) involved in mediating chronic use of nicotine remain unclear. This is particularly true for the neuropharmacological actions of cigarette smoke/nicotine that contribute to smoking behavior, or why smoking is so prevalent in psychiatric disorders [28]and is associated with decreased risk of Parkinson's [35]and Alzheimer diseases [3]. Many of the acute euphoric effects of nicotine are thought to be a consequence of the activation of the mesocorticolimbic dopamine system, especially in the region of the striatum and nucleus accumbens 9, 10, 29, 34. Although dopamine may initiate self-reinforcing behavior, the biochemical consequences of repeated nicotine administration and its termination are less well understood. One neurotransmitter that may relate to long-term nicotine use and withdrawal is enkephalin, a five-amino acid opioid peptide (Tyr-Gly-Gly-Phe-Met) derived from the proenkephalin A family. Enkephalins have been implicated in anxiety, depression 12, 17, 22and memory 4, 18and their biosynthesis in the striatum appears to be regulated by dopamine 25, 36, 41, 44. In addition, enkephalinergic neurons in the striatum and nucleus accumbens are thought to modulate drug self-administration behavior and behavioral sensitization [1]. Although measurement of neuropeptide release remains very difficult, assessment of changes in the activity of enkephalin neurons has been carried out by measuring enkephalin levels in brain tissues 7, 20, 26, 38. However, changes in enkephalin levels do not readily provide an index of their release, and changes in the activity of these neurons may occur without changes in steady-state enkephalin concentration. To provide a better assessment of changes in enkephalin synthesis rates in response to acute and/or chronic nicotine administration and its withdrawal, we measured changes in the steady-state levels of the mRNA for preproenkephalin A in rat striatum and hippocampus which are known to be associated with reward, memory and learning functions which may contribute to the development of addiction.

Section snippets

Animals

Male, Sprague–Dawley rats (Harlan, IN) weighing 300±25 g were housed in individual cages in an environmental room under constant conditions of temperature (24°C), humidity and 12-h light–dark cycle (lights on 0700–1900 h) for 1 week before use in studies. Animals were allowed free access to food and water. Animal experiments were conducted in accordance with NIH `Guide for the Care and Use of Laboratory Animals' and were approved by University of Kentucky, Institutional Animal Care and Use

Results

A single species of mRNA hybridized to the proenkephalin probe was detected on Northern blot with a mobility compatible with a size of approximately 1400 bases, in agreement with published reports.

Treatment with acute nicotine (0.6 mg/kg, s.c.) produced significant increases in preproenkephalin A mRNA (PPE mRNA) in striatum (caudate-putamen+globus pallidus), and hippocampus 30 min after treatment as measured by Northern blot analysis compared to saline-treated rats (Fig. 1).

We also examined the

Discussion

These data show that acute treatment with a single injection of nicotine elevated PPE mRNA levels in rat striatum and hippocampus, but that chronic treatment with nicotine for 14 days produced a decrease in the level of PPE mRNA in these rat brain sites. This is a strong indication of the development of tolerance to the effect of nicotine. An important finding of this study is that the withdrawal effect from chronic nicotine produced a rebound increase in the level of PPE mRNA in striatum and

Acknowledgements

We thank Dr. Steven L. Sabol (Laboratory of Biochemical Genetics, NHLBI, NIH) for providing the proenkephalin mRNA probe. This research was supported by the Kentucky Tobacco Research Board.

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