Elsevier

Brain Research

Volume 888, Issue 2, 12 January 2001, Pages 336-342
Brain Research

Interactive report
Nicotine prevents striatal dopamine loss produced by 6-hydroxydopamine lesion in the substantia nigra1

https://doi.org/10.1016/S0006-8993(00)03087-0Get rights and content

Abstract

While the work of several groups has shown the neuroprotective effects of nicotine in vitro, evidences for the same effects in vivo are controversial, mainly regarding neuroprotection in experimental models of Parkinson’s disease. In this context, we investigated the capability of various systemic administration schedules of nicotine to prevent the loss of striatal dopamine levels produced by partial or extensive 6-hydroxydopamine (6-OHDA) lesion of rat substantia nigra (SN). Eight days after 6- and 10-μg injections of 6-OHDA in the SN there was a significant decrease of dopamine concentrations in the corpus striatum (CS) and a concomitant increase in dopamine turnover. While 10 μg 6-OHDA produced an almost complete depletion of dopamine in the SN, 6 μg decreased dopamine levels by 50%. Subcutaneous nicotine (1 mg/kg) administered 4 h before and 20, 44 and 68 h after 6 μg 6-OHDA, prevented significantly the striatal dopamine loss. Administered only 18 or 4 h before or only 20, 44 and 68 h after, nicotine failed to counteract the loss of dopamine or the increase in dopamine turnover observed in the CS. Nicotine also failed to prevent significantly the decrease of striatal dopamine levels produced by the 10-μg 6-OHDA intranigral dose. Chlorisondamine, a long-lasting nicotinic acetylcholine receptor antagonist, reverted significantly the nicotinic protective effects on dopamine concentrations. These results are showing that putative neuroprotective effects of nicotine in vivo depend on an acute intermittent administration schedule and on the extent of the brain lesion.

Introduction

Although initially introduced in Europe with tobacco plants for medicinal purposes, nicotine has become, through tobacco addiction, a harmful presence in our modern societies. The physiological effects of nicotine are varied, affecting the peripheral (cardiovascular, neuromuscular) and the central nervous system (CNS) [18], and are based on its ability to mimic the actions of acetylcholine at the nicotinic acetylcholine receptors (nAChR). The deleterious effects of tobacco use have precluded a comprehensive study of the effects of nicotine in the CNS. In recent decades, however, several studies demonstrated that nicotine could have a positive effect in several neuronal processes like attention, memory processing, pain, or neuroprotection [9]. The identification of more than 10 genes codifying the different sub-units of the nAChR gave a structural basis for the search of specific subunit combinations with beneficial effects in the CNS [9].

Several reports have shown that there is a negative correlation between smoking and the appearance of Parkinson’s disease. These epidemiological findings gave support to the hypothesis of a neuroprotective role of nicotine [12], [36] and prompted the study of the effects of nicotine stimulation in several models of neurotoxicity. At present, numerous studies have confirmed the protection conferred by nicotine to neuronal cultures against toxic insults like excitotoxins [1], [11], [22], [31], [35], [42] or β-amyloid toxicity [29]. Blockade of the neuroprotection effects by nAChR antagonists provided evidence for the specific mediation by different subtypes of nAChR [29], [31], [43].

In spite of this in vitro evidence, in vivo studies are still controversial when regarding the neuroprotective properties of nicotine treatments. While continuous nicotine infusion has been demonstrated to protect against neuronal loss produced by dopamine pathways hemitransection [25], [26], the striatal depletion of dopamine after injection of 6-hydroxydopamine (6-OHDA) in the substantia nigra (SN) was unaltered by the same treatment [10]. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) systemic application in vivo resulted in a significant decrease of striatal dopamine content that was not prevented by nicotine in some studies [21], while another group showed that nicotine had protective effects against diethyldithiocarbamate enhancement of MPTP lesions [34]. Moreover, in the MPTP model of experimental parkinsonism, nicotine has even shown an enhancement of the neurotoxicity [5], [19].

Beyond these discrepancies, it is likely that the great variety of experimental conditions reported, differing in the schedule and method of nicotine administration, may in part explain the differences observed. Thus, reports using chronic treatments did not show effects in vivo [21], [27], while the acute intermittent administration appeared to show protective effects in the models reported [27], [34].

In this context, and as a contribution to the characterization of the role played by nAChR in Parkinson’s disease, we studied the putative neuroprotective effects of nicotine in the 6-OHDA model of experimental parkinsonism, assessing whether the timing and schedule of nicotine administration as well as the extent of the lesion are factors that could effectively influence the neuroprotection profile.

Section snippets

Animals

Experiments were carried out using male Sprague–Dawley rats (230–260 g). Animals had access to food and water ad libitum, and were housed in groups of six in a temperature controlled environment on a 12-h light/dark cycle.

Drugs and reagents

Chemicals for HPLC analysis, artificial cerebrospinal fluid (aCSF) and saline were purchased from Baker (Phillipsburg, PA, USA). Dopamine (hydrochloride), 3,4-dihydroxyphenylacetic acid (DOPAC), 6-OHDA, (−)-nicotine (tartrate) and l-ascorbic acid were obtained from Sigma (St.

6-OHDA

Intranigral injections of 6 and 10 μg 6-OHDA, produced a significant decrease of dopamine tissue levels in the right CS and SN (ipsilateral, treated side) when compared with the left, non-treated, one (contralateral) (Table 1). As shown in Table 1, the 10-μg dose produced an effect in the dopamine concentrations higher than the 6-μg dose. Control rats injected in the SN with 2 μl of aCSF (in 0.2% ascorbic acid), did not show any difference in dopamine levels between right and left CS (right,

Discussion

The injection of 6-OHDA into the rat SN leads to a progressive and massive death of dopaminergic nerve cells and to a corresponding depletion of dopamine in the CS [3], [13], [28]. It is recognized that 6-OHDA insults involve at least two mechanisms of cell death: free radical production and/or reactivity of quinone products [13], [23], [30], [32]. In agreement with these previous reports [3], [13], [39], the intranigral injection of 6-OHDA produced a significant decrease of dopamine levels in

Acknowledgements

This work was partially supported by Fondo Clemente Estable (CONICYT-BID, No. 2032) and IPICS (International Program for the Chemical Science, Uppsala University, Sweden). The authors wish to thank Novartis Pharmaceutical Corporation for kind donation of Chlorisondamine, Lic. F. Dajas Bailador for critical reading of the manuscript and valuable suggestions, and J. Franco and L. Lavarello for statistical analysis assistance.

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