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Interactive report
Nicotine prevents striatal dopamine loss produced by
1
6-hydroxydopamine lesion in the substantia nigra
*
Gustavo Costa, J.A. Abin-Carriquiry, Federico Dajas
´ ´ ´
Division Neuroquımica, Instituto de Investigaciones Biologicas Clemente Estable, Avda. Italia 3318, 11 600 Montevideo, Uruguay Accepted 23 October 2000
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-mg 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 10mg 6-OHDA produced an almost complete depletion of dopamine in the SN, 6mg decreased dopamine levels by 50%. Subcutaneous nicotine (1 mg / kg) administered 4 h before and 20, 44 and 68 h after 6mg 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-mg 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. 2001 Elsevier Science B.V. All rights reserved.
Theme: Disorders of the nervous system
Topic: Degenerative disease: Parkinson’s
Keywords: Nicotine; Dopamine; Corpus striatum; Substantia nigra; Nicotinic acetylcholine receptor; 6-Hydroxydopamine; Chlorisondamine
1. Introduction that nicotine could have a positive effect in several
neuronal processes like attention, memory processing, Although initially introduced in Europe with tobacco pain, or neuroprotection [9]. The identification of more plants for medicinal purposes, nicotine has become, than 10 genes codifying the different sub-units of the through tobacco addiction, a harmful presence in our nAChR gave a structural basis for the search of specific modern societies. The physiological effects of nicotine are subunit combinations with beneficial effects in the CNS varied, affecting the peripheral (cardiovascular, neuro- [9].
muscular) and the central nervous system (CNS) [18], and Several reports have shown that there is a negative are based on its ability to mimic the actions of acetyl- correlation between smoking and the appearance of Parkin-choline at the nicotinic acetylParkin-choline receptors (nAChR). son’s disease. These epidemiological findings gave support The deleterious effects of tobacco use have precluded a to the hypothesis of a neuroprotective role of nicotine comprehensive study of the effects of nicotine in the CNS. [12,36] and prompted the study of the effects of nicotine In recent decades, however, several studies demonstrated stimulation in several models of neurotoxicity. At present, numerous studies have confirmed the protection conferred
1 by nicotine to neuronal cultures against toxic insults like Published on the World Wide Web on 1 December 2000.
excitotoxins [1,11,22,31,35,42] orb-amyloid toxicity [29].
*Corresponding author. Tel. / fax:1598-2-487-2603.
E-mail address: [email protected] (F. Dajas). Blockade of the neuroprotection effects by nAChR
nists provided evidence for the specific mediation by in aCSF containing 0.2% ascorbic acid. Nicotine and CHL different subtypes of nAChR [29,31,43]. were dissolved in saline.
In spite of this in vitro evidence, in vivo studies are still
controversial when regarding the neuroprotective prop- 2.3. Intranigral injection of 6-OHDA erties of nicotine treatments. While continuous nicotine
infusion has been demonstrated to protect against neuronal Animals were anaesthetized with halothane (Fluothane, loss produced by dopamine pathways hemitransection Zeneca) and placed in a D. Kopf stereotaxic frame. [25,26], the striatal depletion of dopamine after injection of Through a skull hole, the needle (0.022 mm o.d., 0.013 6-hydroxydopamine (6-OHDA) in the substantia nigra mm i.d.) of a Hamilton syringe (5 ml), attached to a (SN) was unaltered by the same treatment [10]. 1-Methyl- micro-injection unit (D. Kopf), was lowered to the SN. 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) systemic ap- Coordinates (H,24.8; L,22.2; V,27.2) were determined plication in vivo resulted in a significant decrease of from bregma, according to the atlas of Paxinos and Watson striatal dopamine content that was not prevented by [37].
nicotine in some studies [21], while another group showed A total of 2.0ml of a 6-OHDA solution (3 and 5mg /ml that nicotine had protective effects against diethyldithio- for the 6- and 10-mg doses) was injected for 4 min and the carbamate enhancement of MPTP lesions [34]. Moreover, needle was slowly withdrawn, allowing the drug to diffuse in the MPTP model of experimental parkinsonism, nicotine for another minute. Body temperature was maintained at has even shown an enhancement of the neurotoxicity 378C using a temperature control system.
[5,19].
Beyond these discrepancies, it is likely that the great 2.4. Experimental groups and nicotine administration variety of experimental conditions reported, differing in schedule
the schedule and method of nicotine administration, may in
part explain the differences observed. Thus, reports using 2.4.1. Partial lesion (6mg6-OHDA in the SN)
chronic treatments did not show effects in vivo [21,27], Five groups of rats (n58) injected with 6-OHDA (6mg) while the acute intermittent administration appeared to in the right SN, received 1 mg / kg nicotine subcutaneously show protective effects in the models reported [27,34]. according to the following protocols: (1) nicotine 18 h In this context, and as a contribution to the characteriza- before 6-OHDA; (2) nicotine 4 h before 6-OHDA; (3) tion of the role played by nAChR in Parkinson’s disease, nicotine 4 h before, and 20, 44 and 68 h after 6-OHDA; (4) we studied the putative neuroprotective effects of nicotine nicotine 20, 44, 68 h after 6-OHDA; (5) similar adminis-in the 6-OHDA model of experimental parkadminis-insonism, tration schedule to (3) plus CHL 10 mg / kg s.c. 30 min assessing whether the timing and schedule of nicotine before the first application of nicotine.
administration as well as the extent of the lesion are factors Each of the five experimental groups had its own control that could effectively influence the neuroprotection profile. group of 6-OHDA plus saline instead of nicotine.
For control of 6-OHDA vehicle, six rats were injected with similar volumes of aCFS with 0.2% ascorbic acid.
2. Materials and methods
2.4.2. Extensive lesion (10 mg6-OHDA in the SN) Animals injected with 10mg 6-OHDA received nicotine 2.1. Animals
or saline treatment according to the administration schedule (3).
Experiments were carried out using male Sprague–Daw-ley rats (230–260 g). Animals had access to food and
2.5. Neurochemical analysis water ad libitum, and were housed in groups of six in a
temperature controlled environment on a 12-h light / dark
For neurochemical analysis rats were decapitated 8 days cycle.
after 6-OHDA injection, brains rapidly removed and the left and right SN and corpus striatum (CS) dissected out 2.2. Drugs and reagents and kept at2708C. Next day tissue samples were weighed, sonicated in perchloric acid 0.1 M (200 and 1000 ml for Chemicals for HPLC analysis, artificial cerebrospinal the SN and CS, respectively) and centrifuged (15 0003g)
fluid (aCSF) and saline were purchased from Baker for 15 min at 48C. Then, samples were injected into an (Phillipsburg, PA, USA). Dopamine (hydrochloride), 3,4- HPLC system (PM-80 BAS, USA) equipped with a C-18 dihydroxyphenylacetic acid (DOPAC), 6-OHDA, (2)-nico- column (5-mm particles, 220 mm34.6 mm; BAS, USA) tine (tartrate) and L-ascorbic acid were obtained from and a electrochemical detector (LC-4C BAS) with
sulphate (0.6 mM), 4% acetonitrile and 1.6% tetrahydro-furan at pH 3.0; with a flow rate of 1.0 ml / min.
2.6. Statistical analysis
Dopamine is presented as percent of right versus left tissue levels, considering the left side (untreated) as 100%. In each experimental group comparison were made against controls as defined in Section 2.4. For turnover analysis, in each experimental group, the ratio DOPAC / DA of the ipsilateral (injected) side was compared with its control (contralateral side). Means comparison was performed
Fig. 1. Striatal dopamine assessed 8 days after the injection of 6-OHDA
using independent t-test (two-tailed). Statistical
signifi-(6 mg) expressed as percent (mean1S.D.) of right versus left CS.
cance was chosen at P,0.05.
Subcutaneous administration of nicotine 4 h before, and 20, 44 and 68 h after 6-OHDA injection counteracted significantly the dopamine decrease (6-OHDA1nicotine versus 6-OHDA1saline; *P,0,05). The same ad-ministration schedule of nicotine did not prevent the dopamine decrease
3. Results
observed with 6-OHDA when CHL was injected 30 min before. For each group, n58. Control striatal concentration of dopamine (contralateral
3.1. 6-OHDA side): saline 17 65162832; nicotine 15 81661996; CHL1saline
15 96361175; CHL1nicotine 16 85861248 (values are expressed as ng / mg of wet tissue weight).
Intranigral injections of 6 and 10mg 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-mg dose produced an effect in the dopamine concentrations higher than the 6-mg dose. Con-trol rats injected in the SN with 2 ml of aCSF (in 0.2% ascorbic acid), did not show any difference in dopamine levels between right and left CS (right, 17 58361733; left, 17 65162832 ng / mg of wet tissue weight). Dopamine turnover, expressed as the ratio DOPAC / DA, was sig-nificantly increased in the ipsilateral CS of 10mg 6-OHDA
treated rats (Fig. 4). In 6mg 6-OHDA treated DOPAC / DA Fig. 2. Striatal dopamine assessed 8 days after the injection of 6-OHDA showed a marked tendency to increase with border line (10 mg) expressed as percent (mean1S.D.) of right versus left CS. Subcutaneous administration of nicotine 4 h before, and 20, 44 and 68 h
statistical significance (P50.06).
after 6-OHDA failed to counteract significantly the dopamine decrease. For each group, n58. Control striatal concentration of dopamine
(con-3.2. 6-OHDA1Nicotine tralateral side): saline 16 29262511; nicotine 16 05461851 (values
expressed as ng / mg of wet tissue weight).
3.2.1. Partial lesion (6mg6-OHDA in the SN)
In experimental group 3, nicotine treatment (4 h before, ratio in the contralateral CS and SN (data shown in the and 20, 44 and 68 h after 6-OHDA injection), prevented respective figure legend).
significantly the 6-OHDA effects on striatal dopamine In experimental groups 1, 2 and 4, nicotine treatment tissue levels (Fig. 1), but not in the SN (Fig. 3). Nicotine only before (18 or 4 h); or only after (20, 44 and 68 h) also reverted the tendency of 6-OHDA treated to show an 6-OHDA injection, failed to have any effect on striatal increased striatal dopamine turnover (Fig. 4). Nicotine by dopamine and DOPAC / DA ratio (Figs. 5 and 6). Nicotine itself did not change dopamine levels and DOPAC / DA by itself did not change dopamine levels and DOPAC / DA
Table 1
Dopamine levels as ng / g of wet tissue weight6S.D. Ipsilateral dopamine level compared with contralateral one for each group
6-OHDA, 6mg 6-OHDA, 10mg
Contralateral Ipsilateral Contralateral Ipsilateral
Corpus striatum 15 5256530 477563.790* 16 29162.511 4586465*
Substantia nigra 10556319 4976300* 9106207 1656214*
Fig. 6. Bars represent the mean1S.D. of dopamine striatum turnover, Fig. 3. Nigral dopamine assessed 8 days after the injection of 6-OHDA
expressed as DOPAC / DA ratio. Dopamine and DOPAC levels were (6 or 10mg) expressed as percent (mean1S.D.) of right versus left SN.
assessed 8 days after injection of 6-OHDA in the right SN. Different Subcutaneous administration of nicotine 4 h before, and 20, 44 and 68 h
protocols of nicotine subcutaneous administration were applied. P1, 18 h after 6-OHDA failed to counteract significantly the dopamine decrease.
before 6-OHDA; P2, 4 h before 6-OHDA; P3, 4 h before and 20, 44 and For each group n58. Control nigral concentration of dopamine
(contrala-68 h after 6-OHDA; P4, 20, 44 and (contrala-68 h after 6-OHDA. Ipsilateral teral side): 6mg 6-OHDA saline 10556319 and nicotine 9616342; 10mg
turnover compared with contralateral one for each group, *P,0.05. For 6-OHDA saline 9106207 and nicotine 7896285 (values are expressed as
each group, n58. ng / mg of wet tissue weight).
ratio in the contralateral CS and SN (data shown in the respective figure legend).
3.2.2. Extensive lesion (10 mg6-OHDA in the SN) When a dose of 10 mg 6-OHDA was used, nicotine treatment according to the administration schedule 3, neither restored significantly striatal dopamine levels (Fig. 2) nor dopamine turnover (Fig. 4). Nicotine by itself did not change dopamine levels and DOPAC / DA ratio in the contralateral CS and SN (data shown in the respective figure legend).
Fig. 4. Bars represent the mean1S.D. of dopamine striatum turnover,
3.3. 6-OHDA1nicotine1CHL
expressed as DOPAC / DA ratio. Dopamine and DOPAC levels were assessed 8 days after injection of 6-OHDA in the right SN. Ipsilateral
When the nicotinic antagonist CHL was administered
turnover compared with contralateral one for each group, *P,0.05. For
each group, n58. before nicotine and 6mg 6-OHDA (experimental group 5),
nicotine did not revert the striatal dopamine loss induced by 6-OHDA (Fig. 1). Dopamine and DOPAC / DA ratio both in ipsilateral and contralateral side did not change after CHL (data shown in the respective figure legend).
4. 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
Fig. 5. Striatal dopamine assessed 8 days after the injection of 6-OHDA least two mechanisms of cell death: free radical production (6 mg) expressed as percent (mean1S.D.) of right versus left CS.
and / or reactivity of quinone products [13,23,30,32]. In
Different protocols of subcutaneous nicotine administration were applied.
agreement with these previous reports [3,13,39], the
in-P1, 18 h before 6-OHDA; P2, 4 h before 6-OHDA; P3, 4 h before and 20,
44 and 68 h after 6-OHDA; P4, 20,44 and 68 h after 6-OHDA. Each tranigral injection of 6-OHDA produced a significant
group compared with it respective saline, *P,0.05. For each group, n58. decrease of dopamine levels in the ipsilateral CS, a Control striatal concentration of dopamine (contralateral side): P1 saline reduction that can be directly correlated with a neuronal 17 98661450; nicotine 18 1196414; P2 saline 17 72263321; nicotine
loss in the SN pars compacta [3,8]. The 6-OHDA
treat-18 52161788; P3 saline 15 5256530; nicotine 15 81661996; P4 saline
ments also produced an increase in the DOPAC / DA ratio,
14 40461621; nicotine 12 64961486 (values are expressed as ng / mg of
reflects an increase in the activity of the remaining the nigral lesion. Although not yet proved, the desensitiza-dopaminergic terminals. This increase in dopamine turn- tion of nAChR has been postulated as the basis for the lack over has been recognized as a functional response to the of effects of continuous and / or chronic nicotine treatment loss of dopaminergic terminals after neuronal death in the [25]. As it is known, nicotine administration to rats SN, to maintain the normal levels of extracellular dopa- produces an increase in nAChR population in the CNS, mine [3,39]. which appears to be a result of nAChR receptor desensiti-The decrease of dopamine concentrations in the SN and zation [20,42]. Desensitization has also been utilized as an CS produced by 6mg 6-OHDA was utilized as the milder explanation for the protective effects of nicotine at the toxic stimulus for the assessment of nicotine protection. level of postsynaptic receptors in the SN, in view that it The 10-mg dose produced a more pronounced decrease of would decrease the activation tone of neurons, probably dopamine concentrations in the SN and the CS and was contributing to their survival after 6-OHDA lesion [25]. therefore used to test nicotine properties against a more However, desensitization cannot explain the protection toxic insult. Altogether, the utilization of two different given by nicotine, when considering that nAChR blockade doses of 6-OHDA, with marked differences in the extent of with CHL, not only failed to be protective per se, but also toxicity achieved, allowed us to assess the importance of significantly prevented the protection observed after nico-the lesion extent in nico-the nicotine protective effects. tine treatment. Accordingly, our results suggest that the Nicotine treatment prevented the striatal dopamine loss functional activation of nAChR is deemed necessary for after the 6-mg 6-OHDA injection when administered 4 h the achievement of nicotine protection.
before and 20, 44 and 68 h after the toxin. The nAChR The intracellular mechanisms by which nicotine exerts antagonist CHL, administered 30 min before this adminis- its effects are not yet fully understood. In vitro, some tration schedule, almost completely reverted the nicotine studies have shown that actions of nicotine are dependent protection after 6-OHDA. Previously, only Maggio et al. upon the entry of calcium to the cell [14,15], but not much [34] had studied the blockade of nicotine protection by the progress has been observed regarding the intracellular antagonist mecamylamine, demonstrating its dependence cascades activated by increased cytoplasmic calcium. In on the activation of nAChR. CHL is a biquaternary amine, vivo, nicotine or nicotine agonist treatments, have been classically utilized as a nicotinic antagonist at autonomic shown to produce regional increases in trophic factors, like ganglia, which produces a remarkably persistent blockade the basic fibroblast growth factor (FGF-2) [6,7]. In this of central nicotinic responses [16,17,38]. Nicotine protec- regard, it has been shown that the glial cell line-derived tion has been linked to different subtypes of nAChR, growth factor (GNDF), can protect SN neurons against mainly the homopentamerica7 and thea4b2 [29,31,43]. It 6-OHDA neurotoxicity [40,41,44]. Other trophic factors is not clear on which nAChR subtype CHL exerts its have been shown to be protective in models of ischaemia, action, though evidence for a rather broad specificity, excitotoxicity and hypoxia [2,4,24]. In agreement with the excluding the a7 subtypes, has been described [38]. lack of protection after continuous nicotine treatment Accordingly, the reversion of nicotine action in our results mentioned above, the growth factor increase obtained with cannot be safely linked to any sub-population of nAChR acute nicotine treatment is not seen after chronic continu-subtypes. ous infusion [10,27]. Moreover, the induction of FGF-2 When nicotine was injected only 18 or 4 h before or expression peaked 4 h after an injection of nicotine and only 20, 44 and 68 h after, it did not prevent the striatal returned to normal levels within 24 or 48 h [6,7]. Conse-dopamine loss. The dissimilar effects observed after di- quently, our protective administration schedule of nicotine verse nicotine treatments suggests that the schedule and would coincide with the peak production of growth factors, means of nicotine administration are crucial in the achieve- suggesting that they could ultimately be the active protec-ment of nicotine protection. In a previous study [10], tive substances.
nicotine infusion in a chronic and continuous manner, While nicotine prevented the effect of the 6-mg injection failed to protect dopamine depletion in the CS after 6- of 6-OHDA, it failed to achieve the same protection when OHDA lesion in the SN. In addition,several studies the higher dose of 6-OHDA (10mg) was injected. More-assessing nicotine protection in MPTP-induced experimen- over, the most significant recovery on dopamine levels tal parkinsonism reported that chronic continuous nicotine after partial lesions, is only seen in the CS, and not in the did not prevented the dopamine loss, and even worsened it SN. These results are indicating that during mild toxic [5,10,21,27]. In contrast, acute intermittent application insults a high percentage of the neuronal population would [27,34] appeared to protect SN neurons. Concurring with still be responsive to the protective actions of nicotine these latter reports, our results are showing that an acute stimulation, a situation that is probably not occurring when intermittent administration schedule is meaningful for higher doses of 6-OHDA are tried. During the progression restoring dopamine concentrations and turnover in an of degenerative diseases like Parkinson’s, neuronal loss experimental model of Parkinson’s disease. In addition, has a progressive development, most probably resembling and besides being intermittent, our data suggest that the the effects of a milder dose of 6-OHDA.
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