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Neorotoxicity Research, 2002 VoL.4 (2). pp. 133-139
Presynaptic Involvement in the Nicotine Prevention of the Dopamine Loss Provoked by 6-OHDA Administration in the Substantia Nigra J. ANDRI~S ABIN-CARRIQUIRY, RONALD MCGREGOR-ARMAS, GUSTAVO COSTA, JESSIKA URBANAVICIUS and FEDERICO DAJAS* Instituto de Investigaciones Biol6gicasClemente Estable, Department of Neurochemistry, Avda Italia 3318, 11600, Montevideo, Uruguay (Received 1 May 2001; Revised 22 May 2001; In final form 22 May 2001)
While nicotine, through stimulation of a specific sub population of nicotinic acetylcholine receptors (nAChR) appears to protect cells in culture against a variety of insults, studies in vivo show controversial results. In a previous paper we have shown that in the 6-hydroxydopamine (6-OHDA) model of experimental parkinsonism, an intermittent administration schedule of nicotine (4 h before and 20, 44 and 68 h after 6-OHDA) was able to prevent the decrease of dopamine (DA) concentration in the corpus striatum (CS) provoked by the partial lesion of the substantia nigra (50% neuronal death after 6 lag of 6OHDA). To further analyze the mechanisms of nicotine effects, we performed a microdialysis study of striatal extracellular DA concentrations utilizing the nicotine administration schedule that was able to prevent DA decrease. Basal extracellular DA concentrations in the CS were maintained after 6-OHDA and were not modified by nicotine. Basal DOPAC levels were decreased after the neurotoxic administration. The response of extracellular DA to potassium chloride (KCI) challenge was significantly lower after 6-OHDA than in control animals. Nicotine significantly reversed this decrease. As previous studies have shown, the striatal DA terminals surviving the 6-OHDA toxic effect are able to keep extracellular DA concentrations close to normal, likely increasing DA synthesis. Nevertheless, the application of a releasing factor such as KC1 shows the fragility of this equilibrium, exposing a decrease in the terminal number. Nicotine, through a further activation of tyrosine hydroxylase and DA synthesis or by prolonging the life of DA terminals, could reverse the effect of 6-OHDA. Keywords: Corpus striatum; Microdialysis; Nicotine; Substantia nigra; Extracellular dopamine; Parkinson's disease; 6-Hydroxydopamine
INTRODUCTION Epidemiological evidence shows that smokers are less p r o n e to develop Parkinson's Disease (PD) than nonsmokers (Court et al., 1998; Nefzger et al., 1968). Several experimental studies, confirm this fact, showing that nicotine prevents cell death in a variety of cell cultures (primary cortical, striatum, PC12, etc.), against cellular aggressions such as oxidative and excitatory stimuli (Akaike et al., 1994; Carlson et al., 1998; Garrido et al., 2000; Kihara et al., 1998; Li et al., 1999; Marin et al., 1994; Rowell and Li, 1997). These studies also p r o v i d e d evidence for the nicotine effects being mediated b y acetylcholine nicotine receptors (nAChR), mainly the ot7and ot4~2 subtypes (Bloom and Kupfer, 1994; Dajas-Bailador et al., 2000; Kihara et al., 1998; Li et al., 1999; S h i m o h a m a et al., 1998). Experimental studies in vivo are controversial. Nicotine appears to p r e v e n t striatal d o p a m i n e loss p r o v o k e d b y hemitransection (Janson et al., 1988; 1989), 6 - h y d r o x y d o p a m i n e (6-OHDA) or 1-methyl4phenyl-l,2,3,6-tetrahydropyridine (MPTP) while it did not show those effects w h e n administered in a chronic w a y in an MPTP experimental model. In others studies, nicotine w o r s e n e d the effects of MPTP (Behmand and Harik, 1992; Blum et al., 1996; Ferger et al., 1998; Fung et al., 1991; Janson et al., 1992; Maggio et aL, 1998). In order to contribute to the u n d e r s t a n d i n g of these contradictions, w e started an experimental approach in vivo in rats developing experimental
*Corresponding author. Tel.: +598-2-4872603.Fax: +598-2-4872603. E-mail:
[email protected] ISSN1029-8428print/ISSN1476-3524online9 2002Taylor&FrancisLtd DOI:10.1080/10298420290015863
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parkinsonism after 6-OHDA injection in the substantia nigra (SN). Utilizing a smaller dose than in classical descriptions of the model and assessing the dopamine (DA) levels in the corpus striatum (CS) 8 days after the injection of the toxin, we were able to show a prevention of the DA loss provoked by nigral 6-OHDA injection in the CS (Costa et al., 2001). The increased turnover regularly observed in the CS after 6-OHDA, was stabilized after nicotine treatment. The pre- or postsynaptic nature of the nicotine effects is among the several unanswered questions generated by these results. The assessment of the extracellular levels of DA in the CS after 6-OHDA, as studied by several research groups (Bjelke et al., 1994; Castafieda et al., 1990a, b; Emmi et al., 1997; Espino et al., 1995; Herrera-Marschitz et al., 1994; Hoffman et al., 1997; Miller and Abercrombie, 1999; Parson et al., 1991; Robinson et al., 1990; 1994; TranNguyen et al., 1996) has allowed the predominantly presynaptic domain of the compensatory mechanism elicited in response to the nigral lesion to be defined. A microdialysis study of the extracellular DA in the CS after the restorative nicotine treatment appeared, therefore, meaningful to undertake. This paper reports the results obtained with this approach.
MATERIAL AND METHODS
Animals Experiments were carried out using male SpragueDawley 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 microdialysis and HPLC analysis, artificial cerebrospinal fluid (aCSF containing 3.65 g NaC1; 93.18mg KC1; 120rag MgC12 and 92.6mg CaC12) and saline were purchased from Baker (Phillipsburg, PA, USA). Dopamine hydrochloride, 3,4-dihydroxyphenylacetic acid (DOPAC), 6-OHDA hydrochloride, ( - ) nicotine hydrogen tartrate salt, Lascorbic acid, urethane and potassium chloride (KC1) were obtained from Sigma (St. Louis, MO, USA). The 6-OHDA solution for intranigral injection was prepared by dissolving it in aCSF containing 0.2% ascorbic acid. Nicotine was dissolved in saline.
Experimental Protocol Two groups of rats (n=8) injected with 6-OHDA (6 ~g) in the right SN, received l m g / k g nicotine subcutaneously, 4 h before and 20, 44 and 68 h after 6OHDA administration. One group was used to
measure DA and DOPAC tissue levels and the other group was used for the microdialysis experiments. Each of the experimental groups had its own control group receiving 6-OHDA plus saline only as vehicle. As a control group for the 6-OHDA vehicle, six rats were injected with equivalent volumes of aCSF containing 0.2% ascorbic acid.
Intranigral Injection of 6-OHDA Animals were anesthetized with halothane (Fluothane, Zeneca) and placed in a D. Kopf stereotaxic frame. Through a skull hole, the needle (0.022 mm o.d., 0.013 mm i.d.) of a Hamilton syringe (5 ~l), attached to a microinjection unit (D. Kopf), was lowered to the SN. Coordinates (H: -4.8, L: -2.2, V: -7.2) were determined from bregma, according to the atlas of Paxinos and Watson. (1986). A total of 2.0 ~l of 6-OHDA solution (3 ~g/~l) was injected over a period of 2 min and the needle was slowly withdrawn, allowing the drug to diffuse for another minute. Body temperature was maintained at 37~ using a temperature control system.
Microdialysis Technique Rats were anesthetized with urethane (Sigma) 3.0 g / k g i.p. and placed in the D. Kopf stereotaxic frame for probe implantation in the CS (coordinates from bregma, H" +0.6; L: - 2.9; V: - 7.2). Microdialysis probes (dialyzing length 4 mm; BAS, USA) were implanted and continuously perfused with aCSE A constant flow rate of 2 ~l/min was maintained using a microdialysis p u m p (CMA/100 micropump, Stockholm, Sweden). Perfusion m e d i u m was changed using a syringe switch selector (CMA/100). Sample collection time was 30min (60 ~l) using a microfraction collector (CMA/140). Fractions were injected into an HPLC for subsequent electrochemical detection. In all experiments, the first two samples were discarded and the following four considered as basal. KC1 was perfused in tube 7 as a 30 min pulse and the two fractions post KC1 were collected.
Neurochemical Analysis For neurochemical analysis of tissue levels, rats were decapitated 8days after 6-OHDA injection, brains rapidly removed and the left and right SN and CS dissected out and kept at - 70~ The following day, tissue samples were weighed, sonicated in perchloric acid 0.1M (200 and 1000~1 for the SN and CS, respectively) and centrifuged (15,000 g) for 15 min at 4~ Then, samples were injected into an HPLC system (PM-80 BAS, USA) equipped with a C-18 column (5~m particles, 220mm • 4.6mm; BAS, USA) and electrochemical detector (LC-4C BAS)
NICOTINEBLOCKSDA LOSSBY 6-OHDA ==Saline 9 Nicotine
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FIG. 1 Effectof nicotine treatment on striatal and nigral tissue levels of DA. Striatal and nigral DAwas assessed 8 days after the injection of 6-OHDA(6 I~g)and is expressed as percent (mean and SD) of right versus left wet tissue weight levels. Subcutaneouspretreatment with nicotine 4h before, and 20, 44 and 68h after 6-OHDAinjection, counteracted the reduction in DA in the CS, but not in the SiN.For each group n=8. *p < 0.05.
with oxidation potential at +0.75 V (glassy w o r k i n g c a r b o n electrode v e r s u s an A g / A g C 1 reference electrode). The mobile phase was c o m p o s e d of citric acid (0.15M), s o d i u m octyl sulfate (0.6mM), 4% acetonitrile and 1.6% t e t r a h y d r o f u r a n at p H 3.0; with a flow rate of 1.0 m l / m i n . For microdialysis analysis, probes were implanted in the CS, 8 d a y s after 6 - O H D A administration. Samples were injected directly in the HPLC system,
==CONTROL 9
using the same column, electrochemical conditions and mobile phase.
Statistical A n a l y s i s Tissue Levels D A is presented as percent of right versus left tissue levels, considering the left side (untreated) as 100%.
116.OHQA O6-OHDA+NIC KCl
450 400 35O
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~ 200 150 100 50
0 60 - 90
90-120
120-150
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180-210
210- 240
240-270
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FIG.2 Effectof different treatments on extracellular DA levels in the CS. Thne course of changes in the extracellular DA level of dialysis of the experimental groups. The mark shows the KC1stimulus. Bars represent the mean and SEM of 5-8 animals. *p < 0.05repeated measure ANOVA,post hoc Tukey-Kramer test.
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J.A. ABIN-CARRIQUIRYet al. [] Saline 9 Nicotine .E E
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FIG.3 Effectof different treatments on basal DA levelsin the CS. Bars represent basal DAvalues of each experimentalgroup (mean and SD, n--5-8 animals). No significantdifferencewas found between nicotine- and saline-treated groups (t-test).
Comparisons were m a d e to the control group. Means comparison was performed using Student's t-test (unpaired). Differences were considered significant at p < 0.05 (one tail). Microdialysis
p e r f o r m e d on logarithmic t r a n s f o r m e d data. Differences were considered significant at p < 0.05 (one tail).
RESULTS
DA and DOPAC dialysates concentrations are expressed as nM (uncorrected for recovery). The analysis of the response to KCI stimulus was performed using one-way repeated measures analysis of variance (ANOVA) followed by TukeyKramer Multiple Comparisons test for each experi mental group. Student's t-test (unpaired) was used for m e a n comparison w h e n necessary. To homo genize variance in KC] stimulus, analysis was
Intranigral injection of 6 tLg 6-OHDA, produced a significant decrease of dopamine in tissue levels in the right CS and SN (ipsilateral, treated side) w h e n compared with the left, non-treated one (contralateral) (data not shown). Control rats injected in the SN with 2 I~l of aCSF (in 0.2% ascorbic acid), did not show any difference in DA levels between right and left CS. (data not shown).
" S a l i n e ==Nicotine
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FIG. 4 Effectof different treatments on basal extracellularDOPAClevels in the CS. Bars represent DOPACvalues of each experimental group (mean and SEM of 5-8 animals). *: Nicotine treatment statisticallydifferent from 6-OHDA;~ 6-OHDAstatisticallydifferent from control.
NICOTINE BLOCKS DA LOSS BY 6-OHDA
137
:"Saline IINicotine 5oo
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FIG. 5 Effect of different treatments in the response of DA levels to KCI stimulation in the CS. Bars represent the mean and SEM of 5 - 8 animals of the extracellular DA level in response to KC1 stimulation, for each experimental group. *: Nicotine treatment statistically different from 6-OHDA; ~ 6-OHDA statistically different from control.
When nicotine was administered 4 h before, and 20, 44, and 68h after 6-OHDA injection, it prevented significantly the 6-OHDA effects on striatal DA tissue levels, but not in the SN (Fig. 1). However, nicotine by itself did not change DA tissue levels in the contralateral CS and SN (data not shown). The values of DA in dialysates from the CS are similar to those obtained by previous studies in basal values as well as after KC1 challenge (Fig. 2). The KC1 stimuli provoked an average 49-fold increase of DA extracellular levels in the control groups. Extracellular DA basal levels after 6-OHDA treatment were not different to those of saline treated animals. ExtraceUular DA basal levels showed a non significant tendency to increase after nicotine treatment when compared with saline treated animals. When intraceUular DA basal levels of the 6-OHDA group were compared with those of 6-OHDA+nicotine, a non significant tendency to increase was observed (Fig. 3) When DOPAC basal levels were analyzed, animals treated with 6-OHDA showed a significant decrease in comparison to the saline control group. This decrease was significantly prevented after nicotine administration. In contrast, nicotine alone did not significantly modify the DOPAC basal levels in the control groups (Fig. 4). After a KC1 (100mM) stimulus there was a significant decrease in the level of extracellular DA obtained in the 6-OHDA treated group, compared to the saline one. This was significantly prevented after subcutaneous nicotine administration. Nicotine alone did notaffect the response to the KC1 stimulus compared with the saline group (Fig. 5).
DISCUSSION As discussed above, results of several studies have shown that nicotine, through nAChR, protects cells in culture against a variety of insults (Bloom and Kupfer, 1994; Carlson et al., 1998; Dajas-Bailador et al., 2000; Kihara et al., 1998; Li et al., 1999; Shimohama et al., 1998). Nevertheless, studies analyzing the problem in vivo are controversial and, thus, in an MPTP model of experimental parkinsonism, nicotine can protect, worsen or have no effects at all on the lesion mainly when expressed as DA/DOPAC levels (Behmand and Harik, 1992; Ferger et al., 1998; Fung et al., 1991). In a previous paper, utilizing the 6OHDA experimental model of PD, we have shown that the effects of nicotine are dependent on the administration schedule and on the extent of the nigral lesion. Administered in an intermittent manner before and after the toxic insult to the SN, nicotine prevents the decrease in DA levels observed in the striatal terminal region. Concomitantly, nicotine also re establishes the increased DA turnover that is observed in the terminals after 6-OHDA lesion (Costa et al., 2001). The tissue assessment of DA levels left unanswered what the nature of the mechanisms involved in the changes of the dopaminergic system is. In an attempt to clarify this matter we undertook the present study. The results confirmed previous studies showing that striatal extracellular DA levels are maintained in spite of the death of nigral neurons (more than 50% in our case). This fact would indicate that regulatory mechanisms are able to keep dopaminergic information flow active (Castafieda et al., 1990a, b; Emmi et al., 1997; Robinson et al., 1990;
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1994). The description of tyrosine hydroxylase (TH) activation after a 6-OHDA caused lesion of the dopaminergic pathways (Melamed et al., 1982; Hefti et al., 1985) could be an explanation of the maintained extracellular DA levels. On the other hand, DOPAC extracellular levels s h o w e d a significant decrease after the neurotoxin administration. DOPAC, a p r o d u c t of DA metabolism, has b e e n related to the activity of the dopaminergic p a t h w a y (Cooper et aI., 1996). In this sense, the decrease observed could be an indication of the diminished n u m b e r of terminals in the striatal region as a consequence of the nigral neuronal death. Additionally, the possibility of a d o w n regulation of the DA degradative processes as part of the overall adaptation of the system to keep DA concentrations normal, should not be discarded. The clear decrease in the DA released after potassium stimulus in 6-OHDA treated animals c o m p a r e d with controls w o u l d be evidence for the same p h e n o m e n a . It is agreed that KC1 challenge, a massive presynaptic releasing factor, reflects the functionality of the nerve terminals (Opacka-Juffry et al., 1995). The terminals remaining after 6-OHDA lesion w o u l d be unable to produce a similar response c o m p a r e d to the control group. In the animals treated with nicotine, the extracellular DA basal levels w e r e not statistically different from the saline or 6-OHDA groups. The complex and p o o r l y u n d e r s t o o d regulation of the DA paracrine transmission in the CS (Bjelke et aI., 1994; Deutch and Roth., 1999) could be responsible for the lack of nicotine effects in this DA domain. W h e n the results of KC1 stimulus after nicotine treatment were analyzed, a significant increase in DA and DOPAC basal levels could be observed. One plausible explanation w o u l d be that nicotine further increases the activity of T H (Smith et al., 1991), p r o d u c i n g an increment in the response of the d o p a m i n e r g i c terminals. The a u g m e n t e d DA response after potassium chloride stimulus could also be explained b y a maintenance in the n u m b e r of responsive terminals. N i c o t i n e e f f e c t s a p p e a r to be m e d i a t e d b y presynaptic DA nAChR (Costa et al., 2001; Marshall et al., 1997) involving an i n d e p e n d e n t calcium d o m a i n as has been demonstrated for nicotine protection after glutamate application to hippocampal cells in culture (Dajas-Bailador et al., 2000). Up to now, in our in vivo model, the involvement of these mechanisms are largely speculative: among other possibilities, a n A C h R - m e d i a t e d c a l c i u m ion entrance to dopaminergic terminals could activate TH. D o w n s t r e a m p h o s p h o r y l a t i o n m e c h a n i s m s could also be related to activation of growth factors that w o u l d contribute to terminal survival, as s h o w n for cells in culture studies (Rosenblad et al., 1999; 2000; Yurek and Fletcher-Turner, 1999). At present,
we are analyzing T H activity in CS after 6-OHDA and nicotine administration to confirm this h y p o t h esis. Further chronic studies are being u n d e r t a k e n to explore the neuronal protective effects of the changes in DA metabolism observed in the CS after nicotine. It is v e r y likely that the important presynaptic regulation of striatal dopaminergic terminals b y cholinergic aspiny neurons could explain the effects of nicotine treatment in our model. Activation of nAChR could be one of the several factors that maintain DA functionality after a SN lesion.
Acknowledgements This p a p e r was partially s u p p o r t e d b y F o n d o Clemente Estable (CONICYT-BID, No. 2032) and IPICS (International P r o g r a m for the Chemical Science, Uppsala University, Sweden). The authors wish to thank MSc Cecilia Scorza for valuable suggestions.
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