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Keywords:

  • amygdala;
  • dopamine;
  • estrogen;
  • Parkinson's disease;
  • rats

Abstract

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Animals and materials
  5. General procedure
  6. Surgery and electrical stimulation
  7. Carbon fiber microelectrodes and fast cyclic voltammetry (FCV)
  8. Radioimmunoassay (RIA)
  9. Statistical analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

In addition to the dopaminergic neurons in the nigrostriatal system, the properties of dopaminergic neurons in the mesolimbic system, such as the amygdala, are also of interest and importance because of their specific neuromodulatory effects in the pathophysiology of Parkinson's disease (PD). Using the fast cyclic voltammetry (FCV) technique, we present evidence to indicate that electrically-evoked dopamine (DA) release from the amygdala, especially the central amygdaloid nucleus (CAN), of ovariectomized (OVX) female rats was significantly enhanced with increasing doses of estradiol benzoate (EB; 30, 50 and 100 µg/kg). Impaired DA release from the amygdala of an OVX rat PD model can also be increased by EB treatment (50 µg/kg) to a level similar to that of controls. The well established neuroprotective effects of estrogen may be beneficial for reducing the dysfunction of dopaminergic neurons in mesolimbic structures of rat PD models and PD patients.

Abbreviations used
CAN

central amygdaloid nucleus

DA

dopamine

EB

estradiol benzoate

FCV

fast cyclic voltammetry

MFB

medial forebrain bundle

NSDA

nigrostriatal dopaminergic

6-OHDA

6-hydroxydopamine

OVX

ovariectomized

PD

Parkinson's disease

RIA

radioimmunoassay

SNpc

substantia nigra pars compacta

VTA

ventral tegmental area

The electrophysiological and chemical properties of the substantia nigra pars compacta (SNpc) dopaminergic neurons are of importance because of their pivotal role in the pathology of Parkinson's disease (PD), whereas dopamine (DA) in the mesolimbic structures, including the amygdala, also has important neuromodulatory effects (Shimizu and Bray 1993; Thompson and Moss 1997). Post-mortem studies have revealed severe neuropathological changes, characterized by the presence of Lewy bodies, in both the accessory cortical nucleus and the central nucleus of the amygdala in PD (Braak et al. 1994). Such pathologies may underlie the emotional deficits which accompany PD (Tessitore et al. 2002).

Gonadal steroid hormones, particularly estrogen, exert substantial modulatory effects on the central nervous system. Within the nigrostriatal dopaminergic (NSDA) system, estrogen is well known to modulate tyrosine hydroxylase activity, DA metabolism, DA release and DA receptor characteristics (Dluzen 2000). Of particular relevance to the present report are the neuroprotective properties of estrogen as demonstrated by neurodegenerative responses of the NSDA system to neurotoxins (Arvin et al. 2000; Dluzen 2000). Such findings suggest an involvement of estrogen in the characteristics of PD incidence rates, PD which is more prevalent in males (Diamond et al. 1990; Bower et al. 1999). It has been noted that the NSDA system is not the only region in which estrogen could exert its neuromodulatory effects. Our previous study showed that DA release from the central amygdaloid nucleus (CAN) is also significantly higher in female than in male rats (Xie et al. 1997). In order to evaluate the possible role of estrogen in the amygdala and its potential relationship with PD, we investigated the in vivo effects of estrogen on DA release from the CAN of ovariectomized (OVX) female rats and in a 6-hydroxydopamine (6-OHDA)-treated rat model of PD.

Animals and materials

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Animals and materials
  5. General procedure
  6. Surgery and electrical stimulation
  7. Carbon fiber microelectrodes and fast cyclic voltammetry (FCV)
  8. Radioimmunoassay (RIA)
  9. Statistical analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

Adult female Wistar rats (200–250 g), OVX bilaterally under chloral hydrate (400 mg/kg, i.p.) anesthesia, were used in these experiments. Animals were acclimatized for 14 days following surgery in a temperature-controlled, 12 : 12 h light-dark cycle environment prior to any experimentation. Food and water were freely available and experiments were conducted according to institutional ethical guidelines.

Dopamine, 6-OHDA and apomorphine were purchased from Sigma (St Louis, MO, USA). Estradiol benzoate (EB) was obtained from No. 9 Pharmaceutical Factory (Shanghai, China) and the estradiol radioimmunoassay (RIA) test kit was from Jiuding Bioengineering Co., Ltd (Tianjin, China)

General procedure

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Animals and materials
  5. General procedure
  6. Surgery and electrical stimulation
  7. Carbon fiber microelectrodes and fast cyclic voltammetry (FCV)
  8. Radioimmunoassay (RIA)
  9. Statistical analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

To evaluate the effect of EB on DA release, OVX rats were assigned to five treatment groups and treated with EB (30 µg/kg, 50 µg/kg or 100 µg/kg, s.c.), vehicle (0.4 mL/kg, sesame oil, s.c.) or no treatment for 3 days. On the fourth day, DA release from the CAN of rats was detected in vivo by fast cyclic voltammetry (FCV, see below). Following FCV detection, rat blood serum was extracted for estradiol RIA analysis.

For detecting the effect of estrogen in a PD model, experimental rats were treated with 6-OHDA, one of the neurotoxins most commonly used to model nigral degeneration experimentally (Deumens et al. 2002). 6-OHDA (5.5 µL at 3.6 µg/mL) was dissolved in 2 mg/mL ascorbate-saline (0.2% ascorbic acid and 0.9% sodium chloride) as described previously (Zhou et al. 2001) and unilaterally injected into the left medial forebrain bundle (MFB) of OVX rats. The 6-OHDA solution was infused over a 5 min period at a rate of 1 µL/min. The needle was allowed to remain in the brain for 5 min before being retracted at the end of the infusion. Fourteen days later, rotational behavior of the rats was tested following treatment with apomorphine (0.05 mg/kg s.c.). Rats that achieved a level of at least 5 rotations/min were regarded as PD model rats (Zhou et al. 2001). The confirmed PD model rats were subsequently treated with EB (50 µg/kg, s.c.), vehicle (0.4 mL/kg, sesame oil, s.c.) or no treatment for 3 days, followed by FCV measurement of DA release in vivo. DA release from OVX female rats without 6-OHDA administration were also observed.

Surgery and electrical stimulation

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Animals and materials
  5. General procedure
  6. Surgery and electrical stimulation
  7. Carbon fiber microelectrodes and fast cyclic voltammetry (FCV)
  8. Radioimmunoassay (RIA)
  9. Statistical analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

Rats were anesthetized with chloral hydrate (400 mg/kg, i.p.) and placed in a stereotaxic apparatus. Holes were drilled through the skull bone for insertion of reference, stimulating and working electrodes. The standard concentric bipolar stimulating electrode and working electrode were positioned in the ventral tegmental area (VTA; stereotaxic co-ordinates were AP: − 5.8 mm posterior to bregma; L: + 0.5 mm lateral to the sagittal sinus; V: − 6.5 mm below the surface of the cortex) and CAN (AP: − 2.5 mm, L: + 3.6 mm, V: − 7.8 mm), respectively. A miniature silver–silver chloride (Ag/AgCl) electrode, which served as the reference, was placed in a small dip in the skull contralateral to the working electrode. The stimulating electrode was lowered 0.5 mm for each 5 min, with continuous stimulation of 200 pulses, 1.5 mA intensity, 0.2 ms pulse width at 100 Hz, until DA release was detected in the CAN. The stimulation was applied to the VTA at intervals of 5 min throughout the experiment.

Carbon fiber microelectrodes and fast cyclic voltammetry (FCV)

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Animals and materials
  5. General procedure
  6. Surgery and electrical stimulation
  7. Carbon fiber microelectrodes and fast cyclic voltammetry (FCV)
  8. Radioimmunoassay (RIA)
  9. Statistical analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

Carbon fiber microelectrodes for FCV were prepared from 8 µm diameter carbon fibers (MPB electrodes, London, UK) in a 2 mm glass capillary tube pulled to a taper. The carbon fiber protruding beyond the glass insulation was cut to a length of 20–60 µm under micromanipulator control. Electrode calibration was performed in the recording chamber after the experiment. The minimum detection limit for DA was 30–50 nm with the electrodes used in these experiments.

Voltammetric measurements were made with a Millar Voltammetric Analyzer (P.D. Systems, West Moseley, UK) as described previously (Stamford 1990). The input voltage to the working electrode consisted of 1.5 cycles of triangular waveform (− 1.0∼ + 1.4 V vs. Ag/AgCl) sweeping initially in the negative direction. DA, which showed an oxidation peak at + 600 mV, was monitored with sample-and-hold circuits for each working electrode. The outputs from the sample-and-hold circuits were displayed on a y-tchart recorder of a computer and an oscilloscope screen through a specific CED 1401 interface (Cambridge Electronic Design Ltd, Cambridge, UK). Data were stored as files using CED software (Signal Averager and Chart; P.D. Systems).

Radioimmunoassay (RIA)

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Animals and materials
  5. General procedure
  6. Surgery and electrical stimulation
  7. Carbon fiber microelectrodes and fast cyclic voltammetry (FCV)
  8. Radioimmunoassay (RIA)
  9. Statistical analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

Blood samples were collected from the rats and centrifuged at 1000 gfor 5 min. The serum from the supernatant fluid was removed for assay of estradiol levels. Serum estradiol was quantified by RIA using a commercially available estradiol RIA kit (Jiuding Bioengineering Co., Ltd). The lowest detectable level of estradiol was 1 pg/mL, with control experiments confirming the linearity of the assay.

Statistical analysis

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Animals and materials
  5. General procedure
  6. Surgery and electrical stimulation
  7. Carbon fiber microelectrodes and fast cyclic voltammetry (FCV)
  8. Radioimmunoassay (RIA)
  9. Statistical analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

All data are expressed as mean ± SEM. The sample number, n, represents the number of rats tested. Statistical levels of significance (p < 0.05) were tested by one-way analysis of variance followed by Dunnett's post hoc comparison (for multiple comparisons) and Student's t-test (comparison between 2 groups), using GraphPad Prism Software v3.01 (Graphpad Software, San Diego CA, USA).

Results

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Animals and materials
  5. General procedure
  6. Surgery and electrical stimulation
  7. Carbon fiber microelectrodes and fast cyclic voltammetry (FCV)
  8. Radioimmunoassay (RIA)
  9. Statistical analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

DA release in vivo was recorded with carbon fiber electrodes in the CAN of rats using FCV. The DA concentrations shown represent the maximally-evoked DA response. DA release from the OVX female rats (n = 7–8) enhanced with increasing doses of EB, in particular the 50 (p < 0.05) and 100 µg/kg doses (p < 0.001, Fig. 1), was significantly increased compared with vehicle controls. RIA results indicated that serum estradiol concentrations increased dose-dependently following EB treatment, with the 50 (p < 0.05) and 100 µg/kg doses (p < 0.001) resulting in significant increases over vehicle controls (Fig. 2). No statistical difference in DA release and serum estradiol concentration was observed between the control rats and vehicle-treated rats.

image

Figure 1. DA release from CAN of OVX rats treated with oil or EB at the indicated dosages. Values represent the mean ± SEM (µm/L); n = 7–8. *p < 0.05 and **p < 0.001 versus vehicle-treated group, Dunnett's test after one-way anova.

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image

Figure 2. Serum estradiol concentration following several doses of EB treatment. Values represent the mean ± SEM (pg/mL); n = 8. *p < 0.05, **p < 0.001 versus vehicle-treated group, Dunnett's test after one-way anova.

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The lowest effective dose for enhancing DA release (50 µg/kg) was subsequently chosen to be used in the PD model rats. DA release from the CAN of the lesioned left side of PD rats was decreased significantly compared with the non-lesioned right side (p < 0.05, Fig. 3), whereas there was no statistical difference between the two sides in control non-PD rats. Following EB treatment, the impaired DA release from the lesioned left side increased to a level similar to that from the left side of non-PD control rats (Fig. 3), and DA release from the CAN of the non-lesioned right side of EB-treated PD rats was nearly twofold more than that from the non-PD control rats (p < 0.001, Fig. 3).

image

Figure 3. DA release from CAN of OVX PD model rats and OVX non-PD rats. Values represent the mean ± SEM (µm/L); n = 8. *p < 0.001 versus corresponding side in non-PD controls, Dunnett's test after one-way anova; #p < 0.05 and ##p < 0.001 versus contralateral side, following Student's t-test.

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Discussion

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Animals and materials
  5. General procedure
  6. Surgery and electrical stimulation
  7. Carbon fiber microelectrodes and fast cyclic voltammetry (FCV)
  8. Radioimmunoassay (RIA)
  9. Statistical analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

The amygdala, a central mesolimbic structure, functions mainly by regulating different aspects of integrated emotional responses and social behavior (Amaral et al. 2003). This site has been reported to receive dopaminergic inputs from the VTA and SNpc (Chinaglia et al. 1992; Kalivas 1993). Our previous studies have indicated that maximum DA release from the CAN evoked by electrical stimulation of VTA in female rats was significantly higher than that in male rats (Xie et al. 1997), suggesting a possible role for estrogen in regulating amygdaloid function. The present study provides more direct in vivo evidence for the neuromodulatory effects of estrogen on DA release from CAN. In order to minimize the influence of endogenous estrogen on DA release, all experimental rats were OVX. Consistent with the effects of estrogen on DA release and re-uptake in the nucleus accumbens (Shimizu and Bray 1993; Thompson and Moss 1997), the present results demonstrate that DA release in vivo from the CAN of OVX rats was increased by subcutaneous EB treatment (Fig. 1). Moreover, our results show a dose-dependent effect of estrogen on DA release (Fig. 2). The mechanisms by which estrogen exerts its promotion of DA release may be related to direct actions on DA terminals which can down-regulate DA autoreceptors (Bazzett and Becker 1994; Schmitz et al. 2002). This leads to a release from the inhibitory action of these receptors, enhanced stimulated DA release and a decrease in the affinity of the DA transporter.

The hallmark of PD is dopaminergic neuronal loss in the SNpc, leading to denervation of the striatum and the cardinal signs and symptoms. There is also considerable evidence for dysfunction of the mesolimbic dopaminergic system in PD, since the orbitofrontal and amygdalar presynaptic dopaminergic functions are also altered in early PD (Bazzett and Becker 1994; Ouchi et al. 1999). In the present study, our results showed that DA release from the CAN of PD rats was seriously affected, similar to the results of other studies which showed morphological changes in the amygdala of PD patients (Braak et al. 1994; Braak and Braak 2000). Interestingly, the impaired DA release from the lesioned left side was restored to a level similar to that in non-PD control rats by EB treatment (Fig. 3), and EB treatment can also restore behavioral changes in PD model rats (Liu and Xie 2002). However, it is not clear whether the recovery of DA release in PD rats was due to the effect of estrogen in repairing damaged amygdaloid tissue, or simply enhancing DA turnover rate in residual intact tissue. It should be noted that DA release from the CAN of the non-lesioned right side of EB-treated PD rats was nearly twofold more than that in non-PD rats (Fig. 3). Such an effect could be due to an increased sensitivity and/or to compensation after contralateral injury (Blanchard et al. 1996). This latter possibility is supported by the findings that amygdaloid DA release from the non-lesioned right side of PD rats appeared slightly higher, although it was not statistically significantly different from that of the right side of non-PD rats (Fig. 3).

A sexually dimorphic (female dominant) resistance to 6-OHDA-induced lesions of the NSDA pathway has been reported (Murray et al. 2003). This sexual dimorphism appears to be due primarily to estrogen. It is well known that estrogen modulates NSDA activities, including striatal tyrosine hydroxylase activity, DA metabolism, DA release, striatal DA receptor characteristics and behavior (Dluzen 2000), and produces neuroprotective effects against the decrease in striatal DA depletion induced by 6-OHDA (Dluzen 1997; Murray et al. 2003). However, the neuroprotective activity of estrogen on the dopaminergic system, especially the NSDA system, has not been accepted universally. Long-term estrogen replacement treatment of OVX rats did not protect nigral dopaminergic neurons from an insult with 6-OHDA (Ferraz et al. 2003), and indicated that the potential neuroprotective effect of estrogen may occur only under special circumstances. A number of differences in nigrostriatal DA response to estrogen have been reported as a function of the time/duration of estrogen exposure (Hruska 1986; Fernandez-Ruiz et al. 1989), the differential site of 6-OHDA administered or the dose of 6-OHDA used (Ferraz et al. 2003). It is worth noting that a retrospective chart review showed that estrogen might be beneficial in early PD, at least prior to the initiation of L-dopa (Saunders-Pullman et al. 1999). In our present study, we chose the lowest efficient dose of EB for detecting the possible effects of estrogen on the amygdala of PD model rats. We consider that a physiological dose and short-term usage of estrogen may exert neuroprotective effects in the central nervous system, particularly in the amygdala (Liu and Xie 2001).

As shown in this study, estrogen has an important neuromodulatory effect on the amygdala. The observed enhancing effect of estrogen on DA release from CAN of PD rats may be beneficial for reducing symptoms in PD, as the amygdala has an impact on neuropyschological and emotional deficits in PD (Ouchi et al. 1999; Tessitore et al. 2002) and DA repletion appeared to partially restore the response of the amygdala in PD patients (Ouchi et al. 1999; Tessitore et al. 2002). However, estrogen replacement therapy is complex and contradictory, and is not a viable option for all patients because of potential side-effects (Reid 2002). We are currently developing phytoestrogens or estrogen-like chemicals (Liu et al. 2003) that may retain the favorable action but minimize the adverse side-effects of estrogens. Further study will also explore the mechanisms underlying the neuroprotective effects of estrogen by observing the activation of classical estrogen receptor-mediated pathways.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Animals and materials
  5. General procedure
  6. Surgery and electrical stimulation
  7. Carbon fiber microelectrodes and fast cyclic voltammetry (FCV)
  8. Radioimmunoassay (RIA)
  9. Statistical analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References

This study was supported by grants from the National Foundation of Natural Science of China (No. 30370498) and the Natural Science Foundation of Shandong Province of China (L2000C01).

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  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Animals and materials
  5. General procedure
  6. Surgery and electrical stimulation
  7. Carbon fiber microelectrodes and fast cyclic voltammetry (FCV)
  8. Radioimmunoassay (RIA)
  9. Statistical analysis
  10. Results
  11. Discussion
  12. Acknowledgements
  13. References
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