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© 2004 The American Society for Nutritional Sciences J. Nutr. 134:3350-3354, December 2004

Nutritional Neurosciences

Vitamin B-6 Deficiency Prolongs the Time Course of Evoked Dopamine Release from Rat Striatum1,2

Fu-In Tang and Ien-Lan Wei3

School of Nursing, National Yang-Ming University, Taipei 112, Taiwan

3To whom correspondence should be addressed. E-mail: weinur{at}ym.edu.tw.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Vitamin B-6–deficient animals exhibit motor abnormalities. To investigate the possible physiologic alterations in the dopaminergic nervous system in vitamin B-6 deficiency, dopamine release in the striatum of vitamin B-6–deficient rats was determined using in vivo electrochemistry. Male Sprague-Dawley rats, 3 wk old, weighing 50–60 g, were randomly assigned to a control (7 mg pyridoxine HCl/kg diet), vitamin B-6–deficient (0 mg pyridoxine HCl/kg diet), or pair-fed (7 mg pyridoxine HCl/kg diet) group. After 8 wk of dietary treatment, plasma concentrations of pyridoxal 5'-phosphate as well as the striatal pyridoxal 5'-phosphate and pyridoxamine 5'-phosphate were significantly lower in the vitamin B-6–deficient group than in the control and pair-fed groups. The dopamine concentrations of the striatum and the magnitude of the dopamine release after local application of KCl did not differ among the groups. However, the time required for KCl-evoked dopamine release to reach its peak level was significantly longer for the vitamin B-6–deficient rats than for controls. In addition, the decay time from the peak to one-half of the KCl-evoked dopamine release was also significantly prolonged in vitamin B-6–deficient rats compared with the control group. The results indicate that the cellular content of dopamine does not reflect the functional state of dopaminergic neurons in vitamin B-6 deficiency. The time course for release of dopamine and decay of the released dopamine is prolonged by vitamin B-6 deficiency, which might contribute to the motor abnormalities of the deficient rats.

KEY WORDS: • vitamin B-6 • striatum • dopamine • voltammetry • rats

The 6 biologically active forms of vitamin B-6 are pyridoxine (PN),4 pyridoxamine (PM), pyridoxal (PL), pyridoxine-5'-phosphate (PNP), pyridoxamine-5'-phosphate (PMP) and pyridoxal-5'-phosphate (PLP). PLP acts as a coenzyme and participates in many biochemical processes (1). Vitamin B-6 deficiency affects the nervous system. In humans, convulsive seizure (2–4), abnormal electroencephalograph (5), and severe neuropathy (6) were reported. In animals, slow movement, ataxia, and muscle weakness were described (7). Significant changes in the width and angle of steps were also detected (8–10). Although the involvement of vitamin B-6 in the formation of neurotransmitters such as {gamma}-aminobutyric acid (GABA) and catecholamines (11) might account for some of the observed neurological abnormalities, the possible physiologic disturbances in the nervous system during vitamin B-6 deficiency should also be considered.

The basal ganglia consist of 4 nuclei, which are involved in the control of movement. The striatum is one of the principal nuclei of the basal ganglia (12). Dopamine (DA) in the striatum is synthesized in the varicosities of nerve terminals derived from the DA-containing neurons of the substantia nigra pars compacta (11). With the arrival of an action potential, the DA stored in the vesicles is released by exocytosis to the synapse (11). The brain DA content of adult rats was reported not to be influenced by vitamin B-6 deficiency (13,14). The tissue content of neurotransmitters represents the intracellular resources (15,16) and may not reflect the changes in neuronal response (17).

The extracellular levels of DA, which are regulated directly by DA release and clearance, modulate the motor activities. The high-speed in vivo voltammetric technique has been widely used to measure extracellular DA concentrations (18–21). This technique allows for a high degree of temporal and spatial resolution (22), thus permitting the measurement of DA release over seconds and in limited areas (19,23). The present study employed this technique to investigate the effect of vitamin B-6 deficiency on DA release in the striatum. Concentrations of striatal DA, DA metabolites [3,4-dihydroxyphenylacetic acid, (DOPAC) and homovanillic acid (HVA)], and vitamin B-6 vitamers were also measured.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Animal treatment. Male Sprague-Dawley rats (n = 60; Laboratory Animal Center of National Yang-Ming University), 3 wk old and weighing ~50–60 g, were randomly assigned to a control, vitamin B-6–deficient, or pair-fed group. Rats in the control group were fed the AIN-93G diet containing 7 mg of PN HCl/kg diet (ICN Biochemicals) (24). Vitamin B-6–deficient rats were fed the AIN-93G diet without PN HCl (ICN Biochemicals). Because vitamin B-6–deficient rats usually consume less food, a pair-fed group was included in the study to eliminate the effect of food reduction. The pair-fed rats consumed the same diet as control rats, but the amount of food was restricted to the mean amount that the deficient group consumed on the previous day. The food intake of all 3 groups was recorded daily. Spilled food was collected, weighed, and its weight subtracted from the gross intake data. Body weight was measured weekly. Rats were housed individually in a room maintained at a constant temperature (23 ± 1°C) under a 12-h light:dark cycle. Animal care conformed to the Guidelines of the Animal Use and Care committee of National Yang-Ming University, Taiwan.

After 8 wk of dietary treatment, 10 rats from each group were used for an in vivo voltammetric study. Another 10 rats in each group were killed by decapitation after overnight food deprivation. Blood samples were collected into tubes containing EDTA. The brain was quickly removed and put on dry ice. Tissue samples of the striatum, obtained by micropuncture (25), were weighed and stored at –80°C for later determination of vitamin B-6 vitamers, dopamine, and its metabolites. The blood samples were centrifuged at 1500 x g for 10 min at 4°C. Plasma was stored at –30°C for later determination of PLP.

    In vivo voltammetry. The in vivo voltammetric study followed the procedure described by Wang et al. (21). In brief, each rat was anesthetized with urethane (1.25 g/kg, i.p.), and placed in a stereotaxic frame with an isothermal pad to maintain the rat’s temperature at 37°C. Part of the skull and dura, which extended approximately from 1 to 4 mm lateral to the midline and from 1 mm posterior to 4 mm anterior to the bregma, was removed bilaterally. At a distance from this site, another small hole was drilled for the miniature Ag/AgCl reference electrode, which was inserted into the brain and cemented with dental acrylic.

In vivo voltametric measurements of extracellular DA concentrations were performed with the IVEC-10 microcomputer-controlled apparatus (Medical Systems). Nafion-coated (5% solution, Aldrich Chemical), carbon-fiber working electrodes were used for the recordings (19). An oxidation potential (+0.55 V for 50 ms) relative to the Ag/AgCl reference electrode was applied at a rate of 10 Hz.

The release of DA was measured by changes in extracellular DA concentrations after the microinjection of KCl (70 mmol/L) into the striatal parenchyma (26). Using sticky wax, the working electrode and the single barrel micropipette (for KCl) were mounted together and the tips were separated by ~150 µm. The electrode/pipette assembly was lowered into the striatum (1.0 mm anterior and 2.5–3.0 mm lateral to the bregma and 4.5–7.0 mm below the cortical surface). The KCl was applied by pressure ejection using a pneumatic pump (PPM-2, Medical Systems). The ejected volume was determined by recording the changes in the fluid meniscus in the pipette monitored by a dissection microscope before and after the ejection.

    Plasma PLP and striatal tissue vitamin B-6 vitamers analyses. Concentrations of plasma PLP and tissue vitamin B-6 vitamers were determined by HPLC. The chromatographic conditions for measuring tissue vitamin B-6 vitamers were described previously (27,28). A Waters (Milford) 10-µm particle size, C18 µBondapak (3.9 x 300 mm) reverse-phase analytic column was used. The plasma PLP concentrations were measured by the method of Bates et al. (29). A Waters 5-µm Symmetry Shield RP8 (4.6 x 250 mm) analytic column was used.

The analytical system consisted of a solvent delivery system (Waters model 501, Milford), an automatic sampler (Waters 717), a data module (Waters 745B), a scanning fluorescence detector (Waters 470), and for delivery of the postcolumn reagent, a solvent delivery pump (Waters model 501) with noise suppressor.

    Measurement of striatal tissue DA, DOPAC and HVA. Concentrations of DA, DOPAC, and HVA in striatum were determined by HPLC using the method of Chu et al. (30). Frozen striatal tissue samples were thawed and sonicated (Vibra Cell; 3 times, each time for 5 s at a 26% power setting and 80% duty cycle) in 160 µL of the mobile phase. The mobile phase consisted of 0.775 mmol/L sodium octyl sulfate, 0.5 mmol/L EDTA, 0.171 mol/L NaH2PO4, and 11% (v:v) methanol, pH 3.0. The homogenate was centrifuged at 15,000 x g for 10 min at 4°C. The resulting supernatant was injected into the HPLC system. The pellet (dissolved in NaOH) was used for protein analysis. The analytical system consisted of a solvent delivery system (BAS PM-80), a Rheodyne model 7125 injector, a BAS LC 4C electrochemical detector and a computer system. A glassy carbon working electrode with a potential of +0.75 V was used. The HPLC column was a phase II ODS 3-µm particle size, 3.2 x 100 mm analytic column. The flow rate was maintained at 0.8 mL/min.

    Protein determination. The tissue pellet sample was dissolved in 1.0 mol/L NaOH and then used for protein analysis. Protein was determined by the method of Lowry et al. (31) with bovine serum albumin as the standard.

    Statistical analyses. Data were analyzed using the SPSS/PC+ or SAS statistics computer program. Body weight and food intake of the rats were analyzed by repeated-measures ANOVA. The F-values for the interaction of group x time for both variables were significant; hence, one-way ANOVA was performed at each time point for each variable. Plasma concentrations of PLP, and striatal vitamin B-6 and DA were evaluated by one-way ANOVA. If the difference among the groups was significant, Scheffé’s multiple range test was used for post-hoc analysis. The KCl dosage, magnitude of DA release, rise time, and decay time (T1/2) were analyzed by generalized-estimating equations to account for clustered sampling; robust variance estimates were computed for the analyses (SAS). Differences were considered significant at P < 0.05. The results are presented as means ± SD.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
The initial body weights of rats in the control (54.4 ± 2.3 g), vitamin B-6–deficient (55.4 ± 2.6 g), and pair-fed (55.2 ± 3.0 g) groups did not differ (P = 0.508). At the end of the experiment, the body weights of the deficient (183.6 ± 32.2 g) and pair-fed (268.4 ± 18.7 g) groups were lower than those of the controls (503.8 ± 47.6 g) (P < 0.0001). The body weights of the deficient group were significantly less than those of the pair-fed group from wk 2 through wk 8 of the experiment. The food intake of the deficient and pair-fed groups was significantly lower than that of the control group from wk 1 of the experiment. The food intake of the deficient and pair-fed groups was ~52% of the control value (13.9 ± 2.6 and 13.7 ± 1.2 g/d vs. 26.4 ± 6.7 g/d, respectively). Convulsive seizure was observed in 1 rat of the deficient group during wk 8 of dietary treatment. This abnormal neurological symptom was not previously reported to occur in diet-induced vitamin B-6–deficient adult rats (8,32,33).

The rats in the vitamin B-6–deficient group were severely deficient in vitamin B-6 because their plasma PLP concentrations (17.8 ± 3.1 nmol/L) were ~2 and 4% of the respective values of the control (856.9 ± 262.6 nmol/L) and pair-fed groups (447.3 ± 154.2 nmol/L) (P < 0.0001). The pair-fed group also had significantly lower levels of plasma PLP than the control group.

The predominate forms of vitamin B-6 vitamers in the striatum were PMP and PLP. The brain’s need for vitamin B-6 during vitamin B-6 deficiency seemed to have priority. The vitamin B-6 concentration in the deficient group was higher in the striatum than in the plasma (Fig. 1). The striatal total B-6 (PMP + PLP) levels of the deficient group were ~57 and 52% of the respective values of control and pair-fed groups. However, differential responses of individual vitamin B-6 vitamers to vitamin B-6 deficiency were observed in the striatum. Vitamin B-6 deficiency affected striatal PLP much more than striatal PMP. The striatal PLP concentrations of the deficient rats were ~70% lower (P < 0.0001), whereas PMP levels were only 14% lower than those of the control group (P < 0.005).



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  		FIGURE 1 Concentrations of vitamin B-6 vitamers in brain striatum of control, vitamin B-6–deficient, and pair-fed rats. Bars represent means ± SD, n = 10 or 9 (deficient). Means without a common letter differ, P < 0.05.

 
Striatal DA concentrations did not differ among the groups (P = 0.076) (Fig. 2). Striatal DOPAC concentrations did not differ between the control and vitamin B-6–deficient groups, whereas the level was greater in the pair-fed group (P < 0.0001). Striatal HVA concentrations were lower in the vitamin B-6–deficient group than in the control and pair-fed groups (P < 0.005).



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  		FIGURE 2 Concentrations of DA, DOPAC, and HVA in striatum of control, vitamin B-6–deficient, and pair-fed rats. Bars represent means ± SD, n = 10 or 9 (deficient). Means without a common letter differ, P < 0.05.

 
Representative recordings of KCl-evoked DA release in the striatum appear in Figure 3. The dosage of locally applied KCl (223.2 ± 86.8, 225.6 ± 94.2, and 216.2 ± 80.3 nL, respectively) and the mean peak levels of KCl-evoked dopamine release (2.73 ± 2.05, 2.71 ± 3.18, and 2.14 ± 1.70 µmol/L, respectively) did not differ among the control, vitamin B-6–deficient, and pair-fed groups. However, the time required for KCl-evoked dopamine release to reach the peak level (rise time) was longer in the vitamin B-6–deficient group than in the control group [df = 302, Z = 3.68, P < 0.0002] (Table 1). The rise time of pair-fed group did not differ from that of the control or B-6 deficient group. In addition, the time required for the peak DA to decline by 50% (T1/2) was significantly prolonged in the deficient group compared with the control group [df = 302, Z = 4.12, P < 0.0001 (Table 1)]. The T1/2 of the pair-fed group did not differ from that of the other 2 groups.



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  		FIGURE 3 Chronoamperometric signals demonstrating typical KCl-evoked dopamine release in striatum of rats in Control (A), Vitamin B-6 deficient (B), and Pair-fed groups (C). *Indicates local application of KCl (70 mmol/L).

 

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  		TABLE 1 Time required for KCl-evoked DA release to reach peak level (rise time) and time required for the peak DA to decline by 50% (T1/2) in control, vitamin B-6-deficient, and pair-fed groups1, 2

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
This is the first study to use the electrochemical method to investigate the response of DA release in vitamin B-6 deficiency. The present in vivo voltammetric experiments demonstrated that KCl stimulation evoked similar elevations in DA release in striatum; however, the time course of the increase varied among groups. Compared with control rats, the rise time was 43% longer (P < 0.05) for vitamin B-6–deficient rats, indicating that the increase in extracellular DA concentration of deficient rats in response to the KCl stimulation was much slower. The KCl-evoked DA release of the pair-fed group did not differ from that of the control or vitamin B-6–deficient group, suggesting that food restriction did not affect DA release in the striatum. Vitamin B-6 deficiency appeared to be the sole factor that influenced DA release. An alteration in dopaminergic neurotransmission paralleled the appearance of motor disturbances (34,35). This slower process in releasing DA into synapse after KCl stimulation in vitamin B-6–deficient rats could therefore cause disturbances in neurotransmission and might contribute to the motor abnormalities of the deficient rats observed in previous studies (8–10).

It is interesting to note that the time required for the DA signal to decline by 50% (T1/2) from peak after local application of KCl was significantly longer in the deficient rats of this study. The T1/2 in the vitamin B-6–deficient group was ~59% greater (P < 0.05) than that in the control group, suggesting that removal of DA from the extracellular compartment was slower in vitamin B-6–deficient rats. Reducing the rate of DA removal might increase the extracellular DA concentrations, which could lead to a prolonged stimulation of DA receptors. In addition, extracellullar DA is toxic to the neurons (36). The reactive oxygen species generated by the metabolism of DA could cause oxidative damage to the nerve terminals (37). Reuptake of DA into nerve terminals is the primary mechanism that terminates the action of DA in the synapse and controls the lifetime of extracellular DA (38). Future studies should determine the reuptake of DA in vitamin B-6–deficient rats by measuring the changes in extracellular dopamine concentrations after local application of exogenous DA.

The changes in the response of dopaminergic neurons to KCl-evoked DA release did not influence the cellular content of DA and DOPAC in the striatum. DOPAC is a intraneuronal metabolite of DA (39). Concentrations of DOPAC and DA in this study did not differ between the control and vitamin B-6–deficient groups, suggesting that vitamin B-6 deficiency did not change the intracellular metabolism of DA in the striatum. Comparable levels of DA were also observed in the hypothalamus of vitamin B-6–deficient rats (13,14). However, results of the present study showed that vitamin B-6–deficient rats had significantly lower levels of HVA. Similar findings were reported in the pups of rats fed a vitamin B-6–deficient diet during gestation and lactation (40,41). HVA is formed extraneuronally (39); this reduction in HVA concentrations indicated that the extraneuronal DA metabolism was reduced in vitamin B-6–deficient rats.

One study showed that DA release might be sufficient to maintain DA at normal levels with the survival of only 20% of the DA innervation (42). This can occur because compensatory mechanisms [such as increased synthesis (43–45) and release of DA (45,46), and reduced clearance of extracellular DA (47)] develop when the dopaminergic nervous system is damaged. In the present study, the reduction in extracellular DA metabolism and the prolonged decay time of released DA might provide a compensatory mechanism for maintaining the extracellular levels of DA in vitamin B-6–deficient rats. The comparable mean peak level of KCl-evoked DA release among control, vitamin B-6–deficient, and pair-fed groups suggests that this mechanism is operative in the present context.

The finding that vitamin B-6 deficiency prolonged the time course of DA release in the present study is intriguing. There are mechanisms by which vitamin B-6 may influence the response of dopaminergic neurons. Dopamine terminals were shown to be susceptible to decreased energy metabolism (48). Our previous study found that the local cerebral glucose utilization rates in the structures of the caudatoputamen were ~55% lower in vitamin B-6–deficient rats than in the controls (33). Thus, decreased energy metabolism in the striatum of vitamin B-6–deficient rats might lead to the prolonged time course in KCl-evoked DA release. Others demonstrated that GABA could modulate the dopaminergic activity in the striatum (49–51). An increase in endogenous GABA facilitated the potassium-stimulated release of DA in the striatum of freely moving rats (51). PLP is the coenzyme of glutamic acid decarboxylase, which is the rate-limiting enzyme for GABA synthesis (7). Significantly low levels of GABA were observed in the brain of vitamin B-6–deficient rats (7). Hence, low levels of GABA in brain of these rats might be another factor that contributed to the altered response in DA release.

In summary, the present in vivo electrochemical study demonstrated that vitamin B-6 deficiency altered the response of dopaminergic neurons in the striatum. Vitamin B-6–deficient rats had an increased rise time of DA release and a longer decay time for the released DA to return to the baseline level. The cellular levels of DA and DOPAC were not altered, whereas HVA levels were decreased in vitamin B-6–deficient rats. These results indicate that cellular levels of DA do not reflect the functional state of dopaminergic neurons in vitamin B-6 deficiency. Compensatory mechanisms in dopaminergic neurons might be activated in vitamin B-6–deficient rats. Decreasing the degradation of extracellular DA and reducing the rate of DA clearance could lead to an increased opportunity for DA to interact with its presynaptic and postsynaptic receptors.


   ACKNOWLEDGMENTS
 
The authors thank Jenn-Tser Pan for his professional assistance and Shiao-Chi Wu for helpful statistical advice.


   FOOTNOTES
 
1 Presented in part at the IX Asian Congress of Nutrition, New Delhi, India [Tang, F. I. & Wei, I. L. (2003) Electrochemical studies of the effects of vitamin B-6 deficiency on dopamine release in striatum of rat brain. Abstracts PFC1–71, p. 139]. Back

2 Supported by a grant from the National Science Council of Republic of China (NSC89–2320-B-010–097). Back

4 Abbreviations used: DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; GABA, {gamma}-aminobutyric acid; HVA, homovanillic acid; PL, pyridoxal; PLP, pyridoxal-5'-phosphate; PM, pyridoxamine; PMP, pyridoxamine-5'-phosphate; PN, pyridoxine; PNP, pyridoxine-5'-phosphate. Back

Manuscript received 1 June 2004. Initial review completed 4 July 2004. Revision accepted 23 September 2004.


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 DISCUSSION
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