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Published in final edited form as: Neurochem Int. 2023 Aug 1;169:105590. doi: 10.1016/j.neuint.2023.105590

Calcitriol protects against reductions in striatal serotonin in rats treated with neurotoxic doses of methamphetamine

Wayne A Cass 1,*, Laura E Peters 1
PMCID: PMC10529237  NIHMSID: NIHMS1922962  PMID: 37536650

Abstract

The present experiments were designed to examine the ability of calcitriol to protect against methamphetamine (METH)-induced reductions in striatal serotonin (5-HT) release and content. Male Fischer-344 rats were administered vehicle or calcitriol (0.3, 1.0, or 3.0 μg/kg, s.c.) once a day for 8 consecutive days. After the seventh day of treatment the animals were given METH (5 mg/kg, s.c.) or saline 4 times in one day at 2 hour intervals. Seven days after the METH or saline treatments in vivo microdialysis experiments were conducted to measure potassium and d-amphetamine evoked overflow of 5-HT from the striatum. In animals treated with vehicle and METH there were significant reductions in both potassium and d-amphetamine evoked overflow of 5-HT. The 1.0 and 3.0 μg/kg/day doses of calcitriol provided significant protection against the 5-HT depleting effects of METH. A similar pattern of neuroprotection was found for post-mortem tissue levels of 5-HT. The calcitriol treatments did not prevent hyperthermia during the multiple injections of METH, indicating that the protective effects of calcitriol are not due to prevention of METH-induced increases in body temperature. These results suggest that calcitriol can provide significant protection against the 5-HT depleting effects of neurotoxic doses of METH.

Keywords: Calcitriol, Methamphetamine, Serotonin, Striatum, Microdialysis

1. Introduction

Methamphetamine (METH) abuse and addiction is a major public health issue in the United States, with the abuse potential of METH likely related to its mood elevating and positive reinforcing effects. The behavioral and neurochemical effects of METH are mediated in part by monoamines; however, METH is also a neurotoxin, affecting both central serotonin (5-hydroxytryptamine; 5-HT) and dopamine terminals (Jayanthi et al., 2021; Nordahl et al., 2003; Schweppe et al., 2020; Shrestha et al., 2022). The abuse potential of METH, together with its neurotoxic effects, make METH an important drug from the standpoint that chronic use by humans may lead to long-term or permanent changes in brain neurochemistry and function.

While calcitriol (1,25-dihydroxyvitamin D3), the active metabolite of vitamin D3, is currently used to treat several conditions such as hypocalcemia and hypoparathyroidism, it has also been shown to have numerous effects in the nervous system (Bivona et al., 2019; Fernandes de Abreu et al., 2009; Garcion et al., 2002; Lason et al., 2023). These effects include reducing the severity of some central nervous system lesions (Garcion et al., 2002; Groves et al., 2014; Kesby et al., 2011), likely by altering cellular metabolic processes (Garcion et al., 2002; Groves et al., 2014; Ibi et al., 2001; Jiang et al., 2014; Shinpo et al., 2000), which may include upregulating trophic factors (Cass et al., 2012; Neveu et al., 1994; Sanchez et al., 2002; Saporito et al., 1994; Veenstra et al., 1997).

The present experiments were designed to examine the ability of calcitriol to protect against METH-induced reductions in striatal 5-HT release and content. In vivo microdialysis was used to evaluate potassium- and d-amphetamine-evoked overflow of 5-HT, and to monitor basal extracellular levels of its primary metabolite 5-hydroxyindole acetic acid (5-HIAA) from the striatum of rats treated with various doses of calcitriol. Postmortem tissue levels of 5-HT and 5-HIAA in the striatum were determined at the conclusion of each experiment.

2. Materials and methods

2.1. Animals

Male Fischer-344 rats were obtained from Harlan Laboratories (Indianapolis, IN). The animals weighed 262–333 g (95 – 138 days of age) at the start of the experiments and 8 animals were included in each treatment group. Male rats were used in order to allow comparisons with previous studies. The animals were housed in pairs under a 12-hr light-dark cycle with food and water freely available. All animal use procedures were approved by the Animal Care and Use Committee at the University of Kentucky and were in strict accordance with National Institutes of Health guidelines. All efforts were made to minimize the number of animals used and to minimize their pain and discomfort.

2.2. Calcitriol injections

Animals were injected once daily for eight consecutive days with vehicle or calcitriol (0.3, 1.0 or 3.0 μg/kg/day). All injections were administered subcutaneously. The calcitriol (Sigma Chemical Co., St. Louis, MO) was first dissolved in propylene glycol at a concentration of 100 μg/ml. For injections the calcitriol in propylene glycol was diluted into 0.9% saline so that the final volume given was 1 ml/kg of body weight. Vehicle treated animals were injected with propylene glycol diluted in 0.9% saline.

2.3. Methamphetamine treatment

METH or saline treatments were given on the seventh day of calcitriol or vehicle administration starting immediately after the calcitriol or vehicle injection. For these treatments the rats were injected subcutaneously with 5 mg/kg METH-HCl (Sigma Chemical Co., St. Louis, MO) in saline (1 ml/kg), or saline alone (1 ml/kg), four times in one day at two-hour intervals. Animals were housed individually during the treatments. Body temperature was taken with a rectal probe prior to the first injection of saline or METH, at one hour after each injection, and at two hours after the last injection. The first injection of the series was given between 8:00 and 9:00 am and the temperature of the room was 21.0 – 22.3°C.

2.4. In Vivo Microdialysis

Microdialysis studies were conducted seven days after the last vehicle or calcitriol injection. The animals were anesthetized with urethane (1.25–1.50 g/kg, i.p.) and placed into a stereotaxic frame. Body temperature was maintained at 37°C with a heating pad coupled to a rectal thermometer. Microdialysis probes (CMA/11 probes, 3.0 mm length of dialysis membrane; CMA/Microdialysis, Acton, MA) were slowly lowered into both the left and right striata (0.0 mm anterior to bregma, 3.0 mm lateral from midline, tip of probe 6.3 mm below the surface of the brain). The probes were perfused at a rate of 1.2 μl/min with artificial cerebrospinal fluid containing 145 mM NaCl, 2.7 mM KCl, 1.2 mM CaCl2, 1.0 mM MgCl2, 0.2 mM ascorbic acid, and 2.0 mM NaH2PO4 (pH adjusted to 7.4 using NaOH). Dialysate fractions were collected at 20-min intervals. Following a two-hour equilibration period and the collection of 3 baseline fractions, 5-HT overflow was stimulated by increasing the KCl concentration in the perfusate to 100 mM (NaCl reduced to 47.7 mM) for a single 20-min fraction, and then two hours later by adding 100 μM d-amphetamine to the perfusate for a single 20-min fraction. Five final fractions with normal artificial cerebrospinal fluid were collected following the d-amphetamine stimulation. Dialysate samples were immediately frozen on dry ice and stored at −80°C until assayed for 5-HT and 5-HIAA.

2.5. Tissue collection and HPLC analysis

After collecting the dialysate fractions the urethane-anesthetized animals were killed by decapitation and their brains rapidly removed and chilled in ice-cold saline. A coronal slice of brain 2 mm thick at the level of the dialysis probes was made with the aid of an ice-chilled brain mold (Rodent Brain Matrix, ASI Instruments, Warren, MI). The location of all dialysis probes was confirmed to be centered in the dorsal striatum at the level of the crossing of the anterior commissure. The striatum was then dissected from each half of the slice. The tissue pieces were placed in preweighed vials, weighed, frozen on dry ice, and then stored at −80°C until assayed for 5-HT and 5-HIAA by high performance liquid chromatography (HPLC). For tissue analysis the samples were prepared as previously described (Cass et al., 2003). For dialysis samples, 20 μl of the dialysate was injected directly onto the HPLC column.

The HPLC system consisted of a Beckman model 118 pump and model 507 autoinjector, and an ESA model 5200A Coulochem II electrochemical detector with a model 5011 dual-detector analytical cell (detector 1 set at +350 mV and detector 2 set at −300 mV). Separations were carried out using an ESA Hypersil ODS 3 μm particle C18 column (4.6 mm × 80 mm). Flow rate was 1.4 ml/min and the mobile phase was a 0.17 M citrate-acetate buffer containing 5 mg/l EDTA, 90 mg/l octanesulfonic acid, and 7–8 % methanol (pH 4.1). Chromatograms were recorded from both detectors using dual-channel strip chart recorders. Retention times of standards were used to identify peaks, and peak heights were used to calculate recovery of internal standard and amount of 5-HT and 5-HIAA.

2.6. Data analysis

All dialysis probes were calibrated in vitro prior to use to determine acceptable probes. However, values were not corrected for in vitro recoveries as uncorrected values may be better correlated to true values (Glick et al., 1994). Basal levels of 5-HIAA were defined as the average value in the three fractions preceding stimulation by excess potassium. Dialysis data were expressed as nM concentration of 5-HT or 5-HIAA in the dialysate and, for evoked overflow, as the total amount of 5-HT or 5-HIAA in the dialysate above, or below, baseline following stimulation with potassium or d-amphetamine. Tissue levels of 5-HT and 5-HIAA were expressed as ng/g wet weight of tissue. For all dialysis and tissue content experiments data from the left and right sides of the brain were averaged to get a single value for each time point and neurochemical per animal. Results were analyzed statistically using analysis of variance (ANOVA) as indicated in the results section. When the ANOVA results indicated significant effects, Newman-Keuls tests were used for post hoc comparisons.

3. Results

3.1. Body temperatures during METH treatments

Body temperatures during the saline and METH treatments are shown in fig. 1. A mixed ANOVA, with group as a between factor and time as a within factor, indicated significant effects for group (p < 0.001), time (p < 0.001), and group by time interactions (p < 0.001). Newman-Keuls post hoc comparisons indicated a significant rise in body temperature in all four METH treated groups compared to the saline treated animals (p < 0.001 for all comparisons), and that there was no difference between the four METH treated groups (p > 0.3 for all comparisons).

Figure 1.

Figure 1.

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Body temperatures of animals during treatment with saline or METH. Animals were treated for eight consecutive days with vehicle or calcitriol. Saline or METH injections were administered on the seventh day of treatment. The timing for the saline and METH injections is indicated by arrows on the x-axis. The data shown are mean values ± SEM for eight animals per group. * p < 0.05 vs. vehicle + saline group (mixed ANOVA with treatment group as a between factor and time as a within factor, followed by Newman-Keuls post-hoc comparisons).

3.2. Dialysate levels of 5-HT and 5-HIAA

Basal extracellular dialysate levels of 5-HIAA in urethane anesthetized rats are shown in Table 1. The results were analyzed using one-way ANOVA. The METH treatments led to a significant decrease in basal levels of 5-HIAA in the vehicle + METH and 0.3 μg/kg/day of calcitriol + METH groups. However, both the 1.0 and 3.0 μg/kg/day doses of calcitriol increased basal 5-HIAA levels in the calcitriol + METH treated animals compared to the vehicle + METH treated animals.

Table 1.

Basal dialysate levels of 5-HIAA from the striatum of animals treated for eight days with vehicle or calcitriol. Saline or METH injections were administered on the seventh day of treatment. Dialysis experiments were performed one week after the saline or METH injections.

Striatal dialysate level (nM)
Group 5-HIAA
Vehicle + Saline 388 ± 16
Vehicle + METH 197 ± 19*
0.3 Calcitriol + METH 218 ±21*
1.0 Calcitriol + METH 364 ± 10#
3.0 Calcitriol + METH 359 ± 14#
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Values are mean ± SEM from 8 animals per group.

*

p < 0.05 vs. Vehicle + Saline group,

#

p < 0.05 vs. Vehicle + METH group (one-way ANOVA followed by Newman-Keuls post hoc comparisons).

The complete time course for the dialysis experiments for 5-HT and 5-HIAA levels are shown in Fig. 2. Overall extracellular 5-HT levels (top panel) from the animals treated with either 1.0 or 3.0 μg/kg/day of calcitriol + METH were greater than those from the vehicle + METH group (p < 0.05 for both; main effect of treatment group). Similarly, extracellular 5-HIAA levels (bottom panel) were higher from the animals treated with either 1.0 or 3.0 μg/kg/day of calcitriol + METH than those from the vehicle + METH group or the 0.3 μg/kg/day of calcitriol + METH group (p < 0.05 for both; main effect of treatment group). In order to facilitate comparisons of the potassium and d-amphetamine evoked overflow of 5-HT and 5-HIAA between the groups the data were expressed as total amount of neurochemical in the dialysate fractions following stimulation by excess potassium or d-amphetamine (Fig. 3). Compared to the vehicle + saline treated animals, potassium-evoked overflow of 5-HT (top panel) was decreased in the vehicle + METH and the 0.3 μg/kg/day of calcitriol + METH treated animals, but not the 1.0 and 3.0 μg/kg/day of calcitriol + METH treated animals. A similar effect was found following d-amphetamine stimulation; however, with the d-amphetamine evoked stimulation the 0.3 μg/kg/day of calcitriol + METH treated animals were not significantly different from the vehicle + saline treated animals or the vehicle + METH treated animals. The 1.0 and 3.0 μg/kg/day of calcitriol + METH treated animals were not significantly different from vehicle + saline treated animals, but were significantly different from the vehicle + METH treated animals. For 5-HIAA there was a decrease in evoked overflow following potassium stimulation (bottom panel). The decrease was reduced for all groups compared to the vehicle + saline group, but the decrease in the 1.0 and 3.0 μg/kg/day of calcitriol + METH treated animals were different from the vehicle + METH treated group. There was a minimal increase in d-amphetamine-evoked overflow of 5-HIAA in all groups, although there were no statistically significant differences between any of the groups.

Figure 2.

Figure 2.

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Dialysate levels of 5-HT (top panel) and 5-HIAA (bottom panel) from the striata of animals treated with vehicle or calcitriol for eight consecutive days, with saline or METH administered on the seventh day of treatment. Microdialysis experiments were performed seven days after the saline or METH treatment. Excess potassium (100 mM) was included in the perfusate for 20-min starting at 0 min (horizontal bar above K+), and 100 μM d-amphetamine was included in the perfusate for 20-min starting at 120 min (horizontal bar above Amphetamine). Values shown are mean ± SEM from 8 animals per group. * p < 0.05 vs. vehicle + saline group, # p < 0.05 vs. vehicle + METH group (mixed ANOVA with time of dialysis sample collection as a within factor, and treatment group as a between factor; followed by Newman-Keuls post-hoc comparisons).

Figure 3.

Figure 3.

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Potassium-evoked and d-amphetamine-evoked overflow of 5-HT (top panel) and 5-HIAA (bottom panel) from the striatum of animals treated with vehicle or calcitriol for eight consecutive days, with saline or METH administered on the seventh day of treatment. Microdialysis experiments were performed seven days after the saline or METH treatment. Values shown are mean ± SEM from 8 animals per group. * p < 0.05 vs. vehicle + saline group, # p < 0.05 vs. vehicle + METH group (one-way ANOVA followed by Newman-Keuls post-hoc comparisons).

3.3. Tissue levels of 5-HT and 5-HIAA

Striatal tissue levels of 5-HT and 5-HIAA are shown in Table 2. Both 5-HT and 5-HIAA were significantly reduced by the METH treatments. However, the 1.0 and 3.0 μg/kg/day of calcitriol did increase striatal 5-HT and 5-HIAA tissue levels so that they were not significantly different from the vehicle + saline treated animals.

Table 2.

Tissue levels of 5-HT and 5-HIAA from the striatum of animals treated for eight days with vehicle or calcitriol. Saline or METH injections were administered on the seventh day of treatment. Tissue was harvested immediately after the dialysis experiments (one week after the saline or METH injections).

Tissue content (ng/g wet weight of tissue)
Group 5-HT 5-HIAA
Vehicle + Saline 598 ± 24 1240±28
Vehicle + METH 287 ± 43* 766 ± 63*
0.3 Calcitriol + METH 290 ±31* 765 ± 86*
1.0 Calcitriol + METH 557 ± 60# 1188 ±81#
3.0 Calcitriol + METH 524 ± 33# 1065 ± 59#
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Values are mean ± SEM from 8 animals per group.

*

p < 0.05 vs. Vehicle + Saline group,

#

p < 0.05 vs. Vehicle + METH group (one-way ANOVA followed by Newman-Keuls post hoc comparisons).

4. Discussion

The goal of the present study was to determine if administration of calcitriol would lead to protection against striatal 5-HT reductions following neurotoxic doses of METH. The results demonstrated that calcitriol, at doses of 1.0 or 3.0 μg/kg/day for eight days, led to significant protection against METH-induced loss of striatal 5-HT release and content one week after administration of the neurotoxin.

Many previous studies that examined the effects of calcitriol in the brain examined a single dose of calcitriol (1.0 μg/kg/day) (Sanchez et al., 2002, 2009; Smith et al., 2006; Wang et al., 2000, 2001). In addition, our lab has previously shown that a single dose of calcitriol (1.0 μg/kg/day) may be protective against loss of striatal tissue content of dopamine and 5-HT following neurotoxic doses of METH (Cass et al., 2006b). However, we wanted to examine both higher and lower doses of calcitriol in order to obtain a more complete understanding of the effects of calcitriol on 5-HT terminals. Thus, in the current study we examined the effects of three doses of calcitriol for their protective effects. The lowest dose used, 0.3 μg/kg/day, had little to no protective effect against neurotoxic doses of METH. However, the middle and higher doses (1.0 and 3.0 μg/kg/day) both had significant, and similar, neuroprotective effects. Both doses provided protection against neurotoxic doses of METH on striatal 5-HT and 5-HIAA release and tissue content, and on basal levels of 5-HIAA release. However, the highest dose may produce adverse side effects, like hypercalcemia (Chavhan et al., 2011; Wang et al., 2000). The differences between the effects of the middle and high doses were relatively minor, suggesting that the 1.0 μg/kg/day dose is high enough to produce significant and substantial protection for striatal 5-HT terminals.

We also looked at both potassium and d-amphetamine-induced overflow of 5-HT. This was to examine both calcium-dependent (potassium), and calcium-independent (d-amphetamine) evoked overflow of 5-HT. The reduction in both types of release suggest that 5-HT terminals are reduced in the striatum following neurotoxic doses of METH. However, the two highest doses of calcitriol (1.0 and 3.0 μg/kg/day) provided substantial protection, possibly indicating protection against METH-induced loss of 5-HT terminals. Interestingly, the two highest doses of calcitriol also protected against changes in striatal 5-HIAA evoked release and tissue content, further supporting a protective effect against METH-induced loss of functional 5-HT terminals in the striatum.

At this point the mechanism for calcitriol induced protection is not known. Several papers have shown that calcitriol can protect against brain disorders, such as Parkinson’s Disease and models, Alzheimer’s Disease and models, cerebral ischemia, experimental autoimmune encephalomyelitis, and inhibiting glioma formation, (Garcion et al., 2002; Groves et al., 2014; Kesby et al., 2011), all of which may involve 5-HT to some degree (for example see Fox et al., 2009; Li et al., 2021; Melnikov et al., 2021; You et al., 2022). Calcitriol can also upregulate trophic factors, particularly glial cell line-derived neurotrophic factor (GDNF)(Cass et al., 2012; Naveilhan et al., 1996; Sanchez et al., 2002 and 2009; Smith et al., 2006; Verity et al., 1999: Wang et al., 2000). However, it has been reported that GDNF does not protect 5-HT terminals well against the neurotoxic effects of METH (Cass, 1996). It is possible that other neurotrophic factors may be more important for serotonergic neurons, and it has been shown that several other factors are upregulated by calcitriol, such as neurotrophin-3, nerve growth factor, and transforming growth factor-ß2 (Neveu et al., 1994; Saporito et al., 1994; Veenstra et al., 1997; Wion et al., 1991). However, there has been very little work on whether these other factors are protective against METH or amphetamine neurotoxicity (Angelucci et al., 2007; Cass et al., 2006a). Thus, further studies will be necessary to more completely define the mechanism by which calcitriol protects 5-HT systems.

The timing for the duration of the calcitriol treatment (8 days) was based on previous calcitriol studies. Wang et al. (2001) found that eight days of calcitriol partially protected against the neurotoxic effects of 6-hydroxydopamine (6-OHDA), and Sanchez et al. (2009) found that seven days of calcitriol, given before or after a 6-OHDA lesion, led to a reduction in 6-OHDA-induced loss of tyrosine hydroxylase positive neurons in the substantia nigra. In addition, seven or eight consecutive days of calcitriol administration (1.0 μg/kg/day) has been shown to upregulate GDNF expression and protein levels in the brain (Sanchez et al., 2002 and 2009; Smith et al., 2006; Wang et al., 2000). Thus, we choose eight days of treatment for examining the potential ability of calcitriol to protect against the neurotoxic effects of METH against 5-HT neurons.

In conclusion, the systemic administration of calcitriol led to protection against METH induced reductions in striatal 5-HT. These results indicate that calcitriol may be able to protect against neurotoxin-induced reductions in brain 5-HT levels and provide evidence that calcitriol may be beneficial in treating disease processes involving serotonergic dysfunction.

Highlights.

  • Calcitriol was studied in rats given neurotoxic doses of methamphetamine

  • Calcitriol protected against methamphetamine-induced reductions in brain serotonin

  • Calcitriol may be beneficial in treating diseases involving serotonin dysfunction

Funding

This work was supported in part by the United States National Institutes of Health (Grant number DA22314).

Footnotes

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Author Statement

Wayne A. Cass: Conceptualization, Methodology, Validation, Analysis, Investigation, Writing – Original Draft, Writing – Review and Editing, Visualization, Supervision, Funding acquisition; Laura E. Peters: Analysis, Investigation.

Declaration of Competing Interests

Neither of the authors have a conflict of interest of any type in association with this work.

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