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p-Chloroamphetamine-Enhanced Neostriatal Dopamine Exocytosis in Rats Neonatally Co-lesioned with 6-OHDA and 5,7-DHT: Relevance to Parkinson’s Disease

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Abstract

Serotoninergic nerves are known to modulate sensitization of dopamine receptors (DA-R) in a rodent model of Parkinson’s disease (PD). However, serotoninergic nerves are not known to have a prominent role on DA exocytosis in intact rats. The current study was undertaken to explore the possible influence of serotoninergic nerves on DA exocytosis in Parkinsonian rats. Rat pups were treated at 3 days after birth with the neurotoxin 6-hydroxydopamine (6-OHDA; 134 μg icv, half into each lateral ventricle; desipramine, 1 h pretreatment), in order to produce marked long-lasting destruction of neostriatal dopaminergic innervation, as evidenced by the 90–95% depletion of DA (p < 0.001) [HPLC/ED] into adulthood. Controls received vehicle/desipramine in place of 6-OHDA. Other groups received the serotoninergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 25 μg base, icv, half in each lateral ventricle; desipramine, 1 h; 75 mg/kg pargyline HCl, 30 min) at 3 days post-birth; or both 6-OHDA+5,7-DHT treatments. In adulthood, an in vivo microdialysis study was undertaken to ascertain that p-chloroamphetamine (PCA, 1 mM in the microdialysate)-evoked DA release in the neostriatum was reduced approximately 50% in the 6-OHDA group, while PCA-evoked DA release in the 6-OHDA+5,7-DHT group was substantially increased, to a level equivalent to that of the vehicle control. The baseline neostriatal microdialysate level of 3,4-dihydroxyphenylacetic acid (DOPAC) was also higher in the 6-OHDA+5,7-DHT group vs 6-OHDA group; also, during the 2nd hour of PCA infusion. PCA-enhanced DA exocytosis occurred in the absence of changes in hydroxyl radical (HO·) in the microdialysate (i.e., assay of 2,3- and 2,5-dihydroxybenzoic acid, 2,3-DHBA; 2,5-DHBA). The overall findings demonstrate that an adulthood serotoninergic nerve lesion enhanced PCA-evoked DA exocytosis in a rodent model of severe PD, while susceptibility to oxidative stress was unchanged. The implication is that serotoninergic nerves may normally suppress the release of DA and/or act as an uptake site and storage sink for accumulated DA in parkinsonian-like neostriatum. Potentially, serotoninergic agonists or antagonists, targeting subtype-selective serotonin receptors, may be viable therapeutic adjuncts in PD.

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Abbreviations

2,3-DHBA:

2,3-Dihydroxybenzoic acid

2,5-DHBA:

2,5-Dihydroxybenzoic acid

5-HIAA:

5-Hydroxyindoleacetic acid

5-HT:

5-Hydroxytryptamine (seroronin)

5,7-DHT:

5,7-Dihydroxytryptamine

6-OHDA:

6-Hydroxydopamine

AMPH:

Amphetamine

DA:

Dopamine

DA R:

Dopamine receptor

DA RSS:

Dopamine receptor supersensitivity

DOPAC:

3,4-Dihydroxyphenylacetic acid

EDTA:

Ethylenediamine tetra-acetic acid

HO:

Hydroxyl radical

HPLC/ED:

High-performance liquid chromatography/electrochemical detection

HVA:

Homovanillic acid

L-DOPA:

L-dihydroxyphenylalanine

n5,7-DHT:

Neonatally administered 5,7-DHT

n6-OHDA:

Neonatally administered 6-OHDA

PCA:

p-Chloroamphetamine

PD:

Parkinson’s disease

R:

Receptor

RSS:

Receptor supersensitivity

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Funding

This study was supported by the National Institute of Neurological Disorders and Stroke, grant NS 39272.

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Author notes

  1. John P. Kostrzewa

    Present address: North Alabama ENT Associates, 927 Franklin St SE Fl 1 Ste 100, Huntsville, AL, 35801, USA

Authors and Affiliations

  1. Department of Pharmacology, Quillen College of Medicine,, East Tennessee State University, Johnson City, TN, 37614, USA

    Richard M. Kostrzewa

  2. Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, PO Box 70577, Johnson City, TN, 37614, USA

    Richard M. Kostrzewa

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Correspondence to Richard M. Kostrzewa.

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Electronic supplementary material

ESM 1

Schematic representation of in vivo microdialysis procedure. The microdialysis probe was surgically implanted in rat neostriatum one day prior to study. All subsequent experimental procedures were conducted in freely moving rats without anesthesia. On the day of study, and after acclimation, p-chloroamphetamine (PCA, 1 mM) was added to the microdialysate which contained 5 nM salicylic acid for enabling indirect analysis of HO●. Effluent was collected and analyzed by HPLC/ED for DA, DOPAC, 5-HT, 5-HIAA, and HO● (PDF 187 kb).

ESM 2

Effect of PCA on DOPAC concentration of neostriatal microdialysates of (a) Saline control rats, (b) neonatally 6-OHDA-lesioned rats, (c) neonatally 5,7-DHT-lesioned rats, and (d) neonatally 6-OHDA + 5,7-DHT-lesioned rats. PCA was administered when the zero-time sample collection was taken for HPLC/ED analysis. Each group is the mean of 4 or 5 samples. + p<0.05, ++ p<0.003 vs. Saline group; * p<0.05, ** p<0.003 vs. 6-OHDA + 5,7-DHT-lesioned group; δ p<0.05, δδ p<0.003 vs. 5,7-DHT-lesioned group (PDF 187 kb).

ESM 3

Effect of PCA on 2,3-dihydroxybenzoic acid (2,3-DHBA) concentration of neostriatal microdialysates of (a) Saline control rats, (b) neonatally 6-OHDA-lesioned rats, (c) neonatally 5,7-DHT-lesioned rats, and (d) neonatally 6-OHDA + 5,7-DHT-lesioned rats. Remainder of legend as in Supplementary FIG. 2 (PDF 187 kb).

ESM 4

Summated effects of PCA on 2,3-DHBA concentration of neostriatal microdialysates of (a) Saline control rats, (b) neonatally 6-OHDA-lesioned rats, (c) neonatally 5,7-DHT-lesioned rats, and (d) neonatally 6-OHDA + 5,7-DHT-lesioned rats. Remainder of legend as in Supplementary FIG. 2 (PDF 187 kb).

ESM 5

Effect of PCA on 2,5-dihydroxybenzoic acid (2,5-DHBA) concentration of neostriatal microdialysates of (a) Saline control rats, (b) neonatally 6-OHDA-lesioned rats, (c) neonatally 5,7-DHT-lesioned rats, and (d) neonatally 6-OHDA + 5,7-DHT-lesioned rats. Remainder of legend as in Supplementary FIG. 2. * p<0.05 vs. 6-OHDA group; δ p<0.05 vs. 6-OHDA + 5,7-DHT group; + p<0.05 vs. Saline group (PDF 187 kb).

ESM 6

Summated effects of PCA on 2,5-DHBA concentration of neostriatal microdialysates of (a) Saline control rats, (b) neonatally 6-OHDA-lesioned rats, (c) neonatally 5,7-DHT-lesioned rats, and (d) neonatally 6-OHDA + 5,7-DHT-lesioned rats. Remainder of legend as in Supplementary FIG. 2. * p<0.05 vs. 6-OHDA + 5,7-DHT group; δ p<0.05 vs. 6-OHDA group; + p<0.05 vs. Saline group (PDF 187 kb).

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Kostrzewa, J.P., Kostrzewa, R.M. p-Chloroamphetamine-Enhanced Neostriatal Dopamine Exocytosis in Rats Neonatally Co-lesioned with 6-OHDA and 5,7-DHT: Relevance to Parkinson’s Disease. Neurotox Res 37, 543–552 (2020). https://doi.org/10.1007/s12640-019-00145-4

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