Prolonged increase in ser31 tyrosine hydroxylase phosphorylation in substantia nigra following cessation of chronic methamphetamine

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Abstract

Methamphetamine (MA) exposure may increase the risk of motor or cognitive impairments similar to Parkinson's disease (PD) by middle age. Although damage to nigrostriatal or mesoaccumbens dopamine (DA) neurons may occur during or early after MA exposure, overt PD-like symptoms at a younger age may not manifest due to compensatory mechanisms to maintain DA neurotransmission. One possible compensatory mechanism is increased tyrosine hydroxylase (TH) phosphorylation. In the rodent PD 6-OHDA model, nigrostriatal lesion decreases TH protein in both striatum and substantia nigra (SN). However, DA loss in the SN is significantly less than that in the striatum. An increase in ser31 TH phosphorylation in the SN may increase TH activity in response to TH loss. To determine if similar compensatory mechanisms may be engaged in young mice after MA exposure, TH expression, phosphorylation, and DA tissue content were evaluated, along with dopamine transporter expression, 21 days after cessation of MA (24 mg/kg, daily, 14 days). DA tissue content was unaffected by the MA regimen in striatum, nucleus accumbens, SN, or ventral tegmental area (VTA), despite decreased TH protein in SN and VTA. In the SN, but not striatum, ser31 phosphorylation increased over 2-fold. This suggests that increased ser31 TH phosphorylation may be an inherent compensatory mechanism to attenuate DA loss against TH loss, similar to that in an established PD model. These results also indicate the somatodendritic compartments of DA neurons are more vulnerable to TH protein loss than terminal fields following MA exposure.

Original languageEnglish
Pages (from-to)121-128
Number of pages8
JournalNeuroToxicology
Volume67
DOIs
StatePublished - 1 Jul 2018

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Phosphorylation
Methamphetamine
Tyrosine 3-Monooxygenase
Substantia Nigra
Dopamine
Parkinson Disease
Ventral Tegmental Area
Dopaminergic Neurons
Neurons
Rodent Diseases
Tissue
Dopamine Plasma Membrane Transport Proteins
Proteins
Oxidopamine
Nucleus Accumbens
Synaptic Transmission

Keywords

  • Aging
  • Dopamine transporter
  • Methamphetamine
  • Parkinson's disease
  • Phosphorylation
  • Tyrosine hydroxylase

Cite this

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title = "Prolonged increase in ser31 tyrosine hydroxylase phosphorylation in substantia nigra following cessation of chronic methamphetamine",
abstract = "Methamphetamine (MA) exposure may increase the risk of motor or cognitive impairments similar to Parkinson's disease (PD) by middle age. Although damage to nigrostriatal or mesoaccumbens dopamine (DA) neurons may occur during or early after MA exposure, overt PD-like symptoms at a younger age may not manifest due to compensatory mechanisms to maintain DA neurotransmission. One possible compensatory mechanism is increased tyrosine hydroxylase (TH) phosphorylation. In the rodent PD 6-OHDA model, nigrostriatal lesion decreases TH protein in both striatum and substantia nigra (SN). However, DA loss in the SN is significantly less than that in the striatum. An increase in ser31 TH phosphorylation in the SN may increase TH activity in response to TH loss. To determine if similar compensatory mechanisms may be engaged in young mice after MA exposure, TH expression, phosphorylation, and DA tissue content were evaluated, along with dopamine transporter expression, 21 days after cessation of MA (24 mg/kg, daily, 14 days). DA tissue content was unaffected by the MA regimen in striatum, nucleus accumbens, SN, or ventral tegmental area (VTA), despite decreased TH protein in SN and VTA. In the SN, but not striatum, ser31 phosphorylation increased over 2-fold. This suggests that increased ser31 TH phosphorylation may be an inherent compensatory mechanism to attenuate DA loss against TH loss, similar to that in an established PD model. These results also indicate the somatodendritic compartments of DA neurons are more vulnerable to TH protein loss than terminal fields following MA exposure.",
keywords = "Aging, Dopamine transporter, Methamphetamine, Parkinson's disease, Phosphorylation, Tyrosine hydroxylase",
author = "Salvatore, {Michael Francis} and Nejtek, {Vicki Allene} and Habibeh Khoshbouei",
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Prolonged increase in ser31 tyrosine hydroxylase phosphorylation in substantia nigra following cessation of chronic methamphetamine. / Salvatore, Michael Francis; Nejtek, Vicki Allene; Khoshbouei, Habibeh.

In: NeuroToxicology, Vol. 67, 01.07.2018, p. 121-128.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Prolonged increase in ser31 tyrosine hydroxylase phosphorylation in substantia nigra following cessation of chronic methamphetamine

AU - Salvatore, Michael Francis

AU - Nejtek, Vicki Allene

AU - Khoshbouei, Habibeh

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Methamphetamine (MA) exposure may increase the risk of motor or cognitive impairments similar to Parkinson's disease (PD) by middle age. Although damage to nigrostriatal or mesoaccumbens dopamine (DA) neurons may occur during or early after MA exposure, overt PD-like symptoms at a younger age may not manifest due to compensatory mechanisms to maintain DA neurotransmission. One possible compensatory mechanism is increased tyrosine hydroxylase (TH) phosphorylation. In the rodent PD 6-OHDA model, nigrostriatal lesion decreases TH protein in both striatum and substantia nigra (SN). However, DA loss in the SN is significantly less than that in the striatum. An increase in ser31 TH phosphorylation in the SN may increase TH activity in response to TH loss. To determine if similar compensatory mechanisms may be engaged in young mice after MA exposure, TH expression, phosphorylation, and DA tissue content were evaluated, along with dopamine transporter expression, 21 days after cessation of MA (24 mg/kg, daily, 14 days). DA tissue content was unaffected by the MA regimen in striatum, nucleus accumbens, SN, or ventral tegmental area (VTA), despite decreased TH protein in SN and VTA. In the SN, but not striatum, ser31 phosphorylation increased over 2-fold. This suggests that increased ser31 TH phosphorylation may be an inherent compensatory mechanism to attenuate DA loss against TH loss, similar to that in an established PD model. These results also indicate the somatodendritic compartments of DA neurons are more vulnerable to TH protein loss than terminal fields following MA exposure.

AB - Methamphetamine (MA) exposure may increase the risk of motor or cognitive impairments similar to Parkinson's disease (PD) by middle age. Although damage to nigrostriatal or mesoaccumbens dopamine (DA) neurons may occur during or early after MA exposure, overt PD-like symptoms at a younger age may not manifest due to compensatory mechanisms to maintain DA neurotransmission. One possible compensatory mechanism is increased tyrosine hydroxylase (TH) phosphorylation. In the rodent PD 6-OHDA model, nigrostriatal lesion decreases TH protein in both striatum and substantia nigra (SN). However, DA loss in the SN is significantly less than that in the striatum. An increase in ser31 TH phosphorylation in the SN may increase TH activity in response to TH loss. To determine if similar compensatory mechanisms may be engaged in young mice after MA exposure, TH expression, phosphorylation, and DA tissue content were evaluated, along with dopamine transporter expression, 21 days after cessation of MA (24 mg/kg, daily, 14 days). DA tissue content was unaffected by the MA regimen in striatum, nucleus accumbens, SN, or ventral tegmental area (VTA), despite decreased TH protein in SN and VTA. In the SN, but not striatum, ser31 phosphorylation increased over 2-fold. This suggests that increased ser31 TH phosphorylation may be an inherent compensatory mechanism to attenuate DA loss against TH loss, similar to that in an established PD model. These results also indicate the somatodendritic compartments of DA neurons are more vulnerable to TH protein loss than terminal fields following MA exposure.

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KW - Parkinson's disease

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