TY - JOUR
T1 - Prolonged increase in ser31 tyrosine hydroxylase phosphorylation in substantia nigra following cessation of chronic methamphetamine
AU - Salvatore, Michael F.
AU - Nejtek, Vicki A.
AU - Khoshbouei, Habibeh
N1 - Funding Information:
This work was funded in part by the National Institutes of Health grant awards DA026947 and NS071122 to HK and AG040261 to MFS.
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/7
Y1 - 2018/7
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.
KW - Aging
KW - Dopamine transporter
KW - Methamphetamine
KW - Parkinson's disease
KW - Phosphorylation
KW - Tyrosine hydroxylase
UR - http://www.scopus.com/inward/record.url?scp=85054331698&partnerID=8YFLogxK
U2 - 10.1016/j.neuro.2018.05.003
DO - 10.1016/j.neuro.2018.05.003
M3 - Article
C2 - 29782882
AN - SCOPUS:85054331698
SN - 0161-813X
VL - 67
SP - 121
EP - 128
JO - NeuroToxicology
JF - NeuroToxicology
ER -