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Chronic Alcohol Drinking Increases L‐Type Voltage‐Gated Calcium Channel Ca v 1.2 in the Substantia Nigra
Author(s) -
Rodriguez Eric A.,
Yamamoto Bryan K
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.09322
Subject(s) - substantia nigra , pars compacta , endocrinology , ventral tegmental area , medicine , chemistry , dopamine , methamphetamine , striatum , tyrosine hydroxylase , nucleus accumbens , dopaminergic , meth , monomer , organic chemistry , acrylate , polymer
Studies report that 77 % of methamphetamine (Meth)‐dependent adults in the United States also have alcohol use disorder. This comorbidity is associated with negative cognitive and behavioral effects. In addition, the serial exposure of alcohol and then methamphetamine (Meth) to adult male Sprague Dawley rats is neurotoxic and marked by a loss of tyrosine hydroxylase‐positive dopamine (DA) cells in the substantia nigra pars compacta (SNpc) that is absent after either drug alone. Dopamine cell loss was associated with caspase‐3 mediated apoptosis after Meth exposure to alcohol drinking rats; however, the effect of alcohol that sensitizes DA cells to Meth‐induced apoptosis remains unknown. Adult male Sprague Dawley rats had access to either two bottles of water or a choice of 10% alcohol and water every other day over 28 days. Rats with access to alcohol every other day had significantly increased L‐type voltage gated calcium channel Ca v 1.2 protein in the substantia nigra (SN) (33 ± 1.4 %) at 1 day after the last day of alcohol drinking compared to water drinking only controls (p<0.05). The increases in Ca v 1.2 were region‐specific since no such changes were detected in tissue from other dopaminergic regions including the dorsal striatum, ventral tegmental area, and nucleus accumbens. Furthermore, the cyclooxygenase‐2 selective and prostaglandin synthesis inhibitor, nimesulide (7.5mg/kg i.p., b.i.d.) administered on days when alcohol was not available, blocked the increases in Ca v 1.2 at 1 day after the alcohol drinking paradigm. Nimesulide administered only during the alcohol drinking paradigm also blocked the loss of DA cells in the SN pars compacta measured 1 week after exposure of Meth (10 mg/kg q 2 hrs X 4 injections). Although previous studies by others showed chronic alcohol exposure increases Ca v 1.2 in other brain regions, this is the first evidence of increases in the SN and that the increases occur in a prostaglandin synthesis‐dependent manner. The results are consistent with the excitotoxic effects produced calcium dysregulation and suggest that prostaglandins and disruption of calcium homeostasis produced by voluntary alcohol drinking sensitize DA cells in the SN to the neurodegenerative effects produced by the serial exposure to alcohol and Meth. Support or Funding Information This work is supported by the National Institutes of Health [DA042737].