Abstract
Acute hypertension produced by methamphetamine (MA) is well known, mainly by the enhancement of catecholamine release from sympathetic terminals. However, the central pressor mechanism of the blood-brain-barrier-penetrating molecule remains unclear. We used radio-telemetry and femoral artery cannulation to monitor the mean arterial pressure (MAP) in conscious free-moving and urethane-anesthetized rats, respectively. Expression of Fos protein (Fos) and phosphorylation of N-methyl-D-aspartate receptor subunit GluN1 in the rostral ventrolateral medulla (RVLM) were detected using Western blot analysis. ELISA was carried out for detection of protein kinase C (PKC) activity in the RVLM. MA-induced glutamate release in the RVLM was assayed using in vivo microdialysis and HPLC. Systemic or intracerebroventricular (i.c.v.) administration of MA augments the MAP and increases Fos expression, PKC activity, and phosphorylated GluN1-ser 896 (pGluN1-ser 896) in the RVLM. However, direct microinjection of MA into the RVLM did not change the MAP. Unilateral microinjection of a PKC inhibitor or a metabotropic glutamate receptor 5 (mGluR5) antagonist into the RVLM dose-dependently attenuated the i.c.v. MA-induced increase in MAP and pGluN1-ser 896. Our data suggested that MA may give rise to glutamate release in the RVLM further to the activation of mGluR5-PKC pathways, which would serve as a central mechanism for the MA-induced pressor effect.
Highlights
Methamphetamine (MA) is a popular and highly addictive psychostimulant that affects neurobehavior and causes cardiovascular dysfunctions including tachycardia, myocardial ischemia, and hypertension [1]
We recently found that the protein kinase C (PKC) signaling pathway is implicated in the blood pressure regulation by an increase in the expression of phosphorylated GluN1 in the sympathetic preganglionic neurons (SPN) [21]
Since N-methyl-D-aspartate receptors (NMDARs) activity is regulated by its phosphorylation state [22], and activation of NMDAR may modulate the neuronal activity in the rostral ventrolateral medulla (RVLM) [13], we evaluated the PKC activity in the RVLM after i.p. and i.c.v. application of MA in conscious and anesthetized rats, respectively
Summary
Methamphetamine (MA) is a popular and highly addictive psychostimulant that affects neurobehavior and causes cardiovascular dysfunctions including tachycardia, myocardial ischemia, and hypertension [1]. A similar result, reported by Li et al [11], showed that the distribution of MA to the brain tissue was significantly higher than to the heart 20 min after i.v. administration. MA shows a preferential distribution to brainstem nuclei that are associated with cardiovascular regulation. These findings inspire us to consider the fact that systemic application of MA may act firstly on the brain presympathetic vasomotor nuclei, leading to its initial hypertension. Afterwards, the glutamate activates metabotropic glutamate receptor 5 (mGluR5) in the RVLM to initiate the protein kinase C (PKC) signaling cascade and the underlying phosphorylation of NMDAR, leading to pressor responses
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