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Up-regulation of Ca(v)1.2 subunit via facilitating trafficking induced by Vps34 on morphine-induced place preference

Masahiro Shibasaki1, Kazuhiro Kurokawa, Koji Mizuno

  • 1Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192, Japan.

European Journal of Pharmacology
|December 2, 2010
PubMed

Insights

Vps34, a PI 3-kinase class III, plays a key role in morphine-induced place preference. This kinase regulates the up-regulation of L-type calcium channels (Ca(v)1.2) in neuronal plasma membranes, contributing to morphine dependence.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Morphine dependence is a significant public health issue.
  • The precise molecular mechanisms underlying morphine-induced psychological dependence are not fully understood.
  • Phosphoinositide 3-kinases (PI 3-kinases) are implicated in various cellular processes, including addiction.

Purpose of the Study:

  • To investigate the role of Vps34, a PI 3-kinase class III, in the development of morphine-induced place preference in mice.
  • To examine the relationship between Vps34, L-type calcium channels (Ca(v)1.2), and morphine dependence.

Main Methods:

  • Repeated in vivo morphine administration in mice.
  • Intracerebroventricular (i.c.v.) administration of nifedipine, wortmannin, and LY294002 (PI 3-kinase inhibitors).
  • Western blot analysis to measure protein levels of Vps34 and Ca(v)1.2 in brain regions (frontal cortex, nucleus accumbens).
  • Primary culture of cerebral cortical neurons exposed to morphine.

Main Results:

  • Morphine-induced place preference was inhibited by nifedipine and PI 3-kinase inhibitors (wortmannin, LY294002).
  • Vps34 and Ca(v)1.2 protein levels significantly increased in the frontal cortex and limbic forebrain of morphine-dependent mice.
  • PI 3-kinase inhibitors suppressed the up-regulation of Ca(v)1.2.
  • Morphine exposure increased Ca(v)1.2 translocation to the plasma membrane in cultured neurons, an effect inhibited by PI 3-kinase inhibitors.

Conclusions:

  • Vps34 is critically involved in the development of morphine-induced place preference.
  • Vps34 mediates the up-regulation of Ca(v)1.2 in the neuronal plasma membrane.
  • Targeting Vps34 and Ca(v)1.2 may offer therapeutic strategies for morphine dependence.

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