PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis

eNeuro. 2018 Jun 11;5(3):ENEURO.0422-17.2018. doi: 10.1523/ENEURO.0422-17.2018. eCollection 2018 May-Jun.

Abstract

Protein interacting with C-kinase 1 (PICK1) is a widely expressed scaffold protein known to interact via its PSD-95/discs-large/ZO-1 (PDZ)-domain with several membrane proteins including the dopamine (DA) transporter (DAT), the primary target for cocaine's reinforcing actions. Here, we establish the importance of PICK1 for behavioral effects observed after both acute and repeated administration of cocaine. In PICK1 knock-out (KO) mice, the acute locomotor response to a single injection of cocaine was markedly attenuated. Moreover, in support of a role for PICK1 in neuroadaptive changes induced by cocaine, we observed diminished cocaine intake in a self-administration paradigm. Reduced behavioral effects of cocaine were not associated with decreased striatal DAT distribution and most likely not caused by the ∼30% reduction in synaptosomal DA uptake observed in PICK1 KO mice. The PICK1 KO mice demonstrated preserved behavioral responses to DA receptor agonists supporting intact downstream DA receptor signaling. Unexpectedly, we found a prominent increase in striatal DA content and levels of striatal tyrosine hydroxylase (TH) in PICK1 KO mice. Chronoamperometric recordings showed enhanced DA release in PICK1 KO mice, consistent with increased striatal DA pools. Viral-mediated knock-down (KD) of PICK1 in cultured dopaminergic neurons increased TH expression, supporting a direct cellular effect of PICK1. In summary, in addition to demonstrating a key role of PICK1 in mediating behavioral effects of cocaine, our data reveal a so far unappreciated role of PICK1 in DA homeostasis that possibly involves negative regulation of striatal TH levels.

Keywords: cocaine; dopamine homeostasis; drug addiction; protein interacting with C-kinase 1; striatum; tyrosine hydroxylase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins
  • Cocaine / administration & dosage*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Dopamine / metabolism*
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dopaminergic Neurons / drug effects*
  • Dopaminergic Neurons / metabolism*
  • Homeostasis / drug effects*
  • Locomotion / drug effects
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Reinforcement, Psychology
  • Signal Transduction / drug effects
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Nuclear Proteins
  • Prkcabp protein, mouse
  • Tyrosine 3-Monooxygenase
  • Cocaine
  • Dopamine