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PKCβ Inhibitors Decrease AMPH‐Stimulated Behaviors: More than One Mechanism?
Author(s) -
Altshuler Rachel D,
Carpenter Colleen A,
Gnegy Margaret E,
Jutkiewicz Emily M
Publication year - 2017
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.31.1_supplement.986.3
Subject(s) - protein kinase c , amphetamine , pharmacology , chemistry , ventral tegmental area , nucleus accumbens , mechanism of action , dopamine , conditioned place preference , extracellular , in vitro , neuroscience , kinase , dopaminergic , medicine , biochemistry , biology
Amphetamines (AMPH) elicit their reinforcing effects by increasing dopamine (DA) release from neurons extending from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). Protein kinase Cβ (PKCβ) has been shown to be important for AMPH's mechanism of action, such that inhibition of PKCβ reduces AMPH‐stimulated extracellular DA levels in vitro . While the effects of PKC inhibitors on AMPH‐stimulated DA efflux have been characterized, it is important to understand the effects of PKCβ inhibition in vivo . We previously showed that intraventricular ( icv ) injections of selective PKCβ inhibitors (ruboxistaurin or enzastaurin) decreases AMPH stimulated locomotor activity, AMPH self‐administration, and AMPH‐stimulated PKC activity but only when given 18 hours before AMPH. The goal of this study was to determine why PKCβ inhibitors given icv require a long pretreatment time before decreasing AMPH behaviors. Our hypothesis is that the site of action of a PKCβ inhibitor, the NAc (site of DA terminals) and VTA (site of DA cell bodies), determines the PKCβ inhibitors' time course. 10 pmols of ruboxistaurin were administered into the NAc or VTA of male Sprague‐Dawley rats 30 mins or 18 hrs prior to evaluating locomotor activity in response to 1 mg/kg AMPH (s.c.). Ruboxistaurin administered directly into the NAc with a 30 min, but not 18 hr, pretreatment decreased AMPH‐stimulated locomotor activity. Conversely, ruboxistaurin given directly into the VTA following an 18 hr, but not 30 min, pretreatment blocked AMPH‐stimulated locomotor activity. Therefore, acute inhibition of PKCβ in the NAc can decrease AMPH‐stimulated activity, but this effect is not observed following icv administration. This may suggest that following icv injections, the concentrations of the PKCβ inhibitor in the NAc are not large enough to affect locomotor activity acutely. The longer pretreatment time necessary for intra‐VTA PKCβ inhibitors to block AMPH‐stimulated behaviors suggests the involvement of a different mechanism that may be less reliant on direct PKC inhibition, such as alterations in transcription or protein synthesis. Overall, we conclude that PKC inhibition decreases AMPH‐stimulated behaviors through a direct and indirect mechanism. Future work will investigate the indirect mechanism, determining if PKCβ inhibitors given directly into the VTA alter PKCβ or DAT levels or function in the NAc. Support or Funding Information Funded by DA11697 and T32‐GM007767.