Aims. The lysophosphatidic acid (LPA) is an ubiquitous lysophospholipid that
acts through G-protein coupled receptors (LPA1-6), and it is involved in the
modulation of emotional and motivational behaviors. Recent literature suggests
a relevant role of the LPA signaling system in alcoholism, specially through the
LPA1 receptor. This work aims to elucidate whether systemic LPA1/3 receptor
blockade with ki16425 would modulate ethanol effects on the brain and behavior.
Methods. This study consisted of four experiments assessing the effect of
intraperitoneal ki16425 administration (20 mg/kg) on ethanol-related behaviors.
Male Wistar rats or mice (Swiss, C57BL/6J or hybrid C57BL/6J×129X1/SvJ
background) were employed in various procedures: I) oral ethanol selfadministration;
II) loss of righting reflex; III) ethanol-induced conditioned place
preference (CPP) and IV) ethanol-withdrawal behavioral symptoms (by
assessing nest building, physical signs and spatial working memory).
Immunohistochemistry was carried out in order to evaluate basal neuronal activity
(c-Fos) in the medial prefrontal cortex (mPFC) and in the hippocampus, as well
as adult hippocampal neurogenesis (AHN) using proliferating cell nuclear antigen
(PCNA) and doublecortin (DCX) markers.
Results. Systemic Ki16425 administration reduced oral self-administration of
ethanol in previously trained rats. Likewise, ki16425 pretreatment in mice
attenuated the sedation induced by ethanol, blocked ethanol rewarding effect in
a CPP paradigm and reduced behavioral symptoms induced by ethanol
withdrawal. Immunohistochemistry revealed a protective effect of ki16425 against
ethanol actions on basal neuronal activity in the mPFC and on AHN.
Conclusions. Our results suggest a potential usefulness of systemic LPA1/3
receptors antagonists as a novel treatment for alcohol-related disorders.
