Systemic blockade of LPA 1/3 lysophosphatidic acid receptors by ki16425 modulates the effects of ethanol on the brain and behavior

Neuropharmacology. 2018 May 1;133:189-201. doi: 10.1016/j.neuropharm.2018.01.033. Epub 2018 Jan 31.

Abstract

The systemic administration of lysophosphatidic acid (LPA) LPA1/3 receptor antagonists is a promising clinical tool for cancer, sclerosis and fibrosis-related diseases. Since LPA1 receptor-null mice engage in increased ethanol consumption, we evaluated the effects of systemic administration of an LPA1/3 receptor antagonist (intraperitoneal ki16425, 20 mg/kg) on ethanol-related behaviors as well as on brain and plasma correlates. Acute administration of ki16425 reduced motivation for ethanol but not for saccharine in ethanol self-administering Wistar rats. Mouse experiments were conducted in two different strains. In Swiss mice, ki16425 treatment reduced both ethanol-induced sedation (loss of righting reflex, LORR) and ethanol reward (escalation in ethanol consumption and ethanol-induced conditioned place preference, CPP). Furthermore, in the CPP-trained Swiss mice, ki16425 prevented the effects of ethanol on basal c-Fos expression in the medial prefrontal cortex and on adult neurogenesis in the hippocampus. In the c57BL6/J mouse strain, however, no effects of ki16425 on LORR or voluntary drinking were observed. The c57BL6/J mouse strain was then evaluated for ethanol withdrawal symptoms, which were attenuated when ethanol was preceded by ki16425 administration. In these animals, ki16425 modulated the expression of glutamate-related genes in brain limbic regions after ethanol exposure; and peripheral LPA signaling was dysregulated by either ki16425 or ethanol. Overall, these results suggest that LPA1/3 receptor antagonists might be a potential new class of drugs that are suitable for treating or preventing alcohol use disorders. A pharmacokinetic study revealed that systemic ki16425 showed poor brain penetration, suggesting the involvement of peripheral events to explain its effects.

Keywords: Alcohol; Autotaxin; Conditioned place preference; Self-administration; Two-bottle choice; Withdrawal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Brain / drug effects*
  • Choice Behavior / drug effects
  • Conditioning, Operant / drug effects
  • Dose-Response Relationship, Drug
  • Ethanol / administration & dosage
  • Hallucinogens / pharmacology
  • Isoxazoles / pharmacology*
  • Lysergic Acid Diethylamide / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Propionates / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptors, Lysophosphatidic Acid / antagonists & inhibitors*
  • Receptors, Lysophosphatidic Acid / metabolism
  • Reflex / drug effects
  • Saccharin / administration & dosage
  • Self Administration

Substances

  • 3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid
  • Hallucinogens
  • Isoxazoles
  • Propionates
  • Receptors, Lysophosphatidic Acid
  • Ethanol
  • Lysergic Acid Diethylamide
  • Saccharin