RAP-103, a multi-chemokine receptor antagonist, displays anxiolytic-like effects and normalizes methamphetamine...

RAP-103 is an orally active, multi-chemokine receptor antagonist (CRA) that inhibits three different chemokine receptors (CCR2, CCR5 and CCR8). Planarians, the simplest animals with bilateral symmetry and CNS cephalization, are useful for screening putative therapeutics because they express neurotransmitter systems and display mammalian-like behaviors when exposed to addictive drugs. We investigated effects of RAP-103 on spontaneous planarian behaviors (light avoidance, motility) and withdrawal responses associated with methamphetamine (METH) abstinence. Acute RAP-103 exposure decreased light avoidance (0.1, 1 μM) and increased motility (1 μM). For both endpoints, RAP-103 displayed an inverted U-shape concentration-effect curve. Maraviroc (1, 10 μM), a CCR5 antagonist, decreased light avoidance (like RAP-103) but reduced motility. RS 504393 (1, 10 μM), a CCR2 antagonist, increased light avoidance and reduced motility. For METH abstinence experiments, planarians were exposed for 5 min to a concentration of METH (1 μM) that did not cause spontaneous behaviors and then removed and placed into water. Planarians were then tested for light avoidance and motility during both early abstinence (0-5 min post-METH exposure) and later abstinence (15-20 min post-METH exposure). Light avoidance was enhanced during early METH abstinence whereas motility was reduced during later abstinence. RAP-103 (0.01, 0.1, 1 μM), administered during METH abstinence, counteracted METH-induced light avoidance but did not rescue METH-induced motility deficits. Our results with planarians show that RAP-103 displays anxiolytic-like and motor-enhancing effects and counteracts METH abstinence-induced behaviors, highlighting the potential of RAP-103 as a chemokine-based CNS therapeutic.