Nicotinic Antagonist UFR2709 Inhibits Nicotine Reward and Decreases Anxiety in Zebrafish.
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ABSTRACT:
SUBMITTER: Viscarra F
PROVIDER: S-EPMC7412259 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
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Nicotinic Antagonist UFR2709 Inhibits Nicotine Reward and Decreases Anxiety in Zebrafish.
Viscarra Franco F González-Gutierrez Juan J Esparza Erica E Figueroa Carla C Paillali Pablo P Hödar-Salazar Martin M Cespedes Camilo C Quiroz Gabriel G Sotomayor-Zárate Ramón R Reyes-Parada Miguel M Bermúdez Isabel I Iturriaga-Vásquez Patricio P
Molecules (Basel, Switzerland) 20200630 13
Zebrafish is becoming a popular animal model in neuropharmacology and drug discovery, mainly due to its ease of handling and low costs involved in maintenance and experimental work. This animal displays a series of complex behaviours that makes it useful for assessing the effects of psychoactive drugs. Here, adult zebrafish were used for assessment of the anxiolytic and anti-addictive properties of UFR2709, a nicotinic receptor (nAChR) antagonist, using two behavioural paradigms to test for addi ...[more]
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Project description:Nicotinic acetylcholine receptors (nAChRs) containing ?6?2 subunits expressed by dopamine neurons regulate nicotine-evoked dopamine release. Previous results show that the ?6?2* nAChR antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) inhibits nicotine-evoked dopamine release from dorsal striatum and decreases nicotine self-administration in rats. However, overt toxicity emerged with repeated bPiDDB treatment. The current study evaluated the preclinical pharmacology of a bPiDDB analogue.The C?? analogue of bPiDDB, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI), was evaluated preclinically for nAChR antagonist activity.bPiDI inhibits nicotine-evoked [³H]dopamine overflow (IC??= 150 nM, I(max)=58%) from rat striatal slices. Schild analysis revealed a rightward shift in the nicotine concentration-response curve and surmountability with increasing nicotine concentration; however, the Schild regression slope differed significantly from 1.0, indicating surmountable allosteric inhibition. Co-exposure of maximally inhibitory concentrations of bPiDI (1 µM) and the ?6?2* nAChR antagonist ?-conotoxin MII (1 nM) produced inhibition not different from either antagonist alone, indicating that bPiDI acts at ?6?2* nAChRs. Nicotine treatment (0.4 mg·kg?¹·da?¹, 10 days) increased more than 100-fold the potency of bPiDI (IC??=1.45 nM) to inhibit nicotine-evoked dopamine release. Acute treatment with bPiDI (1.94-5.83 µmol·kg?¹, s.c.) specifically reduced nicotine self-administration relative to responding for food. Across seven daily treatments, bPiDI decreased nicotine self-administration; however, tolerance developed to the acute decrease in food-maintained responding. No observable body weight loss or lethargy was observed with repeated bPiDI.These results are consistent with the hypothesis that ?6?2* nAChR antagonists have potential for development as pharmacotherapies for tobacco smoking cessation.
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