Nicotine chronic tolerance development and withdrawal in Planaria

Abstract

In rodents, chronic nicotine exposure reduces sensitivity to its unconditioned effects, which then results in addictive-like behaviours (i.e., tolerance development). The studies reported here address the chronic effect of nicotine on an invertebrate model using two planaria species: Schmidtea mediterranea and Dugesia sp. In our experiments, animals were repeatedly exposed to nicotine in a specific context and then they received three consecutive tests: in the presence of water in the nicotine-associated context, to assess the development conditioned compensatory responses – CCRs -(Test1); a test with nicotine carried out in the nicotine-associated context (Test 2); and a test with nicotine in and a distinctive novel context (Test 3) to assess the role of context on the expression of chronic tolerance. Both Dugesia sp. and Schmidtea mediterranea showed evidence for the acute effect of nicotine on motility in a dose dependent manner, but only Schmidtea mediterranea showed evidence of the development of reliable chronic tolerance. Schmidtea mediterranea received repeated nicotine exposure for 5 hours in total during either 5 or 10 days, and the results showed evidence of tolerance development in the Tests 2 and 3, but not CCRs in the Test 1, after 10 days of exposure. On the contrary, animals exposed to the drug for 5 days (one hour/day) displayed CCRs in Test 1, but show no evidence of tolerance to the drug in Tests 2 and 3. We also found that the acute and chronic effects of nicotine are controlled by nicotinic receptor activation because the acute effect of nicotine was partially attenuated, and the chronic tolerance was blocked by the co-administration of mecamylamine. Although chronic tolerance was observed in both nicotine-associated and novel contexts, chronic tolerance was stronger in the nicotine-associated than in the novel context. Overall, these results are consistent with the principles of the habituation model of tolerance (Baker & Tiffany, 1985). Also, these results are consistent with other findings in planaria and rodents suggesting that Schmidtea mediterranea is a useful preclinical model for the study of tolerance development following chronic exposure to drugs of abuse.