Behavioral manifestations of the nicotine abstinence syndrome in the rat: peripheral versus central mechanisms.

The nicotine abstinence syndrome was studied in the rat utilizing a modified rating scale of the opiate abstinence syndrome. Rats were infused with 10.27 mg/kg per day nicotine hydrogen tartrate for 7 days via subcutaneous minipumps. The behavior of each animal was observed before, during and after termination of the nicotine infusion. The abstinence signs in the withdrawal sessions included gasps, genital licks, ptosis, shakes, teeth chatter, yawns and changes in locomotor activity. Abstinence was induced through surgical removal of the pump or through administration of a nicotinic receptor antagonist, acting either centrally and peripherally (mecamylamine 1 mg/kg s.c.) or peripherally only (chlorisondamine 1 mg/kg s.c.). Statistical evaluation revealed a significant increase in overall abstinence signs both at 16 (P < 0.05) and 40 h (P < 0.01) after termination of the nicotine infusion, as compared to the number of signs in the nicotine treated animals' baseline sessions and to the number of signs in control animals (P < 0.05). There was also a significant reduction in locomotor activity during both withdrawal sessions. Animals injected with mecamylamine or chlorisondamine displayed a larger increase in the abstinence score (P < 0.001) than the spontaneously abstinent animals. Acute administration of different doses of nicotine or of the peripherally acting nicotinic receptor agonist tetramethylammonium (0.8 mg/kg s.c.) reversed the behavioral nicotine abstinence syndrome. Our results show that a nicotine abstinence syndrome can be elicited in rats on a chronic nicotine regimen either by acute withdrawal of nicotine or by the administration of nicotinic receptor antagonists and that peripheral nicotinic receptors may contribute significantly to the overall withdrawal reaction.