Reinforcement enhancing effect of nicotine and its attenuation by nicotinic antagonists in rats

Abstract

Rationale: Recent studies have demonstrated that nicotine can enhance operant responding for other nonpharmacological reinforcing stimuli. However, the nature of the reinforcement-enhancing effect of nicotine remains largely unknown.

Objective: The present study determined the dose dependency of the ability of nicotine to increase lever-pressing responses maintained by a compound visual stimulus (VS) in rats and examined its sensitivity to pharmacological antagonism of nicotinic acetylcholine receptors (nAChRs).

Materials and methods: Male Sprague-Dawley rats were trained in daily 1-h sessions to lever press for delivery of a VS (1 s lever light on and 60 s house light off) on a fixed ratio 5 schedule. During these sessions, eight scheduled response-independent intravenous infusions of nicotine (total amount: 0, 0.06, 0.12, 0.24, 0.48 mg kg(-1) h(-1)) were delivered. In pharmacological tests, a nonselective nAChR antagonist mecamylamine, alpha4beta2-selective antagonist dihydro-beta-erythroidine (DHbetaE), and alpha7-selective antagonist methyllycaconitine (MLA) were administered in different groups of rats 30 min before the session.

Results: The VS maintained a moderate level of lever-pressing responses and nicotine dose-dependently increased responses for the VS presentations. Preteatment of mecamylamine and DHbetaE but not MLA significantly attenuated the nicotine-enhanced responding. However, mecamylamine had no effect on responding for the VS in rats that received scheduled saline infusions.

Conclusions: These results demonstrate dose dependency of the reinforcement-enhancing effect of nicotine and suggest that activation of the alpha4beta2- but not alpha7-containing nAChRs may mediate this effect.

Fig. 1

Profiles of responses on the active (top) and inactive (below) levers. Note that the doses of nicotine in the figure legend are the total amount of nicotine rats received during the 1-h sessions. FR5:0.24 means that nicotine dose was switched to 0.24 mg kg⁻¹ h⁻¹ (0.03 mg/kg per infusion) in all nicotine-infused rats. See text for statistical details

Fig. 2

Dose-dependent effect of nicotine administered in a response-independent manner on responses on the active (top) and inactive (below) levers (n=8–11). The numbers of responses were averaged across the last three sessions (sessions 18 to 20) of the FR5 phase. **p< 0.01, ***p<0.001, and ****p<0.0001 different from saline group. ^p<0.05, ^^p<0.01, and ^^^^p<0.0001 different from the 0.06 mg kg⁻¹ h⁻¹ group. +p<0.05 different from the 0.12 mg kg⁻¹ h⁻¹ group

Fig. 3

Effect of mecamylamine on lever responses in rats (n=8) that received scheduled nicotine infusions. ***p<0.001 different from vehicle. ^^p<0.01 different from 0.5 mg/kg. +p<0.05 different from 1 mg/kg

Fig. 4

Effect of mecamylamine on lever responses in rats (n=10) receiving no nicotine infusions

Fig. 5

Effect of DHβE on lever responses in rats (n=12) that received scheduled nicotine infusions. **p<0.01 different from vehicle

Fig. 6

Effect of MLA on lever responses in rats (n=11) that received scheduled nicotine infusions