High reinforcing efficacy of nicotine in non-human primates

Abstract

Although tobacco appears highly addictive in humans, there has been persistent controversy about the ability of its psychoactive ingredient nicotine to induce self-administration behavior in laboratory animals, bringing into question nicotine's role in reinforcing tobacco smoking. Because of ethical difficulties in inducing nicotine dependence in naïve human subjects, we explored reinforcing effects of nicotine in experimentally-naive non-human primates given access to nicotine for periods of time up to two years. Five squirrel monkeys with no experimental history were allowed to intravenously self-administer nicotine by pressing one of two levers. The number of presses on the active lever needed to obtain each injection was fixed (fixed-ratio schedule) or increased progressively with successive injections during the session (progressive-ratio schedule), allowing evaluation of both reinforcing and motivational effects of nicotine under conditions of increasing response cost. Over time, a progressive shift toward high rates of responding on the active lever, but not the inactive lever, developed. The monkeys' behavior was clearly directed toward nicotine self-administration, rather than presentation of environmental stimuli associated with nicotine injection. Both schedules of reinforcement revealed a high motivation to self-administer nicotine, with monkeys continuing to press the lever when up to 600 lever-presses were needed for each injection of nicotine. Thus, nicotine, by itself, in the absence of behavioral or drug-exposure history, is a robust and highly effective reinforcer of drug-taking behavior in a non-human primate model predictive of human behavior. This supports the use of nicotinic ligands for the treatment of smokers, and this novel preclinical model offers opportunities to test future medications for the treatment of nicotine dependence.

Figure 1

A. Monkeys sat in chambers equipped with two levers and distinctly colored light stimuli above the levers. Completion of the response requirement (the ratio) on the active lever produced a brief two-sec presentation of a light stimulus and an intravenous injection of nicotine followed by a timeout (TO) period of 5 to 60 sec. Completion of the ratio requirement on the inactive lever resulted in presentation of a brief two-sec light stimulus of a different color but no injection. The fixed-ratio (FR) response requirement was gradually increased over successive sessions from one to ten (FR 1 to FR 10). B. Mean percentage choice for responding on the active lever by monkeys when they were experimentally naive (first week under a FR 1 schedule) and when they had learned to self-administer nicotine under the FR 10, TO 60 sec schedule (first week under the FR 10 schedule). *P<0.01, compared to first week of training.

Figure 2

Maintenance of self-administration behavior under the FR 10 schedule during the first experience with saline substitution. Mean number (±SEM) of ratios completed on the active lever during three consecutive session with access to nicotine followed by an additional three sessions with saline substituted for nicotine are shown. The brief 2-sec light stimuli were presented following each ratio completion during both the nicotine and saline sessions. Self-administration behavior was not reduced by the substitution of saline injections for nicotine injections during this first exposure to extinction conditions.

Figure 3

Maintenance, extinction and reacquisition of self-administration behavior over consecutive sessions under the FR 10 schedule of reinforcement. Numbers of injections per session during consecutive nicotine (10 µg/kg per injection, filled symbols) and saline self-administration sessions (open symbols) are presented. Symbols represent the mean (±SEM) number of ratios completed on the active (circle) or inactive (triangle) levers per session from five squirrel monkeys. *P<0.05, compared to nicotine sessions.

Figure 4

Influence of nicotine dose on nicotine self-administration and total nicotine intake per session under the FR 10 schedule. Number of fixed ratios completed on the active and inactive levers per session (A) and total nicotine intake per session (B) are presented as a function of injection dose of nicotine (n = 5). Each symbol represents the mean (±SEM) of at least three sessions under each nicotine injection dose condition *P<0.05, **P<0.01 post-hoc comparisons with the saline vehicle (0 µg/kg per injection) conditions.

Figure 5

Influence of nicotine dose on nicotine self-administration and total nicotine intake per session under the progressive-ratio schedule. Number of nicotine injections per session and corresponding breaking-point values (highest ratio completed) under the progressive-ratio schedule (A) and total nicotine intake per session (B) are presented as a function of injection dose of nicotine (n = 5). Each symbol represents the mean (±SEM) of at least three sessions under each nicotine injection dose condition *P<0.05, **P<0.01 post-hoc comparisons with saline vehicle (0 µg/kg per injection) conditions.