Scott T. Barrett

A quantitative analysis of the reward-enhancing effects of nicotine using reinforcer demand.

Reward enhancement by nicotine has been suggested as an important phenomenon contributing toward tobacco abuse and dependence. Reinforcement value is a multifaceted construct not fully represented by any single measure of response strength. The present study evaluated the changes in the reinforcement value of a visual stimulus in 16 male Sprague–Dawley rats using the reinforcer demand technique proposed by Hursh and Silberberg. The different parameters of the model have been shown to represent differing facets of reinforcement value, including intensity, perseverance, and sensitivity to changes in response cost. Rats lever-pressed for 1-min presentations of a compound visual stimulus over blocks of 10 sessions across a range of response requirements (fixed ratio 1, 2, 4, 8, 14, 22, 32). Nicotine (0.4 mg/kg, base) or saline was administered 5 min before each session. Estimates from the demand model were calculated between nicotine and saline administration conditions within subjects and changes in reinforcement value were assessed as differences in Q0, Pmax, Omax, and essential value. Nicotine administration increased operant responding across the entire range of reinforcement schedules tested, and uniformly affected model parameter estimates in a manner suggesting increased reinforcement value of the visual stimulus.

The effects of repeated exposure on the reward-enhancing effects of nicotine.

Nicotine increases operant responding for a weakly reinforcing audiovisual stimulus in rats, but the role of repeated exposure in the development of this effect has not been explicitly investigated. This study investigated, in two experiments, whether repeated nicotine exposure is a requisite for the expression of a reward-enhancing effect in rats, using a probe design by administering nicotine acutely at a range of doses (0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg) both before and after two weeks of daily administration of 0.3 mg/kg of nicotine. Nicotine did not enhance responding for an audiovisual stimulus relative to baseline at any dose when administered before repeated daily administration, but responding was enhanced at 0.1, 0.3, and 1.0 mg/kg of nicotine after daily administration. The results suggest that repeated exposure to nicotine is a requisite for the expression of reward-enhancing effects, and implicate sensitization to the effects of nicotine in this process.

The effects of varenicline on methamphetamine self-administration and drug-primed reinstatement in female rats

While research has revealed heightened vulnerability to meth addiction in women, preclinical models rarely use female subjects when investigating meth seeking and relapse. The goal of the present study was to examine the effects of varenicline (Chantix(®)), a partial α4β2 and full α7 nicotinic acetylcholine receptor agonist, on meth self-administration and reinstatement in female rats. Sprague-Dawley rats were surgically implanted with an indwelling jugular catheter. Half of the rats were then trained to self-administer meth (0.056 mg/kg/infusion) on a variable ratio 3 schedule of reinforcement; the other half earned intravenous saline during daily, 2h sessions. When responding stabilized, varenicline (0.0, 0.3, 1.0, 3.0mg/kg) was tested to determine how it altered meth taking. Varenicline was probed on 4 test days; each test separated by 2 standard self-administration sessions to assure responding remained stable. Following this testing was 15 extinction sessions. Twenty-four hours after the last extinction session were four consecutive days of meth-primed reinstatement. The same 4 doses of varenicline were examined to determine how it altered reinstatement triggered by 0.3mg/kg meth (IP). Rats readily self-administered meth. The higher doses of varenicline did not affect meth-taking in a specific fashion as active lever pressing was also slightly reduced in rats that has access to saline in the self-administration phase. Female rats displayed robust meth-primed reinstatement. Notably, the lower doses of varenicline increased meth-primed reinstatement. This amplified susceptibility to reinstatement (i.e., relapse) may be an impediment for the use of varenicline as a therapeutic to treat meth use disorder.

Nicotine does not enhance discrimination performance in a temporal bisection procedure.

Recent reports of selective disruption of stimulus control by drug administration and other disruptive operations in temporal discrimination procedures may be interpreted as a disruption of attention to the temporal sample stimuli. This experiment assessed the effects of nicotine, a compound that has been widely shown to increase measures of attention, on temporal discrimination performance. Pigeons responded under a psychophysical choice procedure in which responses to one key color were correct after presentation of four shorter sample durations and responses to another key color were correct after presentation of four longer sample durations. Performance under nicotine was characterized by using a model that differentiates the effects of nicotine on stimulus control, bias, and sensitivity of temporal discrimination. Nicotine selectively decreased the measure of stimulus control, but did not systematically affect the measures of timing. Mecamylamine (1.0 mg/kg) failed to antagonize the disruptive effects of nicotine. These results suggest that disruption of temporal discrimination performance in this preparation may not have been dependent on the specific pharmacology of nicotine and underscore the importance of quantitative separation of the effects of various manipulations on stimulus control from effects on timing.

Examining the reinforcement-enhancement effects of phencyclidine and its interactions with nicotine on lever-pressing for a visual stimulus.

Nicotine is a widely-abused drug, yet its primary reinforcing effect does not seem potent as other stimulants such as cocaine. Recent research on the contributing factors toward chronic use of nicotine-containing products has implicated the role of reinforcement-enhancing effects of nicotine. The present study investigates whether phencyclidine (PCP) may also possess a reinforcement-enhancement effect and how this may interact with the reinforcement-enhancement effect of nicotine. PCP was tested for two reasons: (1) it produces discrepant results on overall reward, similar to that seen with nicotine and (2) it may elucidate how other compounds may interact with the reinforcement-enhancement of nicotine. Adult male Sprague-Dawley rats were trained to lever press for brief visual stimulus presentations under fixed-ratio (FR) schedules of reinforcement and then were tested with nicotine (0.2 or 0.4 mg/kg) and/or PCP (2.0mg/kg) over six increasing FR values. A selective increase in active lever-pressing for the visual stimulus with drug treatment was considered evidence of a reinforcement-enhancement effect. PCP and nicotine separately increased active lever pressing for a visual stimulus in a dose-dependent manner and across the different FR schedules. The addition of PCP to nicotine did not increase lever-pressing for the visual stimulus, possibly due to a ceiling effect. The effect of PCP may be driven largely by its locomotor stimulant effects, whereas the effect of nicotine was independent of locomotor stimulation. This dissociation emphasizes that distinct pharmacological properties contribute to the reinforcement-enhancement effects of substances.

Experimental analysis of behavior and tobacco regulatory research on nicotine reduction: EAB & Regulatory Research

With the signing of H.R. 1256, the Family Smoking Prevention and Tobacco Control Act, the United States Food and Drug Administration (FDA) gained regulatory authority over the tobacco industry. A notable clause in this Act permits the FDA to regulate nicotine yields. However, they cannot completely remove this addictive constituent from tobacco products. This restriction has prompted the FDA to seek research on the threshold dose of nicotine that does not support dependence. This idea of threshold dose has led to an interesting reframing of scientific questions. For example, some researchers studying nicotine from this regulatory perspective translated the notion of an addiction threshold to a construct thought to play a role in addiction but which can be more readily operationalized. Examples include reinforcement threshold, discrimination threshold, and reinforcer-enhancement threshold. In this Perspective Paper, we highlight the importance of behavioral pharmacology and, specifically, the experimental analysis of behavior to help establish a scientific basis for policy decisions regarding nicotine yields. Recent research, including exemplars provided herein, note vast individual differences in the effects of nicotine at a known dose. Unfortunately, the behavioral and biological factors that contribute to such individual variations remain to be understood. We believe that behavior analysts are uniquely well-positioned to contribute to this understanding.

Nicotine- and cocaine-triggered methamphetamine reinstatement in female and male Sprague-Dawley rats

Abstract Preclinical studies have demonstrated a return to methamphetamine (meth)‐seeking behavior (reinstatement) induced by injections of meth administered by the experimenter (drug‐prime). Notably, females tend to be more sensitive to drug‐prime; often displaying more reinstatement behavior when compared to males. While meth‐primed reinstatement of meth‐seeking behavior has been established, little is known about the ability of other drugs of abuse to substitute for meth during drug‐primed reinstatement; nicotine and cocaine were the focus of the present work. We also examined if self‐administration and/or reinstated meth‐seeking behavior was affected by repeated nicotine administration. Male and female Sprague‐Dawley rats were trained to self‐administer meth during daily sessions. During this self‐administration phase, rats were placed into 1 of 2 groups: saline or repeated nicotine exposure. Rats in the repeated nicotine group received nicotine injections 4 h after meth self‐administration sessions, whereas the remaining rats received saline. Following self‐administration was extinction in which meth was no longer available and nicotine was no longer administered. After extinction, rats were tested to determine if 0 (saline), 0.2, and 0.4 mg/kg nicotine reinstated meth‐seeking behavior. Three days of re‐extinction followed nicotine testing. Finally, rats received reinstatement tests with 0 (saline), 5, and 10 mg/kg cocaine. Nicotine and cocaine reinstated meth‐seeking behavior in male and female rats with no difference between the sexes. Repeated nicotine administration potentiated meth reinstatement following the 0.4 mg/kg nicotine‐prime. While females may be more sensitive to reinstatement triggered with the original self‐administration drug, this effect may not generalize to priming with other drugs of abuse. HighlightsRepeated nicotine treatment did not alter meth self‐administration.Repeated nicotine treatment facilitated meth extinction.Nicotine and cocaine induced meth‐seeking in male and female rats.Previous nicotine experience potentiated meth reinstatement induced by nicotine.

Caring about Power Analyses

Everyone should care deeply about statistical power and effect size given that the current estimates of wasted nonreproducible and exaggerated research findings range from 50 to 85%, combined with the mandates from the National Institutes of Health (NIH) that proposal reviewers focus on scientific rigor and investigators consider sex as a biological variable. In this Viewpoint, we provide recommendations and resources regarding power analyses aimed at enhancing rigor, and hence decreasing waste, when designing experiments. As part of this effort, we also make recommendations for reporting key statistics that will aid others in estimating sample size based on published research.