Basal activity level in mice predicts the initial and sensitized locomotor response to nicotine only in high responders

Highlights

• It is important to identify factors that may contribute to nicotine responding.

• High basal activity correlated with both the acute and sensitized response to nicotine in mice.

• Only mice with low basal activity demonstrated a significant CPP.

• Basal locomotor activity may be of use to predict nicotine responding.

Abstract

Not all humans become addicted to drugs of abuse following casual use. Thus, it is important to identify factors that may contribute to subsequent drug responding. Previous studies have identified characteristics such as novelty-seeking, impulsivity, and anxiety as factors involved in the progression to drug dependence. The current experiment investigated basal locomotor activity in C57Bl/6N mice as a potential predictor of subsequent nicotine responses. We examined the ability of differences in basal locomotor activity to predict the acute and sensitized response to nicotine, as well as nicotine conditioned reinforcement. A median split was used to distinguish between low and high responders with regard to basal locomotor activity in mice. We then measured the acute response to nicotine (0.5 mg/kg IP) in these mice, followed by measures of conditioned place preference (CPP; 0.5 mg/kg IP) and locomotor sensitization (0.5 mg/kg IP), to determine whether basal locomotion is predictive of subsequent responding to nicotine. High, but not low, basal activity was found to be a predictor of both the acute and sensitized response to nicotine. Interestingly, only mice classified as having low basal activity demonstrated a significant CPP, suggesting that pre-exposure to nicotine differentially affects conditioned reinforcement on the basis of initial activity level. Basal locomotor activity may be an efficient measure of subsequent locomotor responding to nicotine, but only in animals classified as having high basal activity. However, animals with low basal locomotor activity may be more susceptible to the reinforcing properties of nicotine.

Introduction

In humans, not all drug users progress from drug-taking to addiction, with only a small percentage reaching the clinical criterion for a diagnosis of drug dependence [1]. Thus it is critical to determine the factors that lead some individuals to compulsive drug-taking behaviors. In recent years much preclinical research has been devoted to identifying risk factors to predict subsequent drug responding, many of which have been based on measures of locomotor activity. Alterations in locomotor activity in response to drugs of abuse in animals, such as the development of behavioral sensitization, have long been suggested to model the neurobiological adaptations that induce drug craving following drug use in humans [2], [3], [4], especially changes in mesocorticolimbic dopamine circuits that underlie both sensitization and the reinforcing properties of drugs of abuse and drug-associated cues [5], [6].

Previous studies have examined differences in a variety of measurements based on the initial locomotor responsiveness to psychostimulants such as cocaine. For example, Allen et al. [7] demonstrated that only rats classified as low responders (LCRs) based on their acute locomotor response to cocaine developed locomotor sensitization in response to repeated injections, while high responders (HCRs) failed to sensitize to the locomotor activating effects of cocaine. Furthermore, LCRs and HCRs have been shown to differ in both intravenous cocaine CPP [7] and cocaine self-administration [8], with only LCRs exhibiting CPP, and LCRs demonstrating increased responding under a progressive ratio schedule of reinforcement. Thus, LCRs demonstrated an increased sensitivity to the stimulant effects of cocaine, consistent with an increase in sensitivity to cocaine as measured using CPP and self-administration.

Another locomotor activity-based model used to identify susceptibility to subsequent increased drug responding is that of novelty-induced locomotion. An enhanced exploration in novel environments has been suggested to predict vulnerability to drugs of abuse. For example, rats classified as high responders based on their performance in a novel environment demonstrated an increased acute response to amphetamine as compared to low responders [9]. Furthermore, adult mice classified as high and low novelty seekers based on their performance in a novel environment task demonstrated differences in the ability of a sub-threshold dose of cocaine (1 mg/kg) to elicit a CPP, with high novelty seekers demonstrating a preference for a cocaine-paired environment following conditioning, but no preference in the low novelty seekers [10]. Rats classified as high responders to novelty have also been demonstrated to learn to self-administer cocaine faster, and self-administer more cocaine, than their low responder counterparts [11]. Thus, novelty-seeking can be an effective predictor of subsequent drug responses.

Although susceptibility to the abuse of psychostimulants such as cocaine and amphetamine has been examined, few studies have sought to characterize behavioral predictors of nicotine dependence, despite tobacco use being a substantial health problem and the leading risk factor in preventable deaths worldwide. For example, Pastor et al. [12] examined whether the acute locomotor response to nicotine would affect the subsequent establishment of a nicotine CPP in rats classified as either low or high nicotine responders. The authors demonstrated that in low responders, pre-exposure to nicotine failed to induce a CPP following a conditioning regimen that normally results in a conditioned preference (four nicotine exposures), and only showed CPP after extensive conditioning sessions (seven nicotine exposures). In contrast, high nicotine responders failed to show a preference at any conditioning regimen. Thus, pre-exposure to nicotine resulted in an impairment in reinforcement that was greater in high responders. In contrast, rats classified as high responders based on novelty-induced locomotion demonstrated more reliable nicotine self-administration and a higher break point than their low responder counterparts [13]. Thus, the ability to predict subsequent nicotine responding based on differences in the acute locomotor response to the drug or novelty-induced locomotion remains unclear.

The purpose of this study was to examine the ability of basal locomotor activity to predict the acute and sensitized locomotor response to nicotine in animals classified as having low and high basal activity. We also employed a sub-threshold conditioning procedure to assess the effects of nicotine pre-exposure on nicotine CPP in animals separated based on their initial basal locomotor activity level.