The relationship between the locomotor response to a novel environment and behavioral disinhibition in rats

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Abstract

Behavioral disinhibition, a component of impulsivity, has been associated with cocaine abuse and dependence. To examine the relationship between behavioral disinhibition and vulnerability to cocaine use disorders, we employed the high responder (HR)/low responder (LR) rodent model, in which rats that exhibit high levels of activity in response to a novel environment are more sensitive to the effects of psychostimulants. In Experiment 1, performance under a differential reinforcement of low-rate (DRL) schedule was used as a measure of behavioral disinhibition in HR and LR rats. The HR rats displayed more behavioral disinhibition relative to LR rats on the DRL 20- and 35-s schedules. In Experiment 2, rats were divided into groups with high disinhibition (HD) and low disinhibition (LD) based on DRL 20-s performance, then challenged with cocaine. Rats characterized as HD and LD had similar DRL 20-s performance to rats characterized as HR and LR (Experiment 1), respectively, but did not differ in their response to cocaine. The results of this study suggest that the HR phenotype may also be characterized by greater behavioral disinhibition, and that the DRL task is a suitable animal model to investigate the role of behavioral disinhibition in vulnerability to the behavioral effects of cocaine.

Introduction

Impulsivity is a broadly defined personality trait characterized by intolerance for delayed reward, impaired ability to consider the consequences of behaviors and behavioral disinhibition (the inability to withhold a behavioral response; Evenden, 1999b). High levels of impulsivity measured by self-report (Ma et al., 1999, Moeller et al., 2001a, Moeller et al., 2004, Moeller et al., 2005) or behavioral laboratory tasks (Bornovalova et al., 2005, Coffey et al., 2003, Kirby and Petry, 2004, Li et al., 2006, Moeller et al., 2004, Moeller et al., 2002, Moeller et al., 2005) have been associated with cocaine dependence in several studies involving human subjects. In addition, impulsivity has been associated with a greater likelihood of relapse to cocaine use during abstinence (Moeller et al., 2001b, Patkar et al., 2004). While these data suggest that impulsivity is related to the cycle of cocaine use disorders, it is difficult to determine whether impulsivity imparts vulnerability to cocaine dependence, is a consequence of prolonged cocaine use, or both.

A limited number of longitudinal studies have examined the role of impulsivity in vulnerability to psychostimulant use disorders. In these studies, high levels of impulsivity during childhood predicted a greater likelihood of illicit drug use (including cocaine and other psychostimulants) in early adulthood relative to age-matched controls (Lambert and Hartsough, 1998, Masse and Tremblay, 1997). These results suggest that greater impulsivity during childhood may impart vulnerability to stimulant use during adulthood. However, the measures of impulsivity used in these studies (ratings by parents and teachers; diagnosis of attention deficit-hyperactivity disorder, which involves other maladaptive behaviors in addition to impulsivity) are less rigorous measures of impulsivity than those used in studies of impulsivity in adults, providing interpretational difficulties relating adult psychostimulant abuse to childhood impulsivity.

Another factor that complicates our understanding of the relationship between impulsivity and cocaine use disorders is the multidimensional nature of impulsivity. Impulsivity does not appear to be a unitary construct, but rather a trait comprised of several components that contribute to its characteristic poorly conceived, disadvantageous decisions and behaviors (Evenden, 1999a, Evenden, 1999b). These components include poor behavioral disinhibition, failure to consider the consequences of behaviors, and a preference for immediate rather than delayed rewards (Evenden, 1999a, Evenden, 1999b, Moeller et al., 2001a). It is possible that one, some, or all components of impulsive decision-making processes and behaviors are associated with vulnerability to cocaine dependence.

Various well-developed animal models exist to measure different components of impulsive behavior in rats. Two studies have employed these models to examine the relationship between individual differences in impulsive behavior and cocaine self-administration in rats. Despite using different measures of impulsive behavior, both studies report a positive relationship between impulsive behavior and cocaine self-administration (Dalley et al., 2007, Perry et al., 2005). In one study, rats that displayed a preference for a small immediate reward over a large delayed reward acquired cocaine self-administration at a significantly faster rate and self-administered more cocaine relative to rats with a preference for the larger delayed reward (Perry et al., 2005). In another study, rats who had difficulty withholding a nose-poke response during a five-choice serial reaction time task (i.e., made more premature responses) also self-administered more cocaine than rats that made fewer premature responses (Dalley et al., 2007). Two additional studies have measured the relationship between impulsive behavior and experimenter-delivered psychostimulants. Rats that had difficulty withholding a behavioral response to earn a reinforcer demonstrated greater amphetamine-induced hyperactivity relative to rats that were better at withholding behavioral responses (Dellu-Hagedorn, 2006). However, another study failed to find a relationship between behavioral disinhibition and the response to experimenter-delivered amphetamine (Bardo et al., 2006).

While the relationship between impulsive behavior and sensitivity to cocaine in rodents has just begun to receive attention, a more extensive line of research has demonstrated that individual differences in the locomotor response to a novel environment can predict sensitivity to the behavioral effects of psychostimulants and psychostimulant self-administration in rats. Rats that have high levels of activity in response to a novel environment (high responders; HR) are more sensitive to the locomotor stimulating effects of psychostimulants (Bevins and Peterson, 2004, Deminiere et al., 1989, Hooks et al., 1991a, Hooks et al., 1991b), are more likely to self-administer amphetamine (Bevins and Peterson, 2004, Deminiere et al., 1989, Klebaur et al., 2001, Piazza et al., 1989, Piazza et al., 1990) and cocaine (Piazza et al., 2000), and are more sensitive to the conditioned effects of psychostimulants than rats with a low level of novelty-induced locomotor activity (low responders; LR) (Bevins and Peterson, 2004, Jodogne et al., 1994). These data suggest that the phenotypic behavioral response to a novel environment is correlated with vulnerability to the behavioral effects of psychostimulants, including cocaine.

What remains to be conclusively determined is whether the novelty-induced locomotor activity phenotype overlaps with an impulsive phenotype in rats. It is possible that rats that are more vulnerable to psychostimulants (those characterized as HR rats) may also possess behavioral traits that could be characterized as impulsive. To date, studies that have examined this relationship (Bardo et al., 2006, Dalley et al., 2007, Dellu-Hagedorn, 2006, Perry et al., 2005) have produced mixed results. Three of the studies failed to find a significant relationship between the locomotor response to a novel environment and measures of impulsive behavior (Bardo et al., 2006, Dellu-Hagedorn, 2006, Perry et al., 2005), and the fourth study reported a negative correlation between impulsive behavior and the locomotor response to novelty (Dalley et al., 2007). However, each of these studies classified HR/LR status differently, and used different methods to measure components of impulsive behavior in rats.

The inconsistent results in these studies are not surprising; the relationship between a multidimensional trait like impulsivity and vulnerability to the effects of psychostimulants is likely to be very complex. The current study was designed to more fully investigate the relationship between one component of impulsivity (behavioral disinhibition) and vulnerability to the behavioral effects of cocaine, and to determine whether the known vulnerable HR phenotype overlaps with an impulsive phenotype (high behavioral disinhibition) in rats. We chose to measure behavior in the differential reinforcement of low rate (DRL) task, a measure of behavioral disinhibition (Evenden, 1999b). In this task, rats are required to withhold lever-press responding for a specific interval to earn a reinforcer; responses that are made before the interval has elapsed are not reinforced, and are considered an indication of greater behavioral disinhibition (Evenden, 1999b). In Experiment 1, behavioral disinhibition was measured in HR and LR rats under DRL 10-, 20-, 35-, and 70-s schedules to examine behavioral disinhibition under a full range of delay parameters. In Experiment 2, we determined if rats with high and low behavioral disinhibition in the DRL task performed similarly to HR and LR rats, and if rats with different levels of behavioral disinhibition were differentially sensitive to the effects of cocaine on DRL responding.

Section snippets

Animals

Male Sprague–Dawley rats (Harlan Sprague–Dawley, Inc., Indianapolis, IN) weighing 250–275 g (approximately 90 days old) at the time of arrival were used. Rats were allowed to acclimate for 5–6 days to a colony room at a constant temperature (21–23 °C) and humidity (40–50%) on a 12-h light–12-h dark cycle (lights on at 07:00 h). Rats were housed four per cage prior to the first locomotor activity test and two per cage during operant training and testing. Food was available ad libitum in the home

Locomotor response to a novel environment

Locomotor response to a novel environment was measured before (Fig. 1A) and after (Fig. 1B) 12 weeks of DRL training. Fig. 1A demonstrates that HR rats displayed significantly more activity in the activity monitors relative to LR rats (t18 = −18.0, p < 0.001). When tested again after DRL training (4 months between locomotor tests; a different version of the software was used on the second test), HR rats maintained significantly higher levels of activity relative to LR rats (t18 = −3.1, p < 0.01), and

Discussion

Rats separated into groups based on their locomotor response to a novel environment displayed different levels of behavioral disinhibition in the DRL task; specifically, HR rats displayed more behavioral disinhibition relative to LR rats at both the DRL 20- and 35-s schedules. When a separate group of rats was trained on the DRL 20-s task, the rats that showed the greatest behavioral disinhibition in this task (HD rats) performed similarly to the HR rats, and the rats with the least behavioral

Acknowledgements

The authors would like to acknowledge The National Institute on Drug Abuse (T32 DA 07287, F32 DA 0121438, K05 DA 020087, K02 DA 000260, R01 DA 006511) for funding support, and Dr. Julie Ross, Mr. Robert G. Fox, and Ms. Sonja J. Stutz for technical assistance.

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    Present address: Department of Psychology, Augustana College, Rock Island, IA, USA. Tel.: +1 309 794 3376; fax: +1 309 794 7743.

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