Escalation of food-maintained responding and sensitivity to the locomotor stimulant effects of cocaine in mice

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Abstract

Escalation of drug self-administration is a consequence of extended drug access and is thought to be specifically related to addiction, but few studies have investigated whether intake of non-drug reinforcers may also escalate with extended-access. The goal of these studies was to determine the effects of limited and extended-access to food reinforcers on behavioral and pharmacological endpoints in mice. In distinct groups, responding on a lever was maintained by liquid reinforcement, or nose-poke responses were maintained by sucrose pellets or liquid food in sessions lasting 1 h (limited-access) or 10 h (extended-access). The reinforcing strength of each food, as well as reinforcer-associated cues, was tested before and after extended-access using a progressive ratio (PR) schedule, and locomotor activity in response to novelty and increasing doses of cocaine was assessed in an open field setting in all animals after access to food reinforcers. Escalation of lever-pressing behavior reinforced by liquid food, but not nose-poke behavior reinforced by liquid food or sucrose pellets, was observed across successive extended-access sessions. A concomitant increase in the reinforcing strength of liquid food and its associated cues was apparent in mice that escalated their responding, but not in mice that did not escalate. Finally, extended reinforcer access leading to behavioral escalation was accompanied by an increased sensitivity to the psychostimulant effects of cocaine compared to limited-access. These findings indicate that behavioral escalation can develop as a consequence of extended-access to a non-drug reinforcer, although both the nature of the reinforcer (liquid versus solid food) and the topography of the operant response (lever versus nose-poke) modulate its development. These data also suggest that some of the behavioral and pharmacological corrolaries of behavioral escalation observed following extended-access to drug self-administration may not be due to drug exposure, but rather, may result from basic behavioral processes which underlie operant responding maintained by appetitive stimuli.

Introduction

Extended-access to drug reinforcers can result in an “escalation” of drug intake (reviewed by Zernig et al., 2007), as was first demonstrated by Ahmed and Koob (1998) in rats allowed to intravenously self-administer cocaine for either 1 or 6 h. The major finding of this report was that rats restricted to a 1 h access to cocaine maintained a stable level of drug self-administration over successive sessions, while animals allowed extended-access (6 h) to cocaine progressively escalated their drug intakes (from their own baseline) over this experimental duration. This phenomenon has now been replicated in multiple laboratories and species with several other drugs of abuse, including heroin (Ahmed et al., 2000), methamphetamine (Kitamura et al., 2006) and phencyclidine (Carroll et al., 2005). The escalation procedure is generally thought to model “compulsive drug intake,” “increased motivation for drug,” or “loss of control” over drug self-administration, all of which are thought to be critical signs of the transition from controlled drug use to addiction. The increasing popularity of the Ahmed and Koob escalation model is highlighted by the fact that their initial finding has been cited well over 200 times since its publication, and its adoption by other researchers has allowed for a reasonably thorough exploration of the behavioral and neural consequences of escalated drug intake (e.g. Ferrario et al., 2005, Ahmed and Cador, 2006). Surprisingly, however, the specificity of the model has not been extensively tested using non-drug reinforcers. Because of this, addiction-based interpretations of behavioral and neural data derived from the escalation model must be regarded as tenuous at this time.

It is a well known tenet of operant conditioning that behaviors which result in the delivery of palatable foods will increase in frequency—this is a specific example of the general phenomenon of positive reinforcement (c.f., Ferster and Culbertson, 1982). In the drug studies outlined above, drug infusions function as positive reinforcers, and instrumental responses in animal subjects are maintained by drug delivery in sessions of either short (typically 1 h) or long (anywhere between 6 and 11 h) duration. While many investigators have studied within-session changes in patterns of food-reinforced responding (e.g. DeMarse et al., 1999, McSweeney and Murphy, 2000), studies designed to investigate whether extended-access to food reinforcers would lead to escalated intake across sessions have not been previously reported. However, similar experiments have been performed using non-operant techniques. In one such study, escalated sugar intake with bingeing in the first hour of daily access was engendered following 1 month of daily 12 h food deprivation and 12 h access to sugar and chow in rats (Colantuoni et al., 2001). Moreover, mice repeatedly exposed to palatable food in a specific environmental context displayed progressive and persistent increases in locomotor activity in that context, as well as “cross-sensitization” to the stimulant effects of some drugs of abuse (LeMerrer and Stephens, 2006). These data resemble the development of behavioral sensitization to repeated intermittent exposure to drugs of abuse such as cocaine, and suggest that the non-contingent delivery of drug and non-drug appetitive stimuli may result in similar behavioral changes. This interpreation implies a common mechanism underlying both food- and drug-induced behavioral sensitization.

The reinforcing strength of self-administered drugs seems to change as a consequence of behavioral escalation, but the data in this regard are often conflicting. Some previous studies utilizing the Ahmed and Koob escalation procedure with cocaine self-administration have demonstrated increased response rates under progressive ratio (PR) schedules following behavioral escalation, but no change in breakpoint (e.g., Liu et al., 2005). Other studies have quantified increases in maximal breakpoints maintained by high unit doses of cocaine with no corresponding change in sensitivity to lower doses (e.g., Morgan et al., 2005). Still other studies have reported “vertical” shifts in the entire dose–effect function for cocaine under a PR schedule following escalation of intake, suggesting an increased sensitivity to all drug doses including saline (e.g., Paterson and Markou, 2003). Finally, other studies have demonstrated dose-dependent escalation of cocaine self-administration (Roberts et al., 2007).

We thus studied the effects of limited and extended-access to non-drug reinforcers on food-maintained behavior, PR performance, responding during extinction, and sensitivity to the locomotor stimulant effects of various doses of cocaine. To assess the behavioral specificity of these effects, liquid or solid food reinforcers were used to maintain behavior on either a response lever or a nose-poke device. Although previous studies utilizing drug self-administration in mice have demonstrated remarkably similar dose-effect functions generated with lever-press or nose-poke operant responses (Caine et al., 1999, David et al., 2001), the topography of the operant response can profoundly influence the behavioral effects of psychostimulants in other settings (Graeff and De Oliveira, 1975). Thus, the operant response and the particular food reinforcer maintaining behavior were parametrically varied across groups.

Section snippets

Animals

Drug and experimentally naïve male Swiss Webster mice (Charles River Laboratories, Inc., Wilmington, MA) weighing approximately 25 g at the start of behavioral training served as subjects. Mice were housed in a temperature- and humidity-controlled colony room at the Yerkes Center, where lights were set to a 12 h light/dark cycle. Animals had free access to standard rodent chow and water in the home cage. To facilitate food-reinforced responding, access to chow was suspended for 3 h prior to the

Data analysis

Graphical presentation of all data depicts mean ± SEM. Between-group differences in food-maintained behavior, PR performance, extinction responding, and dose–response functions for cocaine-induced locomotor activity and stereotypy were analyzed using a one way repeated measures analysis of variance (ANOVA, F values), or, when normality tests failed, with Friedman's repeated measures ANOVA on ranks (χ2 values). Post hoc tests on all pairwise multiple comparisons were performed after the method of

Drugs

Cocaine HCl was supplied by the National Institute on Drug Abuse (Research Technology Branch, Research Triangle Park, NC), was dissolved in 0.9% physiological saline, and administered intraperitoneally (IP) at a volume of 1.0 ml/100 g.

Food-maintained responding

During the 24 limited-access training sessions, nose-poke behavior maintained by sucrose pellets was rapidly acquired and stably maintained (Fig. 1A, white background) by all animals. When session length was extended to 10 h, the number of reinforcers earned increased by approximately 2-fold, and showed no trend of increasing further over the next 20 extended-access sessions (Fig. 1A, grey background.) A similar pattern was observed with the number of responses emitted during these sessions

Discussion

The major findings of this research are two fold. First, under conditions where the operant response was a nose-poke, extended-access to both a liquid and solid food did not result in an escalation of reinforced behavior and reinforcer consuption and did not cross-generalize to locomotor activity induced by cocaine. Secondly, consistent with previous research using drug reinforcers under lever operant conditions (i.e., Ahmed and Koob, 1998, Ahmed et al., 2000, Carroll et al., 2005, Kitamura et

Acknowledgements

Expert animal husbandry services were provided by the animal care staff at the Yerkes National Primate Research Center. Portions of this manuscript were presented at the 2006 annual meeting of the International Study Group Investigating Drugs as Reinforcers. These studies were funded by US PHS Grants DA020645, RR020146, and by the Yerkes Base Grant RR00165.

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