Low and high locomotor responsiveness to cocaine predicts intravenous cocaine conditioned place preference in male Sprague–Dawley rats

Abstract

Outbred, male Sprague–Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on cocaine-induced locomotor activity in an open-field arena. This difference reflects cocaine's ability to inhibit the striatal dopamine transporter and predicts development of sensitization. To investigate the relationship between initial cocaine locomotor responsiveness and cocaine reward, here we first classified rats as either LCRs or HCRs in a conditioned place preference (CPP) apparatus. Subsequently, we conducted cocaine conditioning trials, twice-daily over 4 days with vehicle and cocaine (10 mg/kg, i.p. or 1 mg/kg, i.v.). When cocaine was administered by the i.p. route, similar to previous findings in the open-field, LCRs and HCRs were readily classified and locomotor sensitization developed in LCRs, but not HCRs. However, cocaine CPP was not observed. In contrast, when cocaine was administered by the i.v. route, the LCR/HCR classification not only predicted sensitization, but also CPP, with only LCR rats exhibiting sensitization and cocaine conditioning. Our findings show that the initial locomotor response to cocaine can predict CPP in male Sprague–Dawley rats under conditions when place conditioning develops, and that LCRs may be more prone to develop conditioning in the context of cocaine reward.

Introduction

Individuals exhibit a wide range of initial responsiveness to both the therapeutic and reinforcing effects of stimulant drugs, and this differential responsiveness is due largely to phenotypic differences (see Lott et al., 2005, Volkow and Swanson, 2003). Individual variability in responsiveness to stimulants may influence subsequent risk for stimulant abuse and addiction. This relationship has been most clearly documented for alcohol where a low level of response to ethanol in young men is associated with an enhanced risk for alcoholism later in life (Schuckit, 1994, Schuckit et al., 2006). Utilizing animal models that are based on differential individual responsiveness to drug(s) may be an effective strategy for identifying the genes and cellular mechanisms that can contribute to vulnerability to drug addiction.

A number of animal models have exploited pre-existing (rather than drug-induced) differences among individuals that correlate with sensitivity to stimulant-induced effects. For example, outbred male Sprague–Dawley (S–D) and Wistar rats can be initially identified as low or high responders to novelty, LRs or HRs, respectively. The greater locomotor activity of HRs in an inescapable novel environment has been correlated with an enhanced vulnerability to self-administer the stimulants amphetamine and cocaine (Piazza et al., 1989, Piazza et al., 2000; see Cain et al., 2004). It should be noted, however, that differential LR/HR novelty locomotor responsiveness was recently linked to different rates of learning the self-administration task, rather than cocaine intake per se (Mitchell et al., 2005). In addition, locomotor response to novelty is not always predictive of amphetamine-or cocaine-induced conditioned place preference (CPP) in rats, and mice categorized as LRs in a CPP chamber exhibit greater low dose cocaine-induced CPP than HRs (Brabant et al., 2005, Erb and Parker, 1994, Gong et al., 1996, Klebaur and Bardo, 1999, Shimosato and Watanabe, 2003.

Initial differences in cocaine-induced locomotor activation have also been reported and correlate well with several neurobiological and behavioral variables. For example, Cynomolgus monkeys that exhibit higher levels of cocaine-induced locomotor activity in a novel open-field arena are more likely to become subordinate in social groups, have lower numbers of basal ganglia dopamine D₂ receptors and are more likely to self-administer cocaine (Morgan et al., 2000, Morgan et al., 2002). In male S–D rats, acute cocaine-induced locomotor activity correlates positively with cocaine-induced enhancement of excitatory synaptic strength in the ventral tegmental area, which contains the cell bodies of the mesocorticolimbic DA neurons (Borgland et al., 2004).

In our laboratory, we have classified groups of outbred male S–D rats as either low or high cocaine responders (LCRs or HCRs, respectively), based on the median split of their open-field locomotor activity during the first 30 min after a cocaine injection (10 mg/kg, i.p.). In response to the initial dose of cocaine, HCRs exhibit significantly higher levels of locomotor activity and significant inhibition of in vivo striatal DA clearance by the dopamine transporter (DAT), relative to vehicle controls and LCRs (Briegleb et al., 2004, Gulley et al., 2003, Sabeti et al., 2002). With repeated cocaine administration, however, the responsiveness of the HCRs remains relatively constant whereas LCRs begin to exhibit marked cocaine-induced locomotor activity (i.e., locomotor sensitization) and significant inhibition of DA clearance (Sabeti et al., 2003). It is important to note that in our experiments S–D rats classified as LCRs and HCRs do not differ in novelty-induced locomotor activity when first placed in the open field apparatus (Briegleb et al., 2004, Gulley et al., 2003), and, conversely, S–D rats characterized by their response to a novel environment (HR/LR) do not consistently differ in their cocaine-induced locomotor activation (Gulley et al., 2003). These data suggest that the mechanisms underlying differential cocaine responsiveness in LCRs/HCRs and LRs/HRs may not be the same in S–D rats.

We designed the present study to determine what contribution, if any, individual differences in initial responsiveness to cocaine have on cocaine place conditioning in male S–D rats. The CPP is an animal model used to infer rewarding effects of drugs by measuring the capacity of a previously drug-paired environment to elicit and maintain approach behavior (for review, see Bardo and Bevins, 2000, Carr et al., 1989, Tzschentke, 1998). In this study, we first characterized outbred, male S–D rats as either LCRs or HCRs in a CPP apparatus and then subsequently conducted a series of cocaine (10 mg/kg, i.p, or 1 mg/kg, i.v.) and vehicle place conditioning trials. We chose the CPP procedure because it can be adapted to induce cocaine CPP with daily injection of cocaine (Dong et al., 2004, Harris and Aston–Jones , 2003, Kotlinska and Biala, 1999, Kotlinska and Biala, 2000, McGeehan and Olive, 2003, Tzschentke and Schmidt, 1997), the pattern of exposure we use in the laboratory to characterize rats as LCRs and HCRs and to measure the differential development of behavioral sensitization (e.g., Briegleb et al., 2004, Gulley et al., 2003, Sabeti et al., 2002, Sabeti et al., 2003).