Cocaine-induced Locomotor Stimulation Research Articles

Sleep Disturbance Alters Cocaine-Induced Locomotor Activity: Involvement of Striatal Neuroimmune and Dopamine Signaling.

Sleep disorders have high comorbidity with drug addiction and function as major risk factors for developing drug addiction. Recent studies have indicated that both sleep disturbance (SD) and abused drugs could activate microglia, and that increased neuroinflammation plays a critical role in the pathogenesis of both diseases. Whether microglia are involved in the contribution of chronic SDs to drug addiction has never been explored. In this study, we employed a mouse model of sleep fragmentation (SF) with cocaine treatment and examined their locomotor activities, as well as neuroinflammation levels and dopamine signaling in the striatum, to assess their interaction. We also included mice with, or without, SF that underwent cocaine withdrawal and challenge. Our results showed that SF significantly blunted cocaine-induced locomotor stimulation while having marginal effects on locomotor activity of mice with saline injections. Meanwhile, SF modulated the effects of cocaine on neuroimmune signaling in the striatum and in ex vivo isolated microglia. We did not observe differences in dopamine signaling in the striatum among treatment groups. In mice exposed to cocaine and later withdrawal, SF reduced locomotor sensitivity and also modulated neuroimmune and dopamine signaling in the striatum. Taken together, our results suggested that SF was capable of blunting cocaine-induced psychoactive effects through modulating neuroimmune and dopamine signaling. We hypothesize that SF could affect neuroimmune and dopamine signaling in the brain reward circuitry, which might mediate the linkage between sleep disorders and drug addiction.

Cocaine-induced locomotor stimulation involves autophagic degradation of the dopamine transporter.

Cocaine exerts its stimulant effect by inhibiting dopamine reuptake leading to increased dopamine signaling. This action is thought to reflect binding of cocaine to the dopamine transporter (DAT) to inhibit its function. However, cocaine is a relatively weak inhibitor of DAT, and many DAT inhibitors do not share the behavioral actions of cocaine. We previously showed that toxic levels of cocaine induce autophagic neuronal cell death. Here, we show that subnanomolar concentrations of cocaine elicit neural autophagy in vitro and in vivo. Autophagy inhibitors reduce the locomotor stimulant effect of cocaine in mice. Cocaine-induced autophagy degrades transporters for dopamine but not serotonin in the nucleus accumbens. Autophagy inhibition impairs cocaine conditioned place preference in mice. Our findings indicate that autophagic degradation of DAT modulates behavioral actions of cocaine.

Activation of the amylin pathway modulates cocaine-induced activation of the mesolimbic dopamine system in male mice

Besides food intake reduction, activation of the amylin pathway by salmon calcitonin (sCT), an amylin and calcitonin receptor agonist, inhibits alcohol-mediated behaviors in rodents. This involves brain areas processing reward, i.e. the laterodorsal (LDTg), ventral tegmental area (VTA) and nucleus accumbens (NAc). However, the effects of stimulation of the amylin pathway on behaviors caused by cocaine and the brain areas involved in these processes have not yet been investigated. We therefore explored in male mice, the effects of systemic administration of sCT on cocaine-induced locomotor stimulation, dopamine release in the NAc and cocaine reward, as well as reward-dependent memory of cocaine, in the conditioned place preference (CPP) paradigm. Moreover, the outcome of systemic sCT and cocaine co-administration for five days on locomotor activity was investigated. Lastly, the impact of sCT infusions into the LDTg, VTA, NAc shell or core on cocaine-evoked locomotor stimulation was explored. We found that sCT attenuated cocaine-induced locomotor stimulation and accumbal dopamine release, without altering cocaine's rewarding properties or reward-dependent memory retrieval in the CPP paradigm. Five days of cocaine administration caused locomotor stimulation in mice pre-treated with vehicle, but not with sCT. In mice infused with vehicle into the aforementioned reward-related areas, cocaine caused locomotor stimulation, a response that was not evident following sCT infusions. The current findings suggest a novel role for the amylinergic pathway as regulator of cocaine-evoked activation of the mesolimbic dopamine system, opening the way for the investigation of the amylin signalling in the modulation of other drugs of abuse.

Cocaine-Induced Locomotor Stimulation is Mediated by Autophagic Degradation of the Dopamine Transporter

Cocaine-Induced Locomotor Stimulation is Mediated by Autophagic Degradation of the Dopamine Transporter

Acute total sleep deprivation potentiates cocaine-induced hyperlocomotion in mice

Sleep deprivation is common place in modern society. Nowadays, people tend to self-impose less sleep in order to achieve professional or social goals. In the social context, late-night parties are frequently associated with higher availability of recreational drugs with abuse potential. Physiologically, all of these drugs induce an increase in dopamine release in the mesolimbic dopaminergic system, which leads to hyperlocomotion in rodents. Sleep deprivation also seems to play an important role in the events related to the neurotransmission of the dopaminergic system by potentiating its behavioral effects. In this scenario, the aim of the present study was to investigate the effects of total sleep deprivation (6h) on the acute cocaine-induced locomotor stimulation in male mice. Animals were sleep deprived or maintained in their home cages and subsequently treated with an acute i.p. injection of 15mg/kg cocaine or saline and observed in the open field. Total sleep deprivation for 6h potentiated the hyperlocomotion induced by acute cocaine administration. In addition, the cocaine sleep deprived group showed a decreased ratio central/total locomotion compared to the cocaine control group, which might be related to an increase in the impulsiveness of mice. Our data indicate that acute periods of sleep loss should be considered risk factors for cocaine abuse.

Behavior of knock-in mice with a cocaine-insensitive dopamine transporter after virogenetic restoration of cocaine sensitivity in the striatum

Cocaine's main pharmacological actions are the inhibition of the dopamine, serotonin, and norepinephrine transporters. Its main behavioral effects are reward and locomotor stimulation, potentially leading to addiction. Using knock-in mice with a cocaine-insensitive dopamine transporter (DAT-CI mice) we have shown previously that inhibition of the dopamine transporter (DAT) is necessary for both of these behaviors. In this study, we sought to determine brain regions in which DAT inhibition by cocaine stimulates locomotor activity and/or produces reward. We used adeno-associated viral vectors to re-introduce the cocaine-sensitive wild-type DAT in specific brain regions of DAT-CI mice, which otherwise only express a cocaine-insensitive DAT globally.Viral-mediated expression of wild-type DAT in the rostrolateral striatum restored cocaine-induced locomotor stimulation and sensitization in DAT-CI mice. In contrast, the expression of wild-type DAT in the dorsal striatum, or in the medial nucleus accumbens, did not restore cocaine-induced locomotor stimulation. These data help to determine cocaine's molecular actions and anatomical loci that cause hyperlocomotion. Interestingly, cocaine did not produce significant reward – as measured by conditioned place-preference – in any of the three cohorts of DAT-CI mice with the virus injections. Therefore, the locus or loci underlying cocaine-induced reward remain underdetermined. It is possible that multiple dopamine-related brain regions are involved in producing the robust rewarding effect of cocaine.

Unique genetic factors influence sensitivity to the rewarding and aversive effects of methamphetamine versus cocaine

Genetic factors significantly influence addiction-related phenotypes. This is supported by the successful bidirectional selective breeding of two replicate sets of mouse lines for amount of methamphetamine consumed. Some of the same genetic factors that influence methamphetamine consumption have been previously found also to influence sensitivity to the conditioned rewarding and aversive effects of methamphetamine. The goal of the current studies was to determine if some of the same genetic factors influence sensitivity to the conditioned rewarding and aversive effects of cocaine. Cocaine conditioned reward was examined in methamphetamine high drinking and low drinking line mice using a conditioned place preference procedure and cocaine conditioned aversion was measured using a conditioned taste aversion procedure. In addition, a general sensitivity measure, locomotor stimulant response to cocaine, was assessed in these lines; previous data indicated no difference between the selected lines in sensitivity to methamphetamine-induced stimulation. In contrast to robust differences for methamphetamine, the methamphetamine high and low drinking lines did not differ in sensitivity to either the rewarding or aversive effects of cocaine. They also exhibited comparable sensitivity to cocaine-induced locomotor stimulation. These data suggest that the genetic factors that influence sensitivity to the conditioned rewarding and aversive effects of methamphetamine in these lines of mice do not influence sensitivity to these effects of cocaine. Thus, different genetic factors may influence risk for methamphetamine versus cocaine use.

The Glucagon-Like Peptide 1 Analogue, Exendin-4, Attenuates the Rewarding Properties of Psychostimulant Drugs in Mice

Glucagon-like peptide 1 (GLP-1) is an incretine hormone that controls consummatory behavior and glucose homeostasis. It is released in response to nutrient ingestion from the intestine and production in the brain has also been identified. Given that GLP-1 receptors are expressed in reward areas, such as the nucleus accumbens and ventral tegmental area, and that common mechanisms regulate food and drug-induced reward we hypothesize that GLP-1 receptors are involved in reward regulation. Herein the effect of the GLP-1 receptor agonist Exendin-4 (Ex4), on amphetamine- and cocaine-induced activation of the mesolimbic dopamine system was investigated in mice. In a series of experiments we show that treatment with Ex4, at a dose with no effect per se, reduce amphetamine- as well as cocaine-induced locomotor stimulation, accumbal dopamine release as well as conditioned place preference in mice. Collectively these data propose a role for GLP-1 receptors in regulating drug reward. Moreover, the GLP-1 signaling system may be involved in the development of drug dependence since the rewarding effects of addictive drugs involves interferences with the mesolimbic dopamine system. Given that GLP-1 analogues, such as exenatide and liraglutide, are clinically available for treatment of type II diabetes, we propose that these should be elucidated as treatments of drug dependence.

MGluR5 knockout mice exhibit normal conditioned place-preference to cocaine

AbstractMetabotropic glutamate receptor 5 (mGluR5) null mutant (-/-) mice have been reported to totally lack the reinforcing or locomotor stimulating effects of cocaine. We tested mGluR5 -/- and +/+ mice for their locomotor and conditioned place- preference response to cocaine. Unlike the previous finding, here we show that compared to mGluR5 +/+ mice, -/- mice exhibit no difference in the locomotor response to low to moderate doses of cocaine (10 or 20 mg/kg). A high dose of cocaine (40 mg/kg) resulted in a blunted rather than absent locomotor response. We tested mGluR5 -/- and +/+ mice for conditioned place-preference to cocaine and found no group differences at a conditioning dose of 10 mg/kg, suggesting normal conditioned rewarding properties of cocaine. These results differ substantially from Chiamulera et al. (2001) and replicates Olsen et al., (2010), who found normal cocaine place-preference in mGluR5 -/- mice at 5 mg/kg. Our results indicate mGluR5 receptors exert a modulatory rather than necessary role in cocaine-induced locomotor stimulation and exert no effect on the conditioned rewarding effects of cocaine.

MGluR5 knockout mice exhibit normal conditioned place-preference to cocaine

AbstractMetabotropic glutamate receptor 5 (mGluR5) null mutant (-/-) mice have been reported to totally lack the reinforcing or locomotor stimulating effects of cocaine. We tested mGluR5 -/- and +/+ mice for their locomotor and conditioned place- preference response to cocaine. Unlike the previous finding, here we show that compared to mGluR5 +/+ mice, -/- mice exhibit no difference in the locomotor response to low to moderate doses of cocaine (10 or 20 mg/kg). A high dose of cocaine (40 mg/kg) resulted in a blunted rather than absent locomotor response. We tested mGluR5 -/- and +/+ mice for conditioned place-preference to cocaine and found no group differences at a conditioning dose of 10 mg/kg, suggesting normal conditioned rewarding properties of cocaine. These results differ substantially from Chiamulera et al. (2001) and replicates Olsen et al., (2010), who found normal cocaine place-preference in mGluR5 -/- mice at 5 mg/kg. Our results indicate mGluR5 receptors exert a modulatory rather than necessary role in cocaine-induced locomotor stimulation and exert no effect on the conditioned rewarding effects of cocaine.

New Synthesis of Tic-Hydantoins Sigma-1 Ligands and Pharmacological Evaluation on Cocaine-Induced Stimulant Effects

Activation of the newly identified σ₁ chaperone protein is involved in several aspects of the psychostimulant and addictive effects of cocaine. The development of ligands that selectively target the σ₁ protein may lead to putative potent anti-cocaine agents. We report here a new and more convergent synthetic pathway to amino side chain substituted hydantoins. Twenty new analogs of our lead compound were synthesized. None of them showed better in vitro affinity for σ₁ receptor than our lead compound. Nevertheless, three of them, obtained as racemates, showed high in vitro affinity and selectivity for σ₁ receptor. A preliminary in vivo evaluation of their pharmacological activity identified compound 22 as one that increases cocaine-induced locomotor stimulation and therefore acts as a potential efficient σ₁ agonist.

Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference

IntroductionRecently we demonstrated that genetic or pharmacological suppression of the central ghrelin signaling system, involving the growth hormone secretagogue receptor 1A (GHS-R1A), lead to a reduced reward profile from alcohol. As the target circuits for ghrelin in the brain include a mesolimbic reward pathway that is intimately associated with reward-seeking behaviour, we sought to determine whether the central ghrelin signaling system is required for reward from drugs of abuse other than alcohol, namely cocaine or amphetamine.ResultsWe found that amphetamine—as well as cocaine-induced locomotor stimulation and accumbal dopamine release were reduced in mice treated with a GHS-R1A antagonist. Moreover, the ability of these drugs to condition a place preference was also attenuated by the GHS-R1A antagonist.ConclusionsThus GHS-R1A appears to be required not only for alcohol-induced reward, but also for reward induced by psychostimulant drugs. Our data suggest that the central ghrelin signaling system constitutes a novel potential target for treatment of addictive behaviours such as drug dependence.

The high affinity dopamine uptake inhibitor, JHW 007, blocks cocaine-induced reward, locomotor stimulation and sensitization

The discovery and evaluation of high affinity dopamine transport inhibitors with low abuse liability is an important step toward the development of efficacious medications for cocaine addiction. We examined in mice the behavioural effects of (N-(n-butyl)-3alpha-[bis(4'-fluorophenyl)methoxy]-tropane) (JHW 007), a benztropine (BZT) analogue that blocks dopamine uptake, and assessed its potential to influence the actions of cocaine in clinically-relevant models of cocaine addiction. In the conditioned place preference (CPP) paradigm, JHW 007 exposure did not produce place conditioning within an ample dose range but effectively blocked the CPP induced by cocaine administration. Similarly, in the CPP apparatus JHW 007 treatment failed to stimulate locomotor activity at any dose but dose-dependently suppressed the hyperactivity evoked by cocaine treatment. In locomotor sensitization assays performed in the open field, JHW 007 did not produce sensitized locomotor behaviour when given alone, but it prevented the sensitized component of the locomotor response elicited by subchronic (8-day) cocaine exposure. In the elevated plus maze (EPM), acute treatment with JHW 007, cocaine and combinations of the BZT analogue and cocaine produced an anxiogenic-like profile. Re-test in the EPM following subchronic (8-day) exposure enhanced the anxiogenic-like effect of the same drug treatments. The present findings indicate that JHW 007 exposure counteracts some critical behavioural correlates of cocaine treatment, including conditioned reward, locomotor stimulation and sensitization, and lend support to the further development of BZT analogues as potential replacement medications in cocaine addiction.

A dopamine transport inhibitor with markedly low abuse liability suppresses cocaine self-administration in the rat

N-substituted benztropine analogs are potent dopamine uptake inhibitors that display pharmacokinetic/dynamic properties consistent with the profile of a substitute medication for cocaine addiction. The purpose of the present experiments was to characterize in rats the addictive-like properties of one such analog, 3 alpha-[bis(4'-fluorophenyl)methoxy]-tropane (AHN-1055), incorporating probes of its stimulant and incentive/motivational effects and of its ability to influence cocaine self-administration. We used open field activity and drug self-administration assays. To examine the effects of AHN-1055 on locomotor behavior, the analog was administered alone (0, 1, 3, and 10 mg/kg intraperitoneally) and in combination with cocaine (15 mg/kg i.p.). The influence of AHN-1055 on cocaine's intake was studied by administering the analog (0, 3, and 10 mg/kg i.p.) before the start of the self-administration sessions. To compare the addictive-like properties of AHN-1055 and cocaine, progressive ratio performance and abstinence-induced context-conditioned relapse were evaluated. AHN-1055 evoked robust and sustained locomotor activity when administered alone and increased cocaine-induced locomotor stimulation. Notably, the analog showed by comparison to cocaine weak reinforcing efficacy in a modified progressive ratio schedule of drug reinforcement, and contrary to cocaine, it showed no ability to promote context-conditioned relapse to drug seeking following stable self-administration and abstinence. Further, AHN-1055 treatment blocked cocaine intake dose-dependently in rats with a steady history of cocaine self-administration without reducing responding for sucrose, a natural reward. These findings demonstrate essential psychopharmacological differences between AHN-1055 and cocaine and highlight important properties of the analog as a possible pharmacotherapy in cocaine addiction.

The Dopamine Uptake Inhibitor 3α-[bis(4′-fluorophenyl)metoxy]-tropane Reduces Cocaine-Induced Early-Gene Expression, Locomotor Activity, and Conditioned Reward

Benztropine (BZT) analogs, a family of high-affinity dopamine transporter ligands, are molecules that exhibit pharmacological and behavioral characteristics predictive of significant therapeutic potential in cocaine addiction. Here, we examined in mice the effects of 3 alpha-[bis(4'-fluorophenyl)metoxy]-tropane (AHN-1055) on motor activity, conditioned place preference (CPP) and c-Fos expression in the striatum. AHN-1055 produced mild attenuation of spontaneous locomotor activity at a low dose (1 mg/kg) and weak stimulation at a higher dose (10 mg/kg). In parallel, the BZT analog significantly increased c-Fos expression in the dorsolateral caudoputamen at the high dose, whereas producing marginal decreases at low and moderate doses (1, 3 mg/kg) in both dorsal and ventral striatum. Interaction assays showed that cocaine's ability to stimulate locomotor activity was decreased by AHN-1055 treatment, but not by treatment with D-amphetamine. Such reduced ability did not result from an increase in stereotyped behavior. Another dopamine uptake inhibitor, nomifensine, decreased cocaine-induced locomotor activity but evoked by itself intense motor stereotypies. Remarkably, the BZT analog dose-dependently blocked cocaine-induced CPP without producing CPP when given alone, and blocked in conditioned mice cocaine-stimulated early-gene activation in the nucleus accumbens and dorsomedial striatum. These observations provide evidence that AHN-1055 does not behave as a classical psychomotor stimulant and that some of its properties, including attenuation of cocaine-induced striatal c-Fos expression, locomotor stimulation, and CPP, support its candidacy, and that of structurally related molecules, as possible pharmacotherapies in cocaine addiction.

Positive allosteric modulation of the human cannabinoid (CB1) receptor by RTI‐371, a selective inhibitor of the dopamine transporter

In our search for an indirect dopamine agonist as therapy for cocaine addiction, several selective inhibitors of the dopamine transporter (DAT), which are 3-phenyltropane analogues, were assayed for their effect on locomotor activity in mice. Interestingly, several of the compounds showed a poor correlation between stimulation of locomotion and DAT inhibition. One of the compounds, 3beta-(4-methylphenyl)-2beta-[3-(4-chlorophenyl)isoxazol-5-yl]tropane (RTI-371), was shown to cross the blood-brain barrier, by binding studies in vivo, and block cocaine-induced locomotor stimulation. As poor pharmacokinetics could not explain the behavioural effects of RTI-371, this compound was screened through our functional assays for activity at other CNS receptors. Initial screening identified RTI-371 as a positive allosteric modulator of the human CB(1) (hCB(1)) receptor. The effect of RTI-371 and other DAT-selective inhibitors on CP55940-stimulated calcium mobilization was characterized in a calcium mobilization-based functional assay for the hCB(1) receptor. Selected compounds were also characterized in a similar assay for human mu opioid receptor activation to assess the specificity of their effects. RTI-371 and several other DAT-selective inhibitors with atypical actions on locomotor behaviour increased the efficacy of CP55940 in a concentration-dependent manner. These results suggest that the lack of correlation between the DAT-binding affinity and locomotor stimulation of RTI-371 could be due at least in part to its activity as a positive modulator of the hCB(1) receptor.

Tic hydantoin sigma-1 agonist: Pharmacological characterization on cocaine-induced stimulant and appetitive effects

Activation of the newly identified σ 1 chaperone protein is involved in several aspects of the psychostimulant and addictive effects of cocaine. The development of ligands that selectively target the σ 1 protein may lead to putative potent anti-cocaine agents. Here, we synthetized substituted hydantoins with high affinity for the σ 1 protein and evaluated their behavioral efficacy. Two pure enantiomers were designed and synthesized: tetrahydroisoquinoleine-hydantoin fused compounds 3 and 4 . They increased cocaine-induced locomotor stimulation or sensitization. The most active enantiomer 4 , facilitated CPP acquisition but failed to substitute for cocaine. When CPP was acquired with cocaine and then extinguished, 4 provoked reactivation of CPP. These observations showed that compound 4 shows a typical profile of σ 1 protein activator, facilitating cocaine-induced behavioral effects. Preliminary ADME properties are in favour of an optimal therapeutic development. Such Tic-hydantoin compound may serve as a new effective agonist therapy in cocaine addiction.

Evidence for Multiple Sites within Rat Ventral Striatum Mediating Cocaine-Conditioned Place Preference and Locomotor Activation

Considerable evidence suggests that psychostimulants can exert rewarding and locomotor-stimulating effects via increased dopamine transmission in the ventral striatum. However, the relative contributions of ventral striatal subregions to each of these effects have been little investigated. In the present study, we examined the contribution of different ventral striatal sites to the rewarding and locomotor-activating effects of cocaine. Initially, the effects of bilateral 6-hydroxydopamine lesions of the nucleus accumbens core or medial shell on cocaine-induced locomotor stimulation (0.5-1.5 mg/kg i.v. or 5-20 mg/kg i.p.) and conditioned place preference (0.5 mg/kg i.v. or 10 mg/kg i.p.) were examined. In a subsequent study, we investigated the effects of olfactory tubercle versus medial shell lesions on cocaine-conditioned place preference and locomotor activity (0.5 mg/kg i.v.). Dopaminergic lesion extent was quantified by radioligand binding to the dopamine transporter. Multiple linear regression was used to identify associations between behavioral effects and residual dopamine innervation in ventral striatal subregions. On this basis, the accumbens core was associated with the locomotor stimulant effects of i.v. and i.p. cocaine. In contrast, the medial shell was associated with the rewarding effect of i.v. cocaine, but not of i.p. cocaine. Finally, the olfactory tubercle was identified as an additional site contributing to conditioned place preference produced by i.v. cocaine. Overall, these findings provide additional evidence that the locomotor stimulant and rewarding effects of systemically administered psychomotor stimulant drugs are segregated within the ventral striatum.

Modification of cocaine-induced behavioral and neurochemical effects by serotonin1A receptor agonist/antagonist in mice

Administration of cocaine causes a locomotor stimulant effect and increases extracellular levels of serotonin (5-HT) and dopamine (DA) in the brains of rodents. Previous studies show that 5-HT1A receptor agonist and antagonist modify the cocaine-induced behavioral and neurochemical effects in the rats. However, the role of the 5-HT system on the effects of cocaine has not been studied in the prefrontal cortex. The present study examined in ddY-strain male mice the effects of the 5-HT1A receptor agonist osemozotan and the receptor antagonist WAY100635 on cocaine-induced locomotor stimulant effect and increases in extracellular levels of 5-HT and DA in the prefrontal cortex. The cocaine-induced locomotor stimulant effect was attenuated by osemozotan and enhanced by WAY100635. The cocaine-induced increase in extracellular levels of 5-HT was attenuated by osemozotan, and enhanced by WAY100635. The cocaine-induced increase in extracellular levels of DA was enhanced by osemozotan, but not affected by WAY100635. These results suggest that the prefrontal 5-HT system plays a pivotal role in the locomotor stimulant effect of cocaine in mice.

Evidence that the relations between novelty-induced activity, locomotor stimulation and place preference induced by cocaine qualitatively depend upon the dose: a multiple regression analysis in inbred C57BL/6J mice

It has been speculated that an individual's response to novelty is a reliable predictor of its vulnerability to develop addiction. However, the relationships between response to novelty and the development of drug-induced conditioned place preference are still unclear. The present study investigates the relationships between locomotor responses to novelty, cocaine-induced locomotor stimulation and conditioned place preference in C57BL/6J mice with multiple regression analyses. Four groups of mice receiving saline, 4, 8 or 12 mg/kg cocaine (i.p.) were submitted to an 8-day unbiased counterbalanced place conditioning protocol. Levels of locomotion on the pre-conditioning session were used as a score of locomotor response to a novel environment. The locomotor activity on the first cocaine-pairing session of the conditioning procedure served as a measure of the locomotion-activating response to a single injection of cocaine. Cocaine-induced dose-dependent locomotor stimulant effects and a significant place preference at all tested doses. A positive correlation was found between the locomotor responses to novelty and the locomotor stimulant effects of cocaine, but was significant only for the highest dose of cocaine (12 mg/kg). In contrast, there was a negative correlation between the locomotor response to novelty and the conditioned place preference induced by 4 mg/kg cocaine. Finally, the locomotor stimulant effects of cocaine do not correlate with cocaine-induced conditioned place preference at any tested dose of cocaine. The relationships between locomotor response to novelty and both cocaine-induced stimulant and rewarding effects can be differentially affected by the dose in inbred C57BL/6J mice.