Reactivation of morphine conditioned place preference by drug priming: role of environmental cues and sensitization

RATIONALE: Relapse is a major characteristic of drug addiction and remains the primary problem in treating drug abuse. Despite a great deal of research, the exact factors that determine renewed drug-seeking and persistent craving for them remain unclear. OBJECTIVE: The present study was designed to evaluate the role of environmental cues and behavioral sensitization in reactivation of place preference following long-term extinction of morphine conditioned place preference (CPP) in rats. METHODS: After being injected with morphine and saline alternately for 6 days to induce morphine CPP, the rats were subjected to extinction of conditioning for 21 days. The rats were then administered various doses of morphine, heroin, or cocaine and confined in the previous drug- or saline-paired compartment. CPP was determined. Some rats were treated with scopolamine or naloxone prior to administration of these three drugs. RESULTS: Morphine CPP disappeared following a 21-day extinction. A single injection of morphine, heroin, or cocaine evoked place preference for the previous drug-paired side. However, place preference for the previous vehicle-paired side was induced after the animals received a single injection of morphine, heroin or cocaine and confined to the previous vehicle-paired compartment. Administration of naloxone prior to drug treatment significantly attenuated the place preference induced by morphine or heroin, but had no significant effect on the place preference elicited by cocaine. Administration of the cholinergic antagonist scopolamine before morphine, heroin and cocaine inhibited the expression of place preference. CONCLUSIONS: Environment-related cues and behavioral sensitization play critical roles in the incentive motivation underlying drug-seeking behaviors.     

Stress and relapse to drug seeking in rats: studies on the generality of the effect

RATIONALE: Intermittent footshock reinstates drug-taking behavior in rats, but not behaviors previously maintained by food reinforcers. Here we tested further the generality of this phenomenon by determining whether restraint and food deprivation stressors would reinstate heroin seeking, whether the environment in which footshock is given modulates footshock-induced reinstatement, and whether footshock would reinstate operant responding previously maintained by brain stimulation reward (BSR). METHODS: Groups of rats were trained to self-administer for 10 days either heroin (0.05-0.1 mg/kg/infusion, IV, three 3-h sessions/day) or brain stimulation into the septal area (trains of monopolar cathodal pulses of 100 micros for 500 ms, one 60-min session/day). After extinction of the heroin-reinforced behavior (10-13 days), the rats were tested for reinstatement after exposure to food deprivation (1 and 21 h), restraint given outside the self-administration environment (5, 15 and 30 min), or intermittent footshock (0.8 mA, 15 min) given in the self-administration environment or in a novel (non-drug) environment. For BSR-trained rats, the effect of footshock on reinstatement after extinction (6-10 days) was compared with that induced by noncontingent brain stimulation (three or six discrete stimulations at the start of the test sessions). RESULTS: Food deprivation reinstated heroin seeking. Footshock reliably reinstated heroin seeking when given in the drug environment, but not when given in a non-drug environment. Similarly, restraint given outside the self-administration environment failed to reinstate heroin seeking. In addition, footshock was as effective as priming brain stimulation in reinstating operant responding previously maintained by BSR. CONCLUSIONS: The effect of footshock on reinstatement of heroin seeking generalizes to food deprivation, and appears to be dependent on the environment in which the stressor is given. The data with BSR indicate that the phenomenon of footshock-induced reinstatement is not selective for drug reinforcers.     

Extinction and spontaneous recovery of ataxic tolerance to ethanol in rats

RATIONALE AND OBJECTIVES: Two experiments with rats using an ethanol ataxia method investigated extinction and spontaneous recovery of tolerance. Tolerance extinction has been shown with a variety of drugs and methods, but until now it has not been shown with ethanol ataxia. Extinction was investigated here because of its connection with cue exposure treatments, and also to allow an assessment of spontaneous recovery. Spontaneous recovery is the return of conditioned responses, such as those potentially contributing to tolerance, when time passes after extinction. In terms of response topography it resembles instances of relapse in humans. Its demonstration constitutes one technique for illustrating that the effects of extinction are often temporary. There are no published reports showing a recovery of tolerance to any drug due to the passage of time after extinction. A demonstration of spontaneous recovery contributes to an understanding of the effects and time course of tolerance extinction. It also raises the possibility that spontaneous recovery involving drug tolerance has mechanisms similar those involved in instances of spontaneous recovery studied more extensively with non-drug methods. METHODS: In one experiment, ataxic tolerance was conditioned to a strobelight conditioned stimulus (CS) by exposing rats to the strobelight while experiencing the effects of an ethanol injection. Tolerance was extinguished in 17 or 24 once-daily trials by presenting the strobelight without ethanol (with saline). The effect of those numbers of trials was assessed on the day after extinction in the presence of the strobelight when ethanol was again injected. The effect was compared to the effect of the strobelight and ethanol in naive rats and in rats that had received only tolerance conditioning. In a second experiment, ataxic tolerance was conditioned and then extinguished over 17 trials, just as in the other experiment. Different groups were then tested 1, 12, 18, and 24 days after extinction in the presence of the strobelight when ethanol was again injected. RESULTS: Ataxic tolerance was fully extinguished after either 17 or 24 trials, as shown by comparisons with the naive and conditioning-only controls. Tolerance was greater (it recovered) when the strobelight CS was reintroduced 24, 18, and even 12 days after extinction, compared with testing 1 day after extinction. CONCLUSIONS: Conditioned ataxic tolerance can be extinguished, just as other conditioned tolerances can. More important, the return of tolerance over time after extinction represents spontaneous recovery of ethanol tolerance, and indicates that as in other conditioning preparations, extinction does not result in unlearning of the original conditioning association. The identification of spontaneous recovery of tolerance isolates a robust source of the potential for drug use relapse: the mere passage of time after extinction.     

Reinstatement of cocaine seeking in 129X1/SvJ mice: effects of cocaine priming,cocaine cues and food deprivation

RATIONALE AND OBJECTIVES: The mechanisms underlying relapse to cocaine seeking induced by exposure to priming cocaine injections, cues associated with cocaine self-administration and environmental stressors have been studied in rats. Here we describe a reinstatement method for studying relapse to cocaine seeking in mice, a suitable species for studying the effect of genetic manipulations such as gene knockout or gene over-expression on compulsive drug use.METHODS: Male mice of the 129X1/SvJ strain were trained for 14-16 days to self-administer cocaine (0.75 mg/kg/infusion; 4 h/day; fixed-ratio-1 schedule of reinforcement; infusions were paired with a light-tone compound cue). Next, the lever-pressing behavior was extinguished by removing the cocaine syringes in the presence (Exps. 1 and 3) or absence (Exp. 2) of the cocaine cue. Subsequently, tests for reinstatement were conducted after exposure to priming injections of cocaine (0, 1.5, 3.0 and 6.0 mg/kg, IV; Exp. 1), response-contingent presentations of the cocaine-associated cue (Exp. 2), or food deprivation stress (1 and 22 h; Exp. 3).RESULTS: The effect of cocaine priming on reinstatement was modest and was only observed at the highest dose tested. On the other hand, reinstatement of cocaine seeking was observed following exposure to the cocaine-associated cue and food deprivation stress.CONCLUSIONS: The present data suggest that factors contributing to relapse to drugs can be studied in the reinstatement model using the common 129X1/SvJ mouse inbred strain.     

The reinstatement model of drug relapse: history,methodology and major findings

Rational and objectives. The reinstatement model is currently used in many laboratories to investigate mechanisms underlying relapse to drug seeking. Here, we review briefly the history of the model and describe the different procedures that have been used to study the phenomenon of reinstatement of drug seeking. The results from studies using pharmacological and neuroanatomical techniques to determine the neuronal events that mediate reinstatement of heroin, cocaine and alcohol seeking by acute priming injections of drugs, drug-associated cues and environmental stressors are summarized. In addition, several issues are discussed, including (1) the concordance between the neuronal mechanisms involved in drug-induced reinstatement and those involved in drug reward and discrimination, (2) the role of drug withdrawal states and periods in reinstatement of drug seeking, (3) the role of neuronal adaptations induced by exposure to drugs in relapse, and (4) the degree to which the rat reinstatement model provides a suitable preclinical model of relapse to drug taking. Conclusions. The data derived from studies using the reinstatement model suggest that the neuronal events that mediate drug-, cue- and stress-induced reinstatement of drug seeking are not identical, that the mechanisms underlying drug-induced reinstatement are to some degree different from those mediating drug discrimination or reward, and that the duration of the withdrawal period following cocaine and heroin self-administration has a profound effect on reinstatement induced by drug cues and stress. Finally, there appears to be a good correspondence between the events that induce reinstatement in laboratory animals and those that provoke relapse in humans.     

The dissociation of heroin-seeking patterns induced by contextual,discriminative, or discrete conditioned cues in a model of relapse to heroin in rats

Rationale The role of heroin-related stimuli in motivating the resumption of heroin use is not fully understood. Objectives The objective was to characterize the relative importance of drug-related contextual stimuli, discriminative stimuli (DS), or discrete conditioned stimuli (CSs) on drug seeking when rats were reintroduced into the operant context after withdrawal. Methods Nose-poke responding by male rats was reinforced with intravenous heroin (0.05 mg/kg per infusion, 4-h session daily) under a progressive ratio schedule of reinforcement for 14 days. Each session began with the illumination of a green light in the active hole that served as DS. Each earned heroin injection was paired with a 5-s compound cue light and the sound of the infusion pump that served as the discrete CSs. Results Response rates of heroin seeking induced by the contextual stimuli were comparable to the average rates of responding during self-administration training, but rates induced by either DS or CSs were greater than those induced by the contextual stimuli alone (P<0.05). The responding induced by contingent presentations of CSs was higher than that of DS after extinction of instrumental behavior. The drug seeking induced by CSs can be maintained after 3 days extinction with DS in the original context, although the responding elicited by DS cannot be recovered after 3 days of extinction with CSs. Conclusions The relapse to drug seeking can be elicited separately by environmental cues, heroin-predictive DS, or discrete CSs in the same rat after withdrawal.     

Blockade of cue- and drug-induced reinstatement of morphine-induced conditioned place preference with intermittent sucrose intake

Sucrose intake has been suggested to alter the expression of morphine-induced conditioned place preference (CPP). To date, the potential effects of sucrose intake on the extinction and drug-induced reinstatement of CPP have not been determined. In the present study, sucrose solution (15%) was given prior to, during, and following the acquisition of morphine-induced CPP. Place preference was subsequently assessed during expression, extinction, and morphine-induced reinstatement. The results showed that the sucrose solution given prior to place conditioning training transiently suppressed the expression of morphine CPP. Sucrose solution given during place conditioning training had no effects on the expression, extinction, and reinstatement of CPP. When the sucrose solution was given following the acquisition of morphine CPP, the extinction of morphine CPP was accelerated, and morphine-induced reinstatement was profoundly inhibited. The above results demonstrated that sucrose intake could differentially affect the expression, extinction, and reinstatement of morphine-induced CPP, depending on the interference schedules. Our findings suggest that offering non-drug rewards could be a valuable approach to maintain abstinence and preventing relapse in drug addicts.     

Rewarding properties of gamma-hydroxybutyric acid: an evaluation through place preference paradigm

Gamma-hydroxybutyric acid (GHB), a putative neurotransmitter or neuromodulator found in the mammalian brain, has been successfully used in clinical practice to alleviate both alcohol and opiate withdrawal symptoms. In the present study we used a conditioned place preference (CPP) paradigm to investigate whether GHB possesses rewarding properties in rats. In order to exclude possible artifacts due to experimental design, we evaluated the possibility of a shift in preference when rats are conditioned either on their non-preferred side or on a randomly assigned side of conditioning. In both experiments GHB was seen to induce CPP. Although to date the physiological role of this compound still remains unclear, there is no doubt that GHB, further to its proven effect on alcohol and opiates, possesses rewarding properties of its own. The abuse liability afforded by this drug suggests the use of particular caution in handling GHB as a clinically useful drug. Received: 27 November 1995 /Final version: 10 February 1997     

Conditioned place preference with morphine: the effect of extinction training on the reinforcing CR

Rats were injected with either morphine (5 mg/kg) or saline in association with one set of distinct environmental stimuli, and injected with saline in association with a different set of stimuli. After four conditioning trials, animals were given a 15-minute free-choice test to determine which stimulus environment was preferred. Animals displayed CPP as a significant increase in duration spent within the morphine-associated environment, but did not display any change in number of entries into that environment. In contrast, when extinction training was given following CPP, animals displayed a significant decrease in duration spent per entry into the morphine-associated environment, but did not display any change in total duration spent in that environment. These results suggest that assessment of the reinforcing conditioned response (CR) in the CPP model may require measurement of both duration spent in and number of entries into the drug-associated environment.     

Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure

Background and rationale The reinstatement model is widely used to study relapse to drug addiction. However, the model’s validity is open to question.Objective We assess the reinstatement model in terms of criterion and construct validity.Research highlights and conclusions We find that the reinstatement model has adequate criterion validity in the broad sense of the term, as evidenced by the fact that reinstatement in laboratory animals is induced by conditions reported to provoke relapse in humans. The model’s criterion validity in the narrower sense, as a medication screen, seems promising for relapse to heroin, nicotine, and alcohol. For relapse to cocaine, criterion validity has not yet been established primarily because clinical studies have examined medication’s effects on reductions in cocaine intake rather than relapse during abstinence. The model’s construct validity faces more substantial challenges and is yet to be established, but we argue that some of the criticisms of the model in this regard may have been overstated.     

Food restriction increases acquisition, persistence and drug prime-induced expression of a cocaine-conditioned place preference in rats

Cocaine conditioned place preference (CPP) is more persistent in food-restricted than ad libitum fed rats. This study assessed whether food restriction acts during conditioning and/or expression to increase persistence. In Experiment 1, rats were food-restricted during conditioning with a 7.0 mg/kg (i.p.) dose of cocaine. After the first CPP test, half of the rats were switched to ad libitum feeding for three weeks, half remained on food restriction, and this was followed by CPP testing. Rats tested under the ad libitum feeding condition displayed extinction by the fifth test. Their CPP did not reinstate in response to overnight food deprivation or a cocaine prime. Rats maintained on food restriction displayed a persistent CPP. In Experiment 2, rats were ad libitum fed during conditioning with the 7.0 mg/kg dose. In the first test only a trend toward CPP was displayed. Rats maintained under the ad libitum feeding condition did not display a CPP during subsequent testing and did not respond to a cocaine prime. Rats tested under food-restriction also did not display a CPP, but expressed a CPP following a cocaine prime. In Experiment 3, rats were ad libitum fed during conditioning with a 12.0 mg/kg dose. After the first test, half of the rats were switched to food restriction for three weeks. Rats that were maintained under the ad libitum condition displayed extinction by the fourth test. Their CPP was not reinstated by a cocaine prime. Rats tested under food-restriction displayed a persistent CPP. These results indicate that food restriction lowers the threshold dose for cocaine CPP and interacts with a previously acquired CPP to increase its persistence. In so far as CPP models Pavlovian conditioning that contributes to addiction, these results suggest the importance of diet and the physiology of energy balance as modulatory factors.     

CP-154,526, a selective, non-peptide antagonist of the corticotropin-releasing factor1 receptor attenuates stress-induced relapse to drug seeking in cocaine- and heroin-trained rats

We have found that peptide antagonists of corticotropin-releasing factor (CRF) receptors attenuate reinstatement of heroin and cocaine seeking induced by footshock. Here we examined the effect of a non-peptide, selective CRF₁ receptor antagonist, CP-154,526, on reinstatement of heroin and cocaine seeking induced by footshock. Rats were trained to self-administer heroin or cocaine (0.1 and 1.0 mg/kg per infusion, IV, respectively) for 9–12 days. Extinction sessions were given for up to 14 days, during which saline was substituted for the drugs. Tests for reinstatement were then conducted after exposure to intermittent footshock (10 or 15 min, 0.5 mA). The footshock stressor reliably reinstated extinguished cocaine- and heroin-taking behavior. Pretreatment with CP-154,526 (15 and 30 mg/kg, SC) significantly attenuated the reinstatement effect of the stressor in both heroin- and cocaine-trained rats. CP-154,526, administered in the absence of the footshock stressor, did not affect extinguished drug seeking. In addition, in a separate experiment, CP-154,526 was shown not to alter high rates of lever pressing for a 10% sucrose solution, suggesting that the suppression of lever pressing in stress-induced reinstatement is not caused by a performance deficit. These results extend previous reports on the role of CRF in reinstatement of drug seeking induced by stressors. The present data also suggest that, to the extent that exposure to environmental stressors provoke relapse to drug use in humans, systemically effective CRF receptor antagonists may be of use in the treatment of relapse to drug use. Received: 12 July 1997/Final version: 20 October 1997     

Neurobehavioral development of CD-1 mice after combined gestational and postnatal exposure to ozone

 Outbred CD-1 mice were exposed continuously to ozone (O₃, 0.6 ppm) from 6 days prior to the formation of breeding pairs to the time of weaning of the offspring on postnatal day 22 (PND 22) or to PND 26. One half of the mice in each of eight O₃ and eight control litters were subjected on PND 24 to a 20-min open-field test after IP treatment by either saline or scopolamine (2 mg/kg). The remaining mice (those exposed until PND 26) were subjected on PNDs 28–31 to a conditioned place preference (CPP) test, using a short schedule with a single IP injection on PND 29 of either d-amphetamine (3.3 mg/kg) or saline. Subsequently, the saline mice of the open-field experiment were used on PND 59 for an activity test in one of the CPP apparatus compartments after IP treatment by either d-amphetamine (same dose) or saline. In addition, the saline mice of the CPP experiment underwent a multi-trial, step-through passive avoidance (PA) acquisition test on PND 59 or 60, followed 24 h later by a single-trial retention test. In the absence of effects on reproductive performance (proportion of successful pregnancies, litter size, offspring viability, and sex ratio), O₃ offspring showed a long-lasting reduction in body weight without modification of sex differences. Ozone effects on neurobehavioral development were not large and quite selective, including: attenuation of the sex differences in several responses (rearing and sniffing in the open-field, activity in the final CPP test session); a change in response choices in the final CPP test, in the absence of a main effect on conditioning; a reduction of grooming in the activity test on PND 29; and impairment of PA acquisition limited to the initial period of training. Received: 3 November 1994/Accepted: 30 January 1995     

Toward understanding ethanol's capacity to be reinforcing: a conditioned place preference following injections of ethanol

Rats that had previously consumed a 6% ethanol (ETOH) solution daily for 26 days and rats without such a history served as subjects in a test for the ability of ETOH to establish a conditioned place preference. The time of putative conditioning was from 4 to 8 min after injections of ETOH, 1 g/kg. The combination of programming the period of putative conditioning to be shortly after injections and using rats habituated to drinking ETOH allowed a conditioned place preference to emerge after only a few conditioning trials. Such a result potentially reveals features of the way ETOH achieves its reinforcing capability and sets the stage for understanding the mechanism of that reinforcement.     

Social reward-conditioned place preference: a model revealing an interaction between cocaine and social context rewards in rats

A recent thrust in drug abuse research is the influence of social interactions on drug effects. Therefore, the present study examined conditioned place preference (CPP) as a model for assessing interactions between drug and social rewards in adolescent rats. Parameters for establishing social reward-CPP were examined, including the number of conditioning sessions/day (1 or 2), the total number of sessions (2, 8, or 16), and the duration of sessions (10 or 30 min). Subsequently, the effects of cocaine or dextromethorphan on social reward-CPP and play behavior were examined. The results demonstrate that social reward-CPP (i.e., preference shift for an environment paired previously with a rat) was similar using either 1 or 2 conditioning sessions/day and either 10 or 30 min sessions; however, social reward-CPP increased as the number of social pairings increased. Additionally, a low dose of cocaine (2 mg/kg, IP) and a low number of social pairings (2 pairings) failed to produce CPP when examined alone, but together produced a robust CPP, demonstrating an interaction between these rewards. The non-rewarding drug, dextromethorphan (30 mg/kg, IP), failed to enhance social reward-CPP, suggesting that drug-enhanced social reward-CPP is specific to rewarding drugs. Surprisingly, there was no relationship between play behaviors and preference shift in drug-naïve animals. Furthermore, cocaine inhibited play behavior despite enhancing social reward-CPP, suggesting that aspects of social interaction other than play behavior likely contribute to social reward. The findings have important implications for understanding the influence of social context on cocaine reward during adolescence.     

Rewarding and aversive properties of IP and SC cocaine: assessment by place and taste conditioning

Three experiments were conducted to compare the effectiveness of intraperitoneally (IP) administered or subcutaneously (SC) administered cocaine to produce place and/or taste conditioning after four conditioning trials. In each experiment, IP (5–20 mg/kg) cocaine produced a place preference, but SC (0.5–20 mg/kg) cocaine at concentrations that prevented necrosis, did not produce a place preference. The failure of SC cocaine to produce a place preference was not a function of conditioning trial duration. On the other hand, SC cocaine (20 mg/kg) produced conditioned taste avoidance, but IP cocaine (20 mg/kg) did not produce conditioned taste avoidance. The results suggest that IP cocaine, but not SC cocaine, is rewarding.     

The validity of the reinstatement model of craving and relapse to drug use

Rationale The reinstatement procedure has been used increasingly as a laboratory model of craving and relapse to drug abuse. With the number of reports involving this procedure growing, its validity as a model of relapse merits discussion. Objectives The present commentary addresses the validity of the reinstatement procedure in relation to the following three types of models: 1) formal equivalence models, which are assessed on the basis of how well they resemble some phenomenon outside the laboratory (i.e. face validity); 2) correlational models, which are assessed on the basis of how well they predict outcomes of various interventions (such as drug administration or environmental change) when effected outside the laboratory (i.e. predictive validity); and 3) functional equivalence models, which are assessed on the basis of whether the laboratory phenomenon is mechanistically identical or reasonably similar to the phenomenon outside the laboratory (i.e. content validity). Methods In order to evaluate the reinstatement model, we briefly examined its various forms and uses, and compared preclinical outcomes to what is known about relapse from the clinical literature. Results In its most general form, the reinstatement model has reasonable face validity; that is, there is a general agreement in appearance or form of the behavior in the model and the clinical target, relapse. This face validity is generally absent for the procedure when it is used as a model of craving. The predictive validity of the model has not been established. Evidence from studies of treatments for drug relapse have not supported the validity of the model, however from studies of the effects of the presentation of various types of stimuli (e.g. drug "priming") there is mixed evidence supporting predictive validity. With regard to functional equivalence, there is reasonable evidence supporting functional commonalities between drug self-administration in laboratory animals and human drug abusers, which lends support to the validity of the reinstatement model. However, there are several specific areas of departure between the methods and results using the model and clinical practices and observations about relapse, suggesting a lack of functional equivalence. Conclusions There is reasonable evidence to support the face validity of the model, but at this time, neither its predictive validity nor functional equivalence has been fully established, which underscores the need for caution in generalizing results from the model to the clinical condition.     

Reinstatement of ethanol-seeking behavior by drug cues following single versus multiple ethanol intoxication in the rat: effects of naltrexone

Rationale A positive relationship exists between chronic ethanol intoxication experiences and the severity of neural hyperactivity and withdrawal seizures. An important possibility is that withdrawal reactions also influence the motivation to obtain and consume ethanol. Objectives To test this hypothesis, the effects of ethanol-cues on the recovery of extinguished ethanol-seeking and the reversal of this effect by naltrexone, were determined in non-dependent rats and in rats subjected to single versus repeated ethanol intoxications. Methods Rats were trained to self-administer and discriminate between 10% ethanol and water. Instrumental responding then was extinguished and the effects of exposure to ethanol and water cues were determined. Subsequently, rats were divided into three groups and exposed to control vapor (CTRL), to 12-day ethanol vapor prior to withdrawal (SW), or to three cycles of 3-day intoxication experiences (MW), respectively. Following intoxication, reacquisition and breaking point for ethanol self-administration and cues-induced reinstatement of drug-seeking were investigated. Results Ethanol cues significantly reinstated responding in the pre- and post-dependence test, but no significant differences between groups was observed. However, the ability of naltrexone to attenuate the response-reinstatement was significantly reduced in MW rats. Moreover, in the progressive ratio schedule, the breaking points for ethanol were significantly increased in the MW animals. Conclusions The results suggest that repeated intoxication did not enhance cue-induced reinstatement of ethanol-seeking. However, naltrexone effects on cues-induced "relapse" appear to be attenuated in MW rats.     

Reinforcing properties of morphine and naloxone revealed by conditioned place preferences: a procedural examination

In rats, conditioned place preferences are produced by morphine and conditioned place aversions produced by naloxone. In the present studies, several issues concerning the demonstration and interpretation of place conditioning findings were examined in a two-compartment (black and white) tilt box: (1) the responses of naive rats to testing, (2) place conditioning in rats with strong unconditioned biases to one of the sides, and (3) modifications of the testing situation so that naive rats respond to the black and white sides with a minimum of initial bias. Experiments involving manipulation of the conditions of training and testing, use of pentobarbital, and use of a three-compartment test box helped to control for morphine's ability to produce state dependent learning as an explanation of its conditioned place preference. In addition, we examined previous place conditioning studies that failed to show aversive effects of naloxone. These negative findings were suggested to be due to the use or procedures insensitive to aversive stimuli and to the IP administration of naloxone. Finally, in the course of the experiments, novel data on general parameters of the place conditioning were provided. Dose-response curves for subcutaneous (SC) morphine (0.04–5.0 mg/kg) and naloxone (0.02–5.0 mg/kg) were established. Conditioned preferences were also shown to occur after at three pairings of SC drug, and they were retained for at least 1 month.     

Differential effects of novelty exposure on place preference conditioning to amphetamine and its oral consumption

Rationale Sensation/novelty seeking is frequently observed in drug abusers. Rats with high locomotor activity in response to inescapable novelty may be more prone to drug addiction. However, it is not clear whether this response to novelty represents reactivity to the novelty-induced stress or seeking for novelty.Objectives We have compared the influence of the response to novelty—presented in a forced stressful or in a free choice non-stressful manner—on vulnerability to addictive properties of amphetamine.Methods Wistar rats were selected according to their (i) reactivity to inescapable novelty and (ii) novelty preference. For this purpose, animals were exposed during two 30-min sessions, 24 h apart, to the same compartment; their motor activity during the first session was used as an index of reactivity. On the third day, they were allowed to choose between this "familiar" environment and a novel one. Rewarding properties of amphetamine (0.2–3.2 mg/kg, s.c.) were determined by place conditioning. Amphetamine oral consumption (10–50 mg/l) in a free-choice paradigm was measured over a period of 32 days.Results Reactivity to novelty and novelty preference were not correlated. Reactivity to inescapable novelty predicted place conditioning induced by the lowest dose of amphetamine, whereas preference for novelty did not. High responders to inescapable novelty consumed less amphetamine than low responders. Novelty preference was positively correlated to amphetamine oral consumption only at the lowest concentration.Conclusions Reactivity to inescapable novelty and novelty preference represent different behavioural components, which are related differentially with amphetamine place conditioning and its oral consumption.