Incentive salience of cocaine across the postpartum period of the female rat

RATIONALE-OBJECTIVES: Our prior conditioned place preference (CPP) work demonstrates that late (day16) postpartum female rats consistently prefer cocaine- over pup-associated chambers, whereas far fewer early postpartum (day8) females prefer the cocaine-associated chamber. The present study examines early and late postpartum females' preference for a cocaine-associated chamber when contrasted with a chamber associated with saline (rather than pups). MATERIALS AND METHODS: Postpartum females were tested for conditioned preference for chambers associated with cocaine (10 mg/kg subcutaneous (SC) or 0.5, 5, 10, or 20 mg/kg intraperitoneal (IP) injections) versus saline; preferences of virgin female and male rats for select cocaine stimuli (10mg/kg SC or IP) were also tested. Locomotion was recorded during CPP conditioning and testing. RESULTS: Early and late postpartum females expressed strikingly similar preference for the cocaine-associated chamber across all administration routes and doses. IP cocaine produced an orderly, inverted U-shaped dose-preference curve, with preference peaking at the 5 mg/kg dose (83% of females). While many postpartum females preferred 10mg/kg cocaine administered either SC or IP, both virgin females and males expressed strong aversion to SC cocaine and, while virgin females strongly preferred IP cocaine, males remained relatively indifferent. Across 10mg/kg IP cocaine-conditioning sessions, locomotor sensitization occurred exclusively in cocaine- but not saline-preferring postpartum females. Locomotor rate was lower in preferred versus nonpreferred chambers at CPP test. CONCLUSIONS: Early and late postpartum females may be equally and uniquely susceptible to sampling and/or abuse of modestly salient doses of cocaine (10mg/kg SC; 5mg/kg IP) compared to virgin females and/or males.     

Distinct Role of Dopamine in the PFC and NAc During Exposure to Cocaine-Associated Cues

BackgroundDopamine neurotransmission plays a critical role in reward in drug abuse and drug addiction. However, the role of dopamine in the recognition of drug-associated environmental stimuli, retrieval of drug-associated memory, and drug-seeking behaviors is not fully understood. MethodsRoles of dopamine neurotransmission in the prefrontal cortex (PFC) and nucleus accumbens (NAc) in the cocaine-conditioned place preference (CPP) paradigm were evaluated using in vivo microdialysis. ResultsIn mice that had acquired cocaine CPP, dopamine levels in the PFC, but not in the NAc, increased in response to cocaine-associated cues when mice were placed in the cocaine chamber of an apparatus with 2 separated chambers. The induction of the dopamine response and the development of cocaine CPP were mediated through activation of glutamate NMDA (N-methyl-D-aspartate)/AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor signaling in the PFC during conditioning. Activation of dopamine D1 or D2 receptor signaling in the PFC was required for cocaine-induced locomotion, but not for the induction of the dopamine response or the development of cocaine CPP. Interestingly, dopamine levels in the NAc increased in response to cocaine-associated cues when mice were placed at the center of an apparatus with 2 connected chambers, which requires motivated exploration associated with cocaine reward. ConclusionsDopamine neurotransmission in the PFC is activated by the exposure to the cocaine-associated cues, whereas dopamine neurotransmission in the NAc is activated in a process of motivated exploration of cues associated with cocaine reward. Furthermore, the glutamate signaling cascade in the PFC is suggested to be a potential therapeutic target to prevent the progression of drug addiction.     

Plasma cocaine levels, metabolites, and locomotor activity after subcutaneous cocaine injection are stable across the postpartum period in rats

Plasma levels of cocaine (COC) and two of its principle metabolites, benzoylecgonine (BE) and ecgonine methyl ester (EME) were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS) in samples collected up to 3 h after a subcutaneous injection of cocaine (10 mg/kg) on six different days between days 4 and 24 postpartum, a period of dramatic change in the endocrine state of the female rat. Locomotor activity was measured in the same animals during this period using automated animal activity monitors. Additional measures in males provide a link to existing literature. We found that plasma levels of cocaine and its metabolites, as well as their respective time courses, are remarkably uniform across the postpartum period in female rats, as are the effects of cocaine on locomotor activity. Data from males show accord with prior published values. COC and BE, but not EME levels, were higher in males, and the time courses of COC and BE levels after injection varied somewhat between postpartum females and males; however, neither baseline nor cocaine-induced locomotor activity differed between postpartum females and males. We conclude that in the postpartum rat, there are no significant differences in the peripheral processing or general accessibility of cocaine to the brain to activate motor systems across the postpartum period. These data are critical to our understanding of differences in the reward salience of cocaine across the postpartum period and in other adult rat models [Mattson BJ, Williams S, Rosenblatt JS, Morrell JI. Comparison of two positive reinforcing stimuli: pups and cocaine throughout the postpartum period. Behav Neurosci 2001;115:683-94, Mattson BJ, Williams SE, Rosenblatt JS, Morrell JI. Preferences for cocaine- or pup-associated chambers differentiate otherwise behaviorally identical postpartum maternal rats. Psychopharmacology (Berl) 2003;167:1-8].     

Apparatus bias and the use of light and texture in place conditioning

In a typical conditioned place preference (CPP) preparation, animals alternately experience drug and vehicle effects in distinct chambers of an apparatus, spending more time in the drug-paired chamber post-conditioning. However, if all animals prefer the same chamber before conditioning, data interpretation may be compromised. Unbiased apparatus has been systematically validated with ethanol in mice ([Cunningham, C.L., Feree, N.K., Howard, M.A. Apparatus bias and place conditioning with ethanol in mice. Psychopharmacology (Berl) 2003;170:409-422]); the present study sought to identify and eliminate bias in a standard black-and-white apparatus and validate that apparatus for CPP with morphine and cocaine in rats. Apparatus bias was assessed in 24 adult female Sprague-Dawley rats. Subjects preferred the black chamber under bright lighting conditions, with no preference in the dark. Subjects then underwent a counterbalanced CPP regimen to 5 mg/kg SC morphine (n=12) or 20 mg/kg IP cocaine (n=12) using only tactile conditioned stimuli. Significant absolute preferences for the drug-paired chamber were produced by both drugs, with no effect of drug-paired chamber assignment on CPP expression; vehicle-treated controls (n=12) showed no preferences. Bias-free CPP to morphine and cocaine using standard apparatus in rats is possible. Implications for place conditioning are discussed, including the potential value of systematically exploiting apparatus bias in addition to eliminating it.     

Conditioned locomotor activity but not conditioned place preference following intra-accumbens infusions of cocaine

In the first experiment, the conditioned place preference (CPP) paradigm was used to examine the rewarding properties of bilateral microinfusions of cocaine HCl into the nucleus accumbens (0, 12.5, 25, 50, or 100 µg). No dose of intra-accumbens cocaine induced a significant CPP. However, bilateral intra-accumbens infusions ofd-amphetamine sulfate (10 µg) or intraperitoneal administration of cocaine HCl (5 or 10 mg/kg) both produced a significant preference for the drug-paired compartment. In the second experiment, the ability of bilateral intra-accumbens infusions of cocaine HCl (50 µg) to elicit conditioned locomotor activity (CLA) was examined. During the conditioning trials, intra-accumbens cocaine significantly increased locomotor activity. On the test day, when no drug was administered, the group that had previously received cocaine in the activity chamber showed significantly greater locomotor activity than the vehicle control group. This demonstration of CLA indicates that rats are able to associate the effects of intra-accumbens infusions of cocaine with environmental stimuli; however, these infusions are not rewarding as measured by the CPP paradigm. In addition, these results may indicate important differences between the neural substrates for cocaine and amphetamine reward and reveal a dissociation between CPP and CLA.     

Influence of the dose and the number of drug-context pairings on the magnitude and the long-lasting retention of cocaine-induced conditioned place preference in C57BL/6J mice

Rationale The place conditioning procedure is increasingly used to study relapse in drug seeking in mice. However, the retention course of drug-induced place preference has not been systematically characterized.Methods The effects of cocaine doses and number of conditioning trials on both the magnitude and the persistence of cocaine-induced conditioned place preference (CPP) were investigated in C57BL/6J mice. Twelve groups of animals were injected with saline, 4, 8 or 12 mg/kg cocaine (i.p.) and submitted to an unbiased counterbalanced place conditioning protocol including one, two or four drug-pairing sessions. Subsequently, the animals were tested at various time intervals after the last conditioning session.Results One cocaine-pairing session was insufficient to induce a CPP. Two and four pairing sessions resulted in significant place preferences of similar magnitude for all tested doses of cocaine, the place preference induced by the greatest number of pairing sessions being the strongest. In the two-pairing groups, place preference lasted less than 14 days for any tested dose of cocaine. In contrast, all four-pairing groups still showed significant place preference 28 days after the last conditioning session. However, the magnitude of cocaine place preference slowly declined at a rate that was dependent upon cocaine dose. On the 35-day post-conditioning interval, only the 12-mg/kg cocaine group still displayed a significant place preference, whereas place preference was undetectable at 42 and 56 days post-conditioning for all groups.Conclusions The number of cocaine-pairing sessions, but not cocaine dose, affected the magnitude of cocaine place preference in mice when tested 1 day after the last conditioning session. In contrast, both cocaine doses and the number of pairing sessions affected the persistence of cocaine place preference. Overall, these results demonstrate that cocaine-induced place preference is a long lasting phenomenon that is strongly affected by the number of drug-pairing trials.     

Characterization of conditioned place preference to cocaine in congenic dopamine transporter knockout female mice

Rationale The dopamine transporter (DAT) is thought to play a major role in the rewarding effects of cocaine. Therefore, it is surprising that cocaine reveals conditioned effects in DAT knockout (DAT-KO) mice.Objectives To examine these findings further, we obtained complete dose–effect curves for DAT-KO and DAT wild-type (DAT-WT) mice in a cocaine conditioned place preference (CPP) procedure.Methods Congenic C57BL6 background female DAT-KO and DAT-WT mice were conditioned in a three-compartment place preference apparatus. Conditioning consisted of three 30-min sessions with cocaine (2.5, 5.0, 10.0, 20.0, or 40.0 mg/kg) and three 30-min sessions with saline. The distribution of time in each choice compartment was determined after each pair of conditioning sessions (one cocaine and one saline session).Results DAT-WT mice revealed CPP over a wide range of cocaine doses (5.0–40 mg/kg), whereas DAT-KO mice revealed CPP over a more restricted range of doses, with consistent CPP only occurring with 10 mg/kg of cocaine.Conclusions CPP for cocaine develops in both DAT-KO and DAT-WT mice; however, the dose range at which CPP develops is much more restricted in DAT-KO mice than in DAT-WT mice. These observations corroborate the significant role of DAT inhibition in cocaines conditioned effects.     

Conditioned rewarding effects of morphine and methadone in mice pre-exposed to cocaine

BackgroundMethadone is widely accepted as the most effective treatment of opioid dependence. However, clinical observations indicate that the medication is less effective in individuals abusing cocaine. Diminished therapeutic efficacy of methadone in cocaine users is intriguing, but its mechanism has not been studied.MethodsHere, the conditioned place preference (CPP) procedure was used to examine the effects of the dose, number of conditioning sessions and pre-exposure to cocaine on the rewarding effects of morphine and methadone. Vehicle-pre-exposed and cocainesensitized mice (five injections of 10 mg/kg over 16 days) were conditioned using methadone (0, 0.1, 0.5, 3, and 5 mg/kg) or morphine (0, 1, and 10 mg/kg). Place preference was measured after one and again after two additional conditioning sessions.ResultsAs expected, morphine at 10 mg/kg produced CPP following just one conditioning session. While a single conditioning session with 1 mg/kg of morphine produced no CPP, the rewarding effect became apparent following two additional conditioning sessions as well as in mice pre-exposed to cocaine. Methadone produced CPP following one conditioning session at doses of 0.5, 3 and 5 mg/kg. However, unlike with morphine, methadone's rewarding effect was not enhanced by two additional conditioning sessions or by pre-exposure with cocaine.ConclusionsPrior exposure to cocaine increases unconditioned motivational effects of morphine but not of methadone.     

Measuring morphine's capacity to establish a place preference

A series of experiments are described providing an assessment of the procedures of conditioned place preference (CPP) testing involving an automated system having 12 separate chambers. Experiment 1 provides data to demonstrate (a) that in these chambers no initial preferences for one side over the other exists among rats, (b) that this neutrality of sides is not affected by session lengths between 15 and 60 min, and (c) that the optimal session length for tests in these chambers is on the order of 30 min. Experiment 2 demonstrates the stability of control groups' scores across a number of conditioning and testing sessions. Experiments 3 and 4 provide data to demonstrate (a) that a positive CPP can be established in our chambers using injections of morphine, (b) that a regimen of dosing with unequal numbers of days of putative and alternate conditioning is a reliable and conservative test of the opioid's ability to establish a CPP, and (c) that although the activity of rats decreases across a session, the general activity of rats before and after conditioning procedures is the same. Experiment 5 replicates the procedures employed by Scoles and Siegel (25) and demonstrates that the tendency for rats to explore novel environments is strong, and care must be taken to provide an opportunity for rats to pair different experiences with each side of the chamber in order for a CPP to emerge.     

Effects of early handling on amphetamine-induced locomotor activation and conditioned place preference in the adult rat

  Rationale: Altered hormonal stress responsiveness has been implicated in psychostimulant responsivity, and early handling represents a mild environmental manipulation which alters the hormonal profile following stress exposure. Objective: The present experiments examined whether early handling in rats would alter locomotor effects of amphetamine, as well as cross-sensitization of locomotor responsiveness after chronic stress. Conditioned place preference (CPP) for amphetamine was also measured. Methods: Handling consisted of daily 15-min isolation periods from days 1–12 postnatally. Novelty- and amphetamine (0, 1.5 mg/kg)-induced locomotion were examined using circular corridors in adult rats that were either restrained repeatedly over 8 days or not disturbed prior to testing. The effects of handling on amphetamine (0, 1, 2, 5 mg/kg) conditioned place preference (CPP) were also examined following 3 days of drug-compartment pairings. Results: Early handling produced a more rapid post-stress recovery in corticosterone levels. Handled animals also exhibited a significant attenuation in amphetamine-induced CPP compared to non-handled controls. Locomotor responsiveness to novelty and amphetamine was not altered by early handling. Although no cross-sensitization was observed, evidence for stress sensitization was seen, but was unaffected by early handling. Conclusions: Handled animals showed an attenuated CPP for amphetamine, data suggesting that sensitivity to the reward value of drugs of abuse in adulthood may be susceptible to relatively minor environmental manipulations early in life. This effect of handling on CPP does not seem to reflect differences in locomotor sensitivity to amphetamine. Received: 5 August 1998 / Final version: 2 November 1998     

GABAA receptors modulate ethanol-induced conditioned place preference and taste aversion in mice

  Rationale: GABA_A receptor antagonists have been shown to reduce ethanol self-administration and ethanol-induced conditioned taste aversion (CTA) in rats, suggesting a role for the GABA_A receptor in modulating ethanol’s motivational effects. Objectives: The present experiments examined the effects of the GABA_A receptor antagonists, bicuculline and picrotoxin, on the acquisition of ethanol-induced conditioned place preference (CPP) and CTA in male DBA/2J mice. Methods: Mice in the CPP experiments received four pairings of ethanol (2 g/kg) with a distinctive floor stimulus for a 5-min conditioning session (CS+ sessions). During CS+ sessions, mice also received bicuculline (0, 1.0, 3.0, or 5.0 mg/kg) or picrotoxin (2.0 mg/kg) before an injection of ethanol. On intervening days (CS– sessions), the pretreatment injection was always vehicle followed by saline injections that were paired with a different floor type. For the preference test, all mice received saline injections and were placed on a half grid and half hole floor for a 60-min session. For the CTA experiments, mice were adapted to a 2-h per day water restriction regimen followed by five conditioning trials every 48 h. During conditioning trials, subjects received an injection of vehicle, bicuculline (0.5 and 2.0 mg/kg), or picrotoxin (0.75 and 2.5 mg/kg) before injection of 2 g/kg ethanol or saline following 1-h access to a saccharin solution. Results: Both picrotoxin and the lowest dose of bicuculline (1.0 mg/kg) significantly increased the magnitude of CPP relative to vehicle-treated controls. Picrotoxin alone did not produce place conditioning. Ethanol-stimulated locomotor activity was significantly reduced during conditioning trials with picrotoxin and the higher doses of bicuculline (3.0 and 5.0 mg/kg). Bicuculline did not alter ethanol-induced CTA; however, picrotoxin dose-dependently increased the magnitude of ethanol-induced CTA. Bicuculline and picrotoxin did not produce CTA when administered alone. Conclusions: Overall, these results suggest that blockade of GABA_A receptors with bicuculline and picrotoxin enhances ethanol’s motivational effects in the CPP paradigm; however, only picrotoxin enhances ethanol’s motivational effects in the CTA paradigm. Received: 12 September 1998 / Final version: 21 December 1998     

The anti-relapse compound acamprosate inhibits the development of a conditioned place preference to ethanol and cocaine but not morphine

The effects of the anti-relapse compound acamprosate (calcium acetylhomotaurinate) on the conditioned rewarding effects of ethanol, cocaine and morphine were studied using the conditioned place preference (CPP) paradigm. During 3 days of drug conditioning, mice were pretreated with saline or acamprosate (30, 100 or 300 mg kg(-1) i.p.) 10 min prior to the administration of ethanol (2 g kg(-1) i.p.), cocaine (15 mg kg(-1) i.p.) or morphine (10 mg kg(-1) i.p.), and subsequently confined to one of two distinct conditioning chambers. On the following day, mice were tested for the expression of CPP. Acamprosate dose-dependently reduced the development of CPP to ethanol and cocaine but not morphine. When tested as the conditioning drug, acamprosate alone produced neither a conditioned place preference nor aversion. These data suggest that acamprosate can suppress the conditioned rewarding effects of ethanol and certain classes of abused substances.     

Inhibition of β-Adrenergic Receptors Induces a Persistent Deficit in Retrieval of a Cocaine-Associated Memory Providing Protection against Reinstatement

Drug-seeking behavior is maintained by encounters with drug-associated cues. Preventing retrieval of drug-associated memories that these cues provoke would therefore limit relapse susceptibility; however, little is known regarding the mechanisms of retrieval. Here, we show that β-adrenergic receptor activation is necessary for the retrieval of a cocaine-associated memory. Using a conditioned place preference (CPP) procedure, rats were conditioned to associate one chamber, but not another, with cocaine. When administered before a CPP trial, propranolol, but not saline, prevented retrieval of a cocaine-associated CPP. In subsequent drug-free trials, rats previously treated with propranolol continued to show a retrieval deficit, as no CPP was evident. This retrieval deficit was long lasting and robust, as the CPP did not re-emerge during a test for spontaneous recovery 14 days later or reinstate following a priming injection of cocaine. Moreover, the peripheral β-adrenergic receptor antagonist sotalol did not affect retrieval. Thus, retrieval of cocaine-associated memories is mediated by norepinephrine acting at central β-adrenergic receptors. Our findings support the use of propranolol, a commonly prescribed β-blocker, as an adjunct to exposure therapy for the treatment of addiction by preventing retrieval of drug-associated memories during and long after treatment, and by providing protection against relapse.     

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.     

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.     

Region-specific effects of brain corticotropin-releasing factor receptor type 1 blockade on footshock-stress- or drug-priming-induced reinstatement of morphine conditioned place preference in rats

Rationale Systemic injections of the selective corticotropin-releasing factor 1 (CRF1) receptor antagonist CP-154,526 attenuate footshock-stress-induced reinstatement of heroin and cocaine seeking and morphine conditioned place preference (CPP). Intracranial injections of the nonselective CRF receptor antagonist d-Phe-CRF into the bed nucleus of the stria terminalis (BNST), but not the amygdala, attenuate footshock-induced reinstatement of cocaine seeking. However, the brain sites involved in the effect of CP-154,526 on footshock-induced reinstatement of opiate seeking are unknown. Objective We used a CPP version of the reinstatement model to examine the role of CRF1 receptors in the BNST, amygdala, and nucleus accumbens (NAc) in footshock- or drug-priming-induced reinstatement of extinguished morphine CPP. Methods Rats acquired morphine CPP over a period of 8 days during which they were given four morphine (10 mg/kg s.c.) and four saline injections and were subsequently confined to distinct chambers for 50 min. Subsequently, the morphine CPP was extinguished in 14 daily sessions during which rats were given saline injections and given access to both the saline- and morphine-paired chambers. The rats were then tested for reinstatement of morphine CPP induced by priming injections of morphine (0 or 3.0 mg/kg s.c.) or by exposure to intermittent footshock (15 min, 0.5 mA). Prior to the test sessions, the rats were given intracranial injections of CP-154,526 (1.0 μg) or vehicle into the BNST, amygdala, or NAc. Results CP-154,526 injections into the BNST, but not the amygdala or NAc, attenuated footshock-stress-induced reinstatement of morphine CPP. In contrast, CP-154,526 injections into the amygdala or NAc, but not the BNST, attenuated morphine-priming-induced reinstatement of morphine CPP. Conclusion The present results demonstrate dissociable roles of CRF1 receptors in the BNST, amygdala, and NAc in footshock-stress- vs morphine-priming-induced reinstatement of drug CPP. The authors J. Wang and Q. Fang contributed equally to this work.     

Dimenhydrinate produces a conditioned place preference in rats

Dimenhydrinate (DMH; trade names Gravol and Dramamine) is a compound of diphenhydramine (DP) and 8-chlorotheophylline in equimolar ratios. DMH has been reported to be abused by humans for its euphoric and hallucinogenic properties but few studies have evaluated its reinforcing effects in animals. To evaluate the hypothesis that DMH and its constituents DP and 8-chlorotheophylline are rewarding in animals, rats were tested for conditioned place preference (CPP). The paradigm consisted of pre-exposure (three 15-min sessions of access to both sides of the chamber), conditioning [eight 30-min pairings of one side with drug (four sessions) and, on alternate days, the other side with vehicle (four sessions)] and test phases (three 15-min sessions of access to both sides of the chamber). Significant preferences for the drug-paired location were found on test session one after conditioning with 60.0, but not 25.0, 40.0 or 50.0 mg/kg of DMH, and after conditioning with 37.8 but not 27.0 or 32.4 mg/kg of DP. No preference was found after conditioning with 23.0, 27.6 or 32.2 mg/kg of 8-chlorotheophylline. All three drugs stimulated locomotor activity during conditioning sessions and DMH and DP showed sensitization over conditioning sessions. DMH doses that showed sensitization (25.0 and 40.0 mg/kg) were lower than the dose (60.0 mg/kg) that produced a CPP revealing a dissociation of locomotor stimulating versus rewarding effects. Results reveal that DMH and DP have rewarding properties, although the molar equivalent dose-response curve for DP appeared to be further to the right than that for DMH. Future investigations into the neurotransmitter systems modulating this effect are awaited.     

Conditioned place preference: no tolerance to the rewarding properties of morphine

The effect of repeated morphine administration on conditioned place preference (CPP) using a novel treatment schedule, i.e., drug treatment was always contingent with the conditioned environmental stimuli, was investigated. We also examined whether changes in the μ- and κ-opioid receptor binding occurred in the brain of morphine-treated animals. Intraperitoneal (i.p.) administration of morphine (2 and 10 mg/kg) induced a place preference after 8 daily conditioning trials (4 morphine injections on alternate trials), the level of preference being the same with the two doses of the opiate. No change in place preference was observed in the morphine-treated rats at 2 mg/kg, when animals were further trained up to a total of 32 conditioning trials (16 morphine injections). Conversely, after 20 conditioning trials (10 morphine injections), a stronger CPP response developed in the morphine-treated rats at 10 mg/kg. Signs of morphine withdrawal were never detected in morphine-treated rats during the experiment. Loss of body weight (index of opiate dependence) was not observed either 24 h or 48 h after the last morphine administration. μ- and κ-opioid receptor density and affinity were not affected by repeated morphine administrations at either dose. The results demonstrate that no tolerance develops to the rewarding properties of morphine. Indeed, a sensitisation effect may occur at increasing doses of the opiate. Furthermore, changes in the rewarding effect of morphine are not dependent upon alterations in opioid receptors involved in the reinforcing mechanisms. Received: 31 October 1996 / Accepted: 7 February 1997     

The dopamine D(3) receptor-preferring partial agonist BP 897 dose-dependently attenuates the expression of amphetamine-conditioned place preference in rats

Previously we reported that systemic administration of the dopamine D3 receptor-preferring partial agonist BP 897 blocked the expression, but not the acquisition, of amphetamine-conditioned activity. This suggested the hypothesis that BP 897 would block the expression, but not the acquisition, of amphetamine-conditioned place preference (CPP). Thus, during preconditioning rats had access to two chambers connected by a tunnel for three 15-min sessions. During eight conditioning days with the tunnel blocked, one chamber was paired with drug administration for four 30-min sessions, alternating with pairing of the other chamber with saline administration. In a drug-free test session, time on the drug-paired side was compared to time spent there in preconditioning; a significant increase was defined as a place preference. Systemic amphetamine (2.0 mg/kg) or amphetamine+BP 897 (1.0, 2.0 mg/kg) during conditioning produced a significant place preference, while administration of BP 897 (1.0 or 2.0 but not 0.5 mg/kg) during the test blocked the amphetamine-CPP. There was no evidence that BP 897 produced a conditioned aversion. Results supported the hypothesis that BP 897 would block expression, but not acquisition, of amphetamine-CPP.     

Differential effects of dopamine antagonists on locomotor activity, conditioned activity and conditioned place preference induced by cocaine in rats

Neuronal substrates that mediate the conditioned effects of cocaine have not been well characterized. To examine dopaminergic mechanisms, three antagonists were tested for their capacity to inhibit the expression of conditioned locomotor activity and conditioned place preference in rats. Antagonists were also assessed against acute cocaine-stimulated locomotor activity for comparison. For locomotor activity conditioning, six conditioning sessions were conducted over a 10-day period. Paired rats received 10 mg/kg cocaine prior to activity sessions and saline after; unpaired controls received saline prior and cocaine after. For place preference conditioning, eight conditioning sessions were conducted over a 13-day period; rats received 10 mg/kg cocaine while restricted to one of two distinct chambers and, on alternate days, they received saline in the other. Antagonists (haloperidol, raclopride and SCH23390; 0.03-0.1 mg/kg) were given only on test days for conditioned effects. All three antagonists significantly and dose-dependently attenuated the direct stimulatory effect of cocaine. SCH23390 showed a tendency to reduce the expression of conditioned locomotor activity, and only haloperidol blocked the expression of conditioned place preference. Thus, direct and conditioned stimulant effects of cocaine were shown to be differentially sensitive to dopamine receptor blockade. Further, conditioned stimulant effects differed from conditioned reinforcing effects in this regard.