Assessment of the impact of pattern of cocaine dosing schedule during conditioning and reconditioning on magnitude of cocaine CPP, extinction, and reinstatement

Rationale and objective

We sought to examine the impact of differing cocaine administration schedules and dosing on the magnitude of cocaine conditioned place preference (CPP), extinction, and stress- and cocaine-induced reinstatement of CPP.

Methods

First, in C57Bl/6J mice, we investigated whether total cocaine administration or pattern of drug exposure could influence the magnitude of cocaine CPP by conditioning mice with a fixed-low dose (F_L; 7.5 mg/kg; total of 30 mg/kg), a fixed-high dose (F_H; 16 mg/kg; total of 64 mg/kg), or an ascending dosing schedule (Asc; 2, 4, 8, and 16 mg/kg; total of 30 mg/kg). Next, we investigated if cocaine or saline is more effective at extinguishing preference by reconditioning mice with either a descending dosing schedule (Desc; 8, 4, 2, and 1 mg/kg) or saline. Finally, we examined if prior conditioning and reconditioning history alters stress (~2–3-min forced swim test) or cocaine-induced (3.5 mg/kg) reinstatement.

Results

We replicated and extended findings by Itzhak and Anderson (Addict. Biol. 17(4): 706–16, 2011) demonstrating that Asc conditioning produces a greater CPP than either the F_L or F_H conditioning schedules. The magnitude of extinction expressed was similar in the Desc reconditioned and saline groups. Moreover, only the saline, and not the Desc reconditioned mice, showed stress and cocaine-induced reinstatement of CPP.

Conclusions

Our results suggest that the schedule of cocaine administration during conditioning and reconditioning can have a significant influence on the magnitude of CPP and extinction of preference and the ability of cocaine or a stressor to reinstate CPP.     

The facilitative effects of d-cycloserine on extinction of a cocaine-induced conditioned place preference can be long lasting and resistant to reinstatement

Rationale and objective

The N-methyl-d-aspartate receptor agonist, d-cycloserine (DCS), accelerates extinction of a cocaine-induced conditioned place preference (CPP) when given after daily extinction tests. Here, we studied the effects of DCS in rats given spaced-extinction sessions at 3- or 7-day intervals using two different extinction procedures.

Materials and methods

Rats were trained on a CPP (four cocaine, 10 mg/kg, i.p., and four saline pairings with one of two compartments). Immediately following the CPP test and all extinction tests (days 4, 7, 10, and 24, experiment 1), DCS (15 mg/kg, i.p.) or saline was administered. In experiment 2, extinction was conducted by exposing rats to the drug-paired cues for 2 or 20 min, three times, at 7-day intervals followed immediately by DCS or saline. After extinction, tests for retention and cocaine-induced reinstatement were given.

Results

In experiment 1, rats given DCS lost the cocaine CPP after one extinction trial, an effect that persisted for 2 weeks after the last DCS injection and that was resistant to cocaine-induced reinstatement. In experiment 2, extinction was facilitated by DCS compared to saline when rats received 2-min exposures to the conditioned stimulus. Longer 20-min exposures minus/plus repeated testing led to retention of extinction in both groups regardless of DCS treatment.

Conclusions

Extinction of appetitive conditioning is facilitated by DCS after 1–3 post-spaced trial injections, and retention is lasting and resistant to reinstatement. The facilitative effects appear early in extinction, but when extinction procedures are intensive, DCS appears to have no additional benefit.     

Effects of the kappa opioid receptor antagonist, norbinaltorphimine, on stress and drug-induced reinstatement of nicotine-conditioned place preference in mice

Rationale

Several studies implicate stress as a risk factor for the development and maintenance of drug addictive behaviors and drug relapse. Kappa opioid receptor (KOR) antagonists have been shown to attenuate behavioral responses to stress and stress-induced reinstatement of cocaine and ethanol seeking and preference.

Objectives

In the current study, we determined whether the selective KOR antagonist, norbinaltorphimine (nor-BNI), would block stress-induced reinstatement of nicotine preference.

Methods

Adult Institute of Cancer Research mice were conditioned with 0.5 mg/kg nicotine, injected subcutaneously (s.c.) for 3 days and tested in the nicotine-conditioned place preference (CPP) model. After 3 days extinction, nor-BNI (10 mg/kg, s.c.) was administered 16 h prior to a priming dose of nicotine (0.1 mg/kg, s.c.), and mice were tested in the CPP model for nicotine-induced reinstatement of CPP. A separate group of mice was subjected to a 2-day modified forced swim test (FST) paradigm to induce stress after 3 days extinction from CPP. Mice were given vehicle or nor-BNI (10 mg/kg, s.c.) 16 h prior to each FST session.

Results

Nor-BNI pretreatment significantly attenuated stress-induced reinstatement of nicotine-CPP, but had no effect on nicotine-primed reinstatement.

Conclusions

Blockade of KORs by selective antagonists attenuates stress-induced reinstatement of nicotine-CPP. Overall, the kappa opioid system may serve as a therapeutic target for suppressing multiple signaling processes which contribute to maintenance of smoking, smoking relapse, and drug abuse in general.     

The effects of varied extinction procedures on contingent cue-induced reinstatement in Sprague-Dawley rats

Rationale

Cue exposure therapy, which attempts to limit relapse by reducing reactivity to cocaine-paired cues through repeated exposures, has had limited success.

Objectives

The current experiments examined cocaine cue-induced anxiogenesis and investigated whether a model of cue exposure therapy would reduce reinstatement of cocaine seeking in rats with a history of cocaine self-administration.

Methods

Male rats experienced daily intravenous cocaine self-administration. Rats then experienced exposure to either the self-administration context or the context plus noncontingent presentations of cocaine-paired cues. Immediately following exposure, anxiety-like behavior was measured using elevated plus maze and defensive burying tests. In a second group of rats, self-administration was followed by 7 days of exposure to the context, context + noncontingent cue exposure, lever extinction, or cue + lever extinction. All animals then underwent two contingent cue-induced reinstatement tests separated by 7 days of lever extinction.

Results

Exposure to noncontingent cocaine-paired cues in the self-administration context increased anxiety-like behavior on the defensive burying test. Animals that experienced lever + cue extinction displayed the least cocaine seeking on the first reinstatement test, and lever extinction reduced cocaine seeking below context exposure or context + noncontingent cue exposure. All animals had similar levels of cocaine seeking on the second reinstatement test.

Conclusion

Noncontingent cue exposure causes anxiety, and noncontingent cue and context exposure are less effective at reducing contingent cue-induced reinstatement than lever or lever + cue extinction. These data indicate that active extinction of the drug-taking response may be critical for reduction of relapse proclivity in former cocaine users.     

On the persistence of cocaine-induced place preferences and aversions in rats

Rationale

Rats develop preferences for places associated with the immediate rewarding effects of cocaine and aversions for places paired with the drug’s delayed negative effects. The motivation to seek cocaine should therefore depend upon the relative magnitude of these two opposing effects of the drug.

Objective

The current study tested this notion by assessing the relative persistence of the positive and negative associations formed between environmental cues and the immediate or delayed effects of cocaine.

Methods

Rats were administered 1.0 mg/kg intravenous cocaine and placed into a distinctive environment either immediately or 15-min after injection, alternating daily with pairings of a second environment with saline. After four drug-place and four saline-place pairings, rats were returned to their home cages for 1, 7, or 21 days after which a 15-min place preference test was conducted. In a second experiment, the effectiveness of a single reconditioning session (one drug-place and one saline-place pairing) to reactivate learned cocaine-place associations was assessed after 1 or 3 weeks of drug abstinence.

Results

Places associated with the immediate effects of cocaine were preferred (CPP), while places associated with the delayed effects of cocaine were avoided (CPA). The persistence of these effects differed with CPP remaining viable at 3 weeks of withdrawal, while CPA was no longer present after 1 week. Reconditioning with an additional cocaine-place pairing failed to reinstate the CPA.

Conclusions

Cue-induced “relapse” of cocaine-seeking behavior may be fueled in part by an increased persistence of positive relative to negative associations with drug-paired stimuli.     

Topiramate increases the rewarding properties of cocaine in young-adult mice limiting its clinical usefulness

Rationale

Topiramate is an anticonvulsant drug which has been evaluated as a therapeutic option for the treatment of cocaine addiction during the last decade.

Objectives

The purpose of this study was to evaluate the effects of topiramate on the reinforcing actions of cocaine. To this aim, the topiramate-mediated regulation of acquisition and extinction phases of the cocaine conditioned place preference (CPP) was assessed in young-adult mice using three experimental designs.

Methods

Topiramate (50 mg/kg, p.o.) was given as follows: (1) during cocaine (1 and 25 mg/kg, i.p.) conditioning sessions (4 days) and cocaine (25 mg/kg) post-conditioning session; (2) 2 weeks before and during cocaine conditioning (25 mg/kg); and (3) during extinction of CPP induced by cocaine (25 mg/kg). In the first experimental design, changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene expressions were measured in the ventral tegmental area (VTA).

Results

Topiramate significantly increased cocaine-induced CPP and delayed or failed to produce extinction after the first cocaine reinstatement extinction in the first and second experiments. Furthermore, treatment with topiramate after place conditioning blocked the extinction of cocaine-induced CPP. TH and DAT gene expression in the VTA was significantly lower both with topiramate alone and in combination with cocaine compared with animals receiving only cocaine.

Conclusions

These findings suggest that topiramate increases the rewarding properties of cocaine, at least in part, by regulating dopaminergic signaling in the mesolimbic circuit. Consequently, the results of this study do not support the use of topiramate for the treatment of problems related to cocaine dependence.

Highlights

? Topiramate increases the rewarding properties of cocaine in CPP? Topiramate alters dopaminergic signaling in the mesolimbic circuit? Topiramate delays the extinction of cocaine-induced CPP? TH and DAT gene expression in the VTA decreases with topiramate and/or with cocaine? Results show that it should limit the use of topiramate in cocaine-dependent subjects

     

Effects of cocaine combined with a social cue on conditioned place preference and nucleus accumbens monoamines after isolation rearing in rats

Rationale

Social interaction during drug exposure can potentiate cocaine reward. Isolation rearing (ISO) during adolescence increases social interaction and may amplify this potentiation.

Objectives

The objectives of this study are to determine whether ISO alters conditioned place preference (CPP) for cocaine when combined with a social cue and to determine whether ISO alters the effects of cocaine when combined with social cue on nucleus accumbens shell (NAcS) dopamine (DA) and serotonin (5-HT).

Methods

Male and female rats were either ISO or group (GRP) reared for 4 weeks during adolescence. CPP was performed using a low dose of cocaine (2 mg/kg or saline) with or without exposure to a novel same-sex conspecific during conditioning. In vivo microdialysis was performed using the same parameters.

Results

ISO rats engaged in more social and aggressive behaviors during conditioning relative to GRP. Cocaine reduced social and aggressive behaviors in all rats. CPP was not influenced by rearing condition. Cocaine produced significant CPP, and a social cue produced CPP only in males. In contrast, the interaction of cocaine and a social cue on NAcS DA and 5-HT differed depending upon rearing condition. In isolates, cocaine-induced DA was attenuated, while cocaine plus a social cue produced potentiated DA and 5-HT.

Conclusions

Exposure to a low dose of cocaine in the presence of a social cue produced additive effects on CPP while producing synergistic effects on DA and 5-HT in the NAcS of ISO rats. The aversive effects of this compound stimulus may negate the rewarding effects in isolates.     

Drugs of abuse as memory modulators: a study of cocaine in rats

Rationale

It has been proposed that drugs of abuse reinforce behavior partly, or wholly, because they facilitate learning by enhancing memory consolidation. Cocaine can clearly serve as a reinforcer, but its effect on learning has not been fully characterized.

Objectives

To explore the effects of different regimens of pre- and post-training cocaine administration on win-stay and object learning.

Methods

Cocaine naïve and cocaine pre-exposed (30 mg/kg/day, ×5 days followed by 7 days drug-free) male Sprague-Dawley rats received cocaine (0, 1, 2.5, 7.5, or 20 mg/kg, i.p.) immediately following training on a win-stay task in a radial maze or following the sample phase of an object learning task. Win-stay performance was also assessed in tests of extinction and after a set shift.

Results

Post-training cocaine did not improve accuracy on the win-stay task and produced performance deficits at 20 mg/kg. These deficits were attenuated by prior cocaine exposure. There was indirect evidence of facilitated learning in extinction and set shift tests, but the effective dosage was different (2.5 and 7.5 mg/kg, respectively). Post-training cocaine produced dose-dependent improvements in object learning.

Conclusion

Post-training cocaine administration can facilitate learning, but this effect is highly dependent on the dose and the type of task employed.     

Abstinence-dependent transfer of lithium chloride-induced sucrose aversion to a sucrose-paired cue in rats

Rationale

Responding for a drug- or sucrose-paired cue increases over forced abstinence (incubation of craving). If the incentive value of a cue depends on the incentive value of the primary reward, devaluing the primary reward should reduce cue reactivity.

Objectives

We investigated whether conditioned taste aversion (CTA) to sucrose would transfer to a sucrose-paired cue after 1 or 30 days of forced abstinence and whether CTA after 1 day of forced abstinence would affect incubation of craving.

Materials and methods

Rats self-administered 10% sucrose paired with a tone + light cue for 10 days. After 1 (Exp.1) or 30 (Exp.2) days of forced abstinence, rats received two home-cage pairings of sucrose with either LiCl (65 mg/kg, IP) to produce CTA or saline as a control. Two days later, rats responded for the cue alone. The following day, sucrose consumption was assessed in the same operant conditioning chamber. Exp.1 rats were tested again 1 month later to determine if CTA would affect incubation of craving.

Results

Exp.1: CTA after 1 day of forced abstinence did not attenuate cue reactivity when tested immediately after CTA, nor did the treatment affect incubation of craving or incubation of sucrose consumption. Exp.2: CTA after 1 month of forced abstinence resulted in a significant reduction in cue reactivity.

Conclusion

The incentive values of sucrose and the conditioned representation of sucrose increase over an extended period of forced abstinence. This incubation appears to facilitate the transfer of an aversion to the primary reward to the conditioned cue.     

A randomized, placebo-controlled laboratory study of the effects of d-cycloserine on craving in cocaine-dependent individuals

Rationale

d-Cycloserine (DCS), a partial glutamate N-methyl-d-aspartate (NMDA) receptor agonist, enhances extinction of conditioned fear responding; preliminary data suggest that it may facilitate extinction of drug cue reactivity.

Objective

This study investigates DCS effects on cocaine cue craving and drug use in cocaine-dependent subjects.

Methods

Thirty-two subjects were randomly assigned to receive (1) DCS only, (2) DCS before sessions 1 and 3, placebo (PBO) before session 2, or (3) PBO only 15-min before each of 3 1-h cocaine cue exposure sessions conducted 1 day apart. Craving ratings were obtained before, during, and after sessions. Drug use and cue-induced craving were assessed 1 week after the last cue session.

Results

Repeated presentation of cocaine cues resulted in decreased craving both within and between sessions. DCS did not facilitate extinction learning and may have enhanced craving. The group that received three doses of DCS had significantly higher craving than the PBO group at the baseline ratings taken before sessions 2 and 3, as well as significantly higher cue-induced craving at follow-up. The group that received two doses of DCS did not differ from the PBO group. There were no group differences in postextinction cocaine use.

Conclusions

The reduction of cocaine cue reactivity in the PBO group suggests that the study procedures were sufficient to produce extinction. Under these conditions, DCS did not facilitate extinction and may have enhanced craving. Further studies of glutamatergic agents and extinction in cocaine dependence should include consideration of procedural variables that could have a major impact on study outcomes.     

Cue-induced resumption of heroin and cocaine seeking in rats using a conflict model of abstinence and relapse

Rationale and objectives

Most animal research on drug relapse involves the reinstatement model where abstinence is a result of drug removal (extinction). However, abstinence in humans often results from the aversive consequences that accompany drug seeking (conflict situation). This study was aimed at using a conflict-based animal model of abstinence/relapse in rats self-administering heroin or cocaine.

Methods

Rats were trained to self-administer heroin (0.05 mg kg^?1 injection^?1) or cocaine (0.5 mg kg^?1 injection^?1) with each injection paired with a light cue. After stable responding was demonstrated, the floor near the levers was electrified, creating a barrier, in order to model the negative consequences of continued drug seeking. Shock intensities were increased over sessions until no responses occurred for three consecutive sessions. During a relapse test, where shock was maintained,the capacity of noncontingent drug cue presentations to induce active lever pressing was assessed.

Results

Ten of ten heroin animals and three of eight cocaine animals exposed to noncontingent cue presentations resumed responding. During the relapse test, for both drug groups, active lever pressing was significantly higher than during abstinence but only in the heroin group was it significantly higher than inactive lever pressing.

Conclusions

The implementation of negative consequences for drug seeking can result in its cessation just as they might in human addicts. Similarly, exposure to drug cues can lead to resumption of drug seeking. This model may be useful for studying the mechanisms underlying abstinence and relapse and for developing strategies to prevent relapse.     

Exaggerated cue-induced reinstatement of cocaine seeking but not incubation of cocaine craving in a developmental rat model of schizophrenia

Rationale

Patients with schizophrenia exhibit high comorbidity for substance abuse, but the biological underpinnings of this dual-diagnosis condition are still unclear. Previous studies have shown that rats with a neonatal ventral hippocampal lesion (NVHL), a widely used developmental animal model of schizophrenia, exhibit increased cocaine and methamphetamine self-administration and cocaine-induced reinstatement.

Objective

Here, we assessed whether a NVHL would also potentiate cue-induced reinstatement of cocaine seeking and the time-dependent increases in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving) in adult rats.

Methods

Rats were trained to self-administer cocaine (3 or 6 h/day with 0.75 mg?kg^?1?infusion^?1 paired with a tone-light cue) for 10 days, followed by extinction training (3 h/day) and cue-induced reinstatement of cocaine seeking. Other rats were tested for incubation of cocaine craving, assessed in extinction tests 1 and 30 days after the last self-administration session.

Results

Although there was no significant difference in cocaine intake between NVHL and sham controls, NVHL rats took significantly longer to reach an a priori set extinction criterion and exhibited enhanced cue-induced reinstatement. However, while cue-induced cocaine seeking was higher after 30 days than after 1 day of withdrawal (incubation of cocaine craving), the NVHL had no effect on this incubation.

Conclusion

These data confirm previous reports on enhanced resistance to extinction after NVHL and demonstrate that NVHL rats exhibit enhanced cue-induced reinstatement of cocaine seeking after extinction, a measure of drug relapse.     

Cocaine self-administration reinforced on a progressive ratio schedule decreases with continuous d-amphetamine treatment in rats

Rationale

To date, there is no medication specifically approved for cocaine addiction. Agonist medications are used clinically in the treatment of other addictions, which suggests that this method of drug therapy could potentially be successful in treating cocaine addiction as well.

Objective

The objective of this study was to determine the effect of extended d-amphetamine treatment on responding on a progressive ratio (PR) schedule reinforced by cocaine.

Materials and methods

Rats were trained to self-administer cocaine (0.19, 0.38, 0.75, or 1.5 mg/kg/injection) or food on a PR schedule. After stable baseline breakpoints (the number of reinforcers earned in one session) were established over 3 days, animals were implanted with osmotic mini-pumps that continuously delivered d-amphetamine (5 mg/kg/day) for a duration of either 7 or 14 days. Breakpoints were then determined during and/or after this treatment period.

Results

Rats demonstrated dose-dependent decreases in cocaine-reinforced responding over the d-amphetamine treatment period. Breakpoints for doses of 0.75 mg/kg/injection and below decreased significantly when compared to baseline and remained decreased for up to 14 days after mini-pump removal, whereas those for the highest dose of cocaine remained unchanged. Additionally, d-amphetamine treatment during a 14-day abstinence period from cocaine self-administration had no effect on breakpoints when tested the day after mini-pump removal.

Conclusions

These data suggest that the reduction in cocaine-reinforced responding after continuous d-amphetamine treatment cannot be accounted for by tolerance alone. Instead, the roles of learning and the interaction between cocaine and d-amphetamine must be considered and examined in future studies.     

Effect of food restriction on cocaine locomotor sensitization in Sprague–Dawley rats

Rationale

The interaction between repeated cocaine exposure and food restriction on sensitization to the stimulatory effects of cocaine has not been characterized.

Objectives

To compare cocaine sensitization in rats free fed and food restricted, and begin to explore the role of the stress-responsive dynorphin/kappa opioid system.

Methods

Male rats were maintained for 10 days on two feeding conditions: free fed or food restricted (85 % of free fed weight). Test 1 of locomotor reactivity to cocaine (3, 9, or 15 mg/kg, IP) was followed by a sensitizing regimen of cocaine exposure (0 or 30 mg/kg/day × 5 days, IP), by a 10-day drug-free period, and by Test 2 of reactivity to the same cocaine dose. In a second experiment, rats received an injection of norbinaltorphimine (nor-BNI; 0, 5 or 20 mg/kg, SC) 10 days prior to each locomotion test, and plasma corticosterone (CORT) was assessed after Test 2.

Results

On Test 1, it was found that food restriction enhanced locomotor responses to all doses of cocaine. On Test 2, it was found that free fed and food restricted animals displayed similar sensitized responses to cocaine. This, however, was not observed in nor-BNI-treated rats. Furthermore, 20 mg/kg nor-BNI reduced both the locomotor response to cocaine on Test 2 and the effect of cocaine and food restriction on CORT plasma levels.

Conclusions

These results indicate that the interaction between cocaine sensitization and food restriction is not synergistic, and that it involves activation of kappa-opioid receptors.     

Persistent reduction of cocaine seeking by pharmacological manipulation of adenosine A1 and A2A receptors during extinction training in rats

Rationale

Adenosine receptor stimulation and blockade have been shown to modulate a variety of cocaine-related behaviors.

Objectives

These studies identify the direct effects of adenosine receptor stimulation on cocaine seeking during extinction training and the persistent effects on subsequent reinstatement to cocaine seeking.

Methods

Rats self-administered cocaine on a fixed ratio one schedule in daily sessions over 3 weeks. Following a 1-week withdrawal, the direct effects of adenosine receptor modulation were tested by administering the adenosine A₁ receptor agonist, N⁶-cyclopentyladenosine (CPA, 0.03 and 0.1 mg/kg), the adenosine A_2A agonist, CGS 21680 (0.03 and 0.1 mg/kg), the presynaptic adenosine A_2A receptor antagonist, SCH 442416 (0.3, 1, and 3 mg/kg), or vehicle prior to each of six daily extinction sessions. The persistent effects of adenosine receptor modulation during extinction training were subsequently tested on reinstatement to cocaine seeking induced by cues, cocaine, and the dopamine D₂ receptor agonist, quinpirole.

Results

All doses of CPA and CGS 21680 impaired initial extinction responding; however, only CPA treatment during extinction produced persistent impairment in subsequent cocaine- and quinpirole-induced seeking. Dissociating CPA treatment from extinction did not alter extinction responding or subsequent reinstatement. Administration of SCH 442416 had no direct effects on extinction responding but produced dose-dependent persistent impairment of cocaine- and quinpirole-induced seeking.

Conclusions

These findings demonstrate that adenosine A₁ or A_2A receptor stimulation directly impair extinction responding. Interestingly, adenosine A₁ receptor stimulation or presynaptic adenosine A_2A receptor blockade during extinction produces lasting changes in relapse susceptibility.     

Role of GABAA receptors in dorsal raphe nucleus in stress-induced reinstatement of morphine-conditioned place preference in rats

Rationale

The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Our data indicate that stress inhibits the dorsal raphe nucleus (DRN)-5-HT system via stimulation of GABA synaptic activity by the stress neurohormone corticotropin-releasing factor and, more recently, that morphine history sensitizes DRN-5-HT neurons to GABAergic inhibitory effects of stress.

Objectives

We tested the hypothesis that DRN GABA_A receptors contribute to stress-induced reinstatement of morphine-conditioned place preference (CPP).

Methods

First, we tested if activation of GABA_A receptors in the DRN would reinstate morphine CPP. Second, we tested if blockade of GABA_A receptors in the DRN would attenuate swim stress-induced reinstatement of morphine CPP. CPP was induced by morphine (5 mg/kg) in a 4-day conditioning phase followed by a conditioning test. Upon acquiring conditioning criteria, subjects underwent 4 days of extinction training followed by an extinction test. Upon acquiring extinction criteria, animals underwent a reinstatement test. For the first experiment, the GABA_A receptor agonist muscimol (50 ng) or vehicle was injected into the DRN prior to the reinstatement test. For the second experiment, the GABA_A receptor antagonist bicuculline (75 ng) or vehicle was injected into the DRN prior to a forced swim stress, and then, animals were tested for reinstatement of CPP.

Results

Intraraphe injection of muscimol reinstated morphine CPP, while intraraphe injection of bicuculline attenuated swim stress-induced reinstatement.

Conclusions

These data provide evidence that GABA_A receptor-mediated inhibition of the serotonergic DRN contributes to stress-induced reinstatement of morphine CPP.     

The effects of chronic food restriction on cue-induced heroin seeking in abstinent male rats

Rationale and objectives

Previous research with an animal model of relapse has shown that acute food deprivation will reinstate extinguished drug seeking. Recent evidence with humans, however, suggests that chronic food restriction rather than acute food deprivation is related to increases in drug taking and relapse, emphasizing a need for an animal model to elucidate the neural mechanisms mediating the effects of chronic food restriction on drug seeking. Here we studied the effects of chronic food restriction during a period of abstinence on heroin seeking in rats.

Methods

Rats were trained to self-administer heroin over 10 days (0.1 mg/kg/infusion; i.v.). Rats were then removed from the operant conditioning chambers and exposed to a mild food restriction (resulting in 10–15 % decrease in body weight) or given unrestricted access to food for 14 days while abstinent. The abstinence period was followed by a drug-seeking test under extinction conditions. Subsequent experiments manipulated the length of restriction and test conditions.

Results

Rats that were food restricted throughout the abstinence period demonstrated a robust increase in cue-induced heroin seeking compared to sated rats. Re-feeding prior to testing or decreasing the length of the food restriction period prevented the augmentation of drug seeking.

Conclusions

A combination of chronic food restriction and a concurrent state of hunger appears to be necessary for an increase in cue-induced heroin seeking following abstinence. The procedure presented here may serve as a useful model to study the increased risk for relapse following dietary manipulations in abstinent subjects.     

The cannabinoid CB2 receptor is necessary for nicotine-conditioned place preference, but not other behavioral effects of nicotine in mice

Rationale

Whereas cannabinoid CB₁ receptors have long been known to contribute to the rewarding effects and dependence liability of many drugs of abuse, recent studies have implicated the involvement of cannabinoid CB₂ receptors.

Objective

Here, we evaluated the role of CB₂ receptors in the rewarding properties of nicotine, as assessed in the conditioned place preference (CPP) paradigm and mecamylamine-precipitated withdrawal in nicotine dependent mice.

Methods

Using complementary pharmacological and genetic approaches, we investigated the involvement of CB₂ receptors in nicotine- and cocaine-induced CPP in mice and mecamylamine-precipitated withdrawal in nicotine-dependent mice. We also determined whether deletion of CB₂ receptors affects nicotine-induced hypothermia and hypoalgesia.

Results

Nicotine-induced (0.5 mg/kg) CPP was completely blocked by selective CB₂ antagonist, SR144528 (3 mg/kg) in wild-type mice, and was absent in CB₂ (?/?) mice. Conversely, the CB₂ receptor agonist, O-1966 (1, 3, 5, 10, 20 mg/kg) given in combination with a subthreshold dose of nicotine (0.1 mg/kg) elicited a place preference. In contrast, O-1966 (20 mg/kg) blocked cocaine (10 mg/kg)-induced CPP in wild type mice, while CB₂ (?/?) mice showed unaltered cocaine CPP. CB₂ (+/+) and (?/?) nicotine-dependent mice showed almost identical precipitated withdrawal responses and deletion of CB₂ receptor did not alter acute somatic effects of nicotine.

Conclusions

Collectively, these results indicate that CB₂ receptors are required for nicotine-induced CPP in the mouse, while it is not involved in nicotine withdrawal or acute effects of nicotine. Moreover, these results suggest that CB₂ receptors play opposing roles in nicotine- and cocaine-induced CPP.     

The effects of the novel DA D3 receptor antagonist SR 21502 on cocaine reward, cocaine seeking and cocaine-induced locomotor activity in rats

Rationale

There is a focus on developing D3 receptor antagonists as cocaine addiction treatments.

Objective

We investigated the effects of a novel selective D3 receptor antagonist, SR 21502, on cocaine reward, cocaine-seeking, food reward, spontaneous locomotor activity and cocaine-induced locomotor activity in rats.

Methods

In Experiment 1, rats were trained to self-administer cocaine under a progressive ratio (PR) schedule of reinforcement and tested with vehicle or one of three doses of SR 21502. In Experiment 2, animals were trained to self-administer cocaine under a fixed ratio schedule of reinforcement followed by extinction of the response. Then, animals were tested with vehicle or one of the SR 21502 doses on cue-induced reinstatement of responding. In Experiment 3, animals were trained to lever press for food under a PR schedule and tested with vehicle or one dose of the compound. In Experiments 4 and 5, in separate groups of animals, the vehicle and three doses of SR 21502 were tested on spontaneous or cocaine (10 mg/kg, IP)-induced locomotor activity, respectively.

Results

SR 21502 produced significant, dose-related (3.75, 7.5 and 15 mg/kg) reductions in breakpoint for cocaine self-administration, cue-induced reinstatement (3.75, 7.5 and 15 mg/kg) and cocaine-induced locomotor activity (3.75, 7.5 and 15 mg/kg) but failed to reduce food self-administration and spontaneous locomotor activity.

Conclusions

SR 21502 decreases cocaine reward, cocaine-seeking and locomotor activity at doses that have no effect on food reward or spontaneous locomotor activity. These data suggest SR 21502 may selectively inhibit cocaine’s rewarding, incentive motivational and stimulant effects.     

Dose-dependent effectiveness of wheel running to attenuate cocaine-seeking: impact of sex and estrous cycle in rats

Rationale

Exercise has shown promise as an intervention for drug addiction; however, little is known regarding the exercise conditions that most effectively reduce relapse vulnerability and whether these conditions differ by sex.

Objective

Here, we examined sex differences in the dose-dependent effects of wheel running, an animal model of exercise, during abstinence on subsequent cocaine-seeking.

Methods

Male and female rats self-administered cocaine (1.5 mg/kg/infusion) under extended access conditions (24 h/day, 4 discrete trials/h) for 10 days. Rats were then given voluntary access to either an unlocked or locked running wheel for 1, 2, 6, or 24 h/day during the 14-day abstinence period. Separate groups of rats were housed in polycarbonate cages during abstinence to control for physical activity that the wheel may provide. Subsequent cocaine-seeking was assessed under a within-session extinction/cue-induced reinstatement procedure. Estrous cycle was monitored in females to determine whether the effectiveness of wheel running varied by estrous cycle phase.

Results

Although females ran more than males, males were more sensitive to the effects of running and showed a dose-dependent decrease in cocaine-seeking with longer access resulting in greater suppression. The dose–effect relationship was less straightforward in females and access to both a locked and unlocked wheel decreased cocaine-seeking with effects dependent on estrous cycle phase. Notably, extended (6 and 24 h/day), but not limited (1 and 2 h/day) access to a wheel surmounted the heightened vulnerability observed in females during estrus.

Conclusion

Taken together, our findings suggest that the effectiveness of wheel running is dose-, sex-, and estrous cycle-dependent.