Effects of time of feeding on psychostimulant reward, conditioned place preference, metabolic hormone levels, and nucleus accumbens biochemical measures in food-restricted rats

Rationale

Chronic food restriction (FR) increases rewarding effects of abused drugs and persistence of a cocaine-conditioned place preference (CPP). When there is a single daily meal, circadian rhythms are correspondingly entrained, and pre- and postprandial periods are accompanied by different circulating levels of metabolic hormones that modulate brain dopamine function.

Objectives

The present study assessed whether rewarding effects of d-amphetamine, cocaine, and persistence of cocaine-CPP differ between FR subjects tested in the pre- and postprandial periods.

Materials and methods

Rats were stereotaxically implanted with intracerebral microinjection cannulae and an electrode in lateral hypothalamus. Rewarding effects of d-amphetamine and cocaine were assessed using electrical self-stimulation in rats tested 1–4 or 18–21 h after the daily meal. Nonimplanted subjects acquired a cocaine-CPP while ad libitum fed and then were switched to FR and tested for CPP at these same times.

Results

Rewarding effects of intranucleus accumbens (NAc) d-amphetamine, intraventricular cocaine, and persistence of cocaine-CPP did not differ between rats tested 18–21 h food-deprived, when ghrelin and insulin levels were at peak and nadir, respectively, and those tested 1–4 h after feeding. Rats that expressed a persistent CPP had elevated levels of p-ERK1, GluA1, and p-Ser845-GluA1 in NAc core, and the latter correlated with CPP expression.

Conclusions

Psychostimulant reward and persistence of CPP in FR rats are unaffected by time of testing relative to the daily meal. Further, NAc biochemical responses previously associated with enhanced drug responsiveness in FR rats are associated with persistent CPP expression.     

Influence of abstinence and intervals between extinction trials on the expression of cocaine-conditioned place preference in adolescent rats

Rationale

Disruption of acquired drug–cue associations can effectively decrease relapse. The benefits of extinction training as opposed to abstinence have been reported. Timing of extinction trials is an important variable. Finding an effective extinction regimen can optimize addiction therapies.

Objective

To determine the effects of different drug-free periods on cocaine-conditioned place preference (CPP) in rats that either did or did not receive non-reinforced exposure to drug-associated stimuli.

Materials and methods

Male adolescent rats were trained for cocaine-CPP (5, 10, or 15 mg/kg, i.p.) in a biased manner for 8 days and then tested following different intervals.

Results

Rats treated with 15 mg/kg cocaine displayed high and equal CPP on the first test, performed 1, 4, 7, or 14 days following conditioning. Expression of CPP during the test performed 1 day after conditioning was equal in the groups conditioned with 5, 10, or 15 mg/kg cocaine. When the interval before the first test was extended to 14 days, the group treated with 5 mg/kg did not show CPP. Rats treated with the three doses and tested repeatedly at 1, 7, and 14 days did not display CPP on the third test. CPP after treatment with 10 or 15 mg/kg cocaine was already extinguished in the second test but only for an interval of 1–14 days.

Conclusions

Maintenance of CPP was evident at least 2 weeks after forced abstinence. Extinguished CPP can be obtained after a single extinction trial, performed close to original training and followed by prolonged abstinence. However, with low doses of cocaine, abstinence alone may be sufficient to disrupt drug–cue associations.     

The effects of prenatal cocaine,post-weaning housing and sex on conditioned place preference in adolescent rats

Rationale

Gestational exposure to cocaine now affects several million people including adolescents and young adults. Whether prenatal drug exposures alter an individual’s tendency to take and/or abuse drugs is still a matter of debate.

Objectives

This study sought to answer the question “Does prenatal exposure to cocaine, in a dose-response fashion, alter the rewarding effects of cocaine using a conditioned place preference (CPP) procedure during adolescence in the rat?” Further, we wanted to assess the possible sex differences and the role of being raised in an enriched versus impoverished environment.

Methods

Virgin female Sprague-Dawley rats were dosed daily with cocaine at 30 mg/kg (C30), 60 mg/kg (C60), or vehicle intragastrically prior to mating and throughout gestation. Pups were culled, fostered and, on postnatal day (PND) 23, placed into isolation cages or enriched cages with three same-sex littermates and stimulus objects. On PND43–47, CPP was determined across a range of cocaine doses.

Results

C30 exposure increased sensitivity to the rewarding effects of cocaine in adolescent males, and being raised in an enriched environment further enhanced this effect. Rats exposed to C60 resembled the controls in cocaine CPP. Overall, females were modestly affected by prenatal cocaine and enrichment.

Conclusions

These data support the unique sensitivity of males to the effects of gestational cocaine, that moderate prenatal cocaine doses produce greater effects on developing reward circuits than high doses and that housing condition interacts with prenatal treatment and sex such that enrichment increases cocaine CPP mostly in adolescent males prenatally exposed to moderate cocaine doses.     

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.     

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.     

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.     

Differential alteration of the effects of MDMA (ecstasy) on locomotor activity and cocaine conditioned place preference in male adolescent rats by social and environmental enrichment

Rationale

Ecstasy (MDMA) is used predominately by adolescents and young adults. Young MDMA users are more likely than non-users to use other drugs, including cocaine. The response to stimulant drugs can be affected by environmental factors; however, little information exists about the role that housing plays in mediating effects of MDMA in adolescence.

Objectives

The present experiment examined whether social and environmental factors alter effects of MDMA on activity and cocaine reward.

Methods

Male adolescent rats were housed on PND 23. Isolated rats were housed alone (1 rat/cage) in an impoverished environment with no toys (II) or enriched with toys (IE). Social rats were housed three/cage with (SE3) or without (SI3) toys. Starting on PND 29, 5 mg/kg MDMA or saline was injected and activity was measured for 60 min once daily for five consecutive days. On PND 36–40, cocaine CPP was conducted.

Results

Saline vehicle-induced activity of II rats was higher than other groups, and all groups became sensitized to the locomotor-stimulant effects of MDMA. In II rats, maximal CPP was increased after MDMA pre-exposure compared to vehicle. Environmental enrichment blocked this; however, dose–effect curves for cocaine CPP shifted to the left in both IE and SE3 rats. In rats with just social enrichment, there were no effects of MDMA on cocaine CPP.

Conclusion

Drug prevention and treatment strategies should take into account different environments in which adolescents live. These findings show that MDMA increases cocaine reward in male adolescents, and social enrichment diminishes, while environmental enrichment enhances this.     

Effects of dopamine receptor antagonists on the acquisition of ethanol-induced conditioned place preference in mice

Rationale

Studies support differential roles of dopamine receptor subfamilies in the rewarding and reinforcing properties of drugs of abuse, including ethanol. However, the roles these receptor subfamilies play in ethanol reward are not fully delineated.

Objective

To examine the roles of dopamine receptor subfamilies in the acquisition of ethanol-induced conditioned place preference (CPP), we pretreated animals systemically with antagonist drugs selective for dopamine D1-like (SCH-23390) and D2-like (raclopride) receptors prior to ethanol conditioning trials.

Methods

Effects of raclopride (0–1.2 mg/kg) and SCH-23390 (0–0.3 mg/kg) on the acquisition of ethanol-induced CPP were examined in DBA/2J mice (experiments 1 and 2). Based on significant effects of SCH-23390, we then determined if SCH-23390 (0.3 mg/kg) produced a place preference on its own (experiment 3). To evaluate whether SCH-23390 impaired learning, we used a conditioned place aversion (CPA) paradigm and pretreated animals with SCH-23390 (0–0.3 mg/kg) before conditioning sessions with LiCl (experiment 4).

Results

Whereas raclopride (0–1.2 mg/kg) did not affect acquisition, SCH-23390 (0.1–0.3 mg/kg) impaired the development of ethanol-induced CPP. SCH-23390 (0.3 mg/kg) did not produce place preference when tested alone and SCH-23390 (0.1–0.3 mg/kg) did not perturb the acquisition of LiCl-induced CPA.

Conclusions

Our results support a role for dopamine D1-like but not D2-like receptors in ethanol’s unconditioned rewarding effect as indexed by CPP. Blockade of D1-like receptors did not affect aversive learning in this procedure.     

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 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.     

Reduction of the reinforcing effectiveness of cocaine by continuous d-amphetamine treatment in rats: importance of active self-administration during treatment period

Rationale

Continuous administration of d-amphetamine has shown promise as a treatment for psychostimulant addiction. In rodent studies, constant infusion of d-amphetamine (5 mg/kg/day) has been shown to reduce cocaine-reinforced responding in the dose range of 0.19–0.75 mg/kg/inf.

Objectives

The present study tested whether these effects were a reflection of pharmacological interactions between d-amphetamine and cocaine or if they resulted from associative learning mechanisms

Methods

After stable progressive ratio (PR) baselines were established, rats were implanted with subcutaneous osmotic minipumps filled with either d-amphetamine (5 mg/kg/day—groups 1 and 2) or saline (group 3). During the treatment period, groups 1 and 3 self-administered cocaine at a dose that was previously shown to produce the most robust effects in combination with d-amphetamine treatment (0.19 mg/kg/inf), while group 2 received passive cocaine infusions.

Results

In replication of previous studies, d-amphetamine treatment resulted in a significant (35 %) decrease in breakpoints relative to saline controls. By contrast, no reductions in breakpoints were observed in animals that received passive cocaine infusions during the treatment period (group 2).

Conclusions

Active self-administration of cocaine during the treatment period appears to be an important factor in reducing cocaine-reinforced breakpoints. These findings suggest learning mechanisms are involved in the therapeutic effects of continuous d-amphetamine, and pharmacological interaction mechanisms such as cross-tolerance cannot completely account for the observed decreases in cocaine seeking.     

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.     

Effects of psychotropic drugs on second messenger signaling and preference for nicotine in juvenile male mice

Rationale

A common treatment strategy for pediatric attention deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) is combined methylphenidate (MPH) and fluoxetine (FLX). This has raised concerns because MPH?+?FLX treatment may have pharmacodynamic properties similar to cocaine, potentially increasing drug abuse liability.

Objectives

To examine the short- and long-term consequences of repeated vehicle, MPH, FLX, MPH?+?FLX, and cocaine treatment on gene expression in juvenile (postnatal days [PD] 20–34) and adult (PD 70–84) male mice. We further assessed whether juvenile drug treatment influenced subsequent sensitivity for nicotine in adulthood.

Methods

Juvenile and adult C57BL/6J mice received vehicle, MPH, FLX, MPH?+?FLX, or cocaine twice-daily for 15 consecutive days. Mice were sacrificed 24 h or 2 months after the last drug injection to assess drug-induced effects on the extracellular signal-regulated protein kinase-1/2 (ERK) pathway within the ventral tegmental area. Subsequent sensitivity for nicotine (0.05, 0.07, and 0.09 mg/kg) was measured using the place-conditioning paradigm (CPP) 24 h and 2 months after juvenile drug exposure.

Results

MPH?+?FLX, or cocaine exposure in juvenile mice increased mRNA expression of ERK2 and its downstream targets (CREB, cFos, and Zif268), and increased protein phosphorylation of ERK2 and CREB 2 months after drug exposure. Similar mRNA findings were observed in the adult-treated mice. Findings on gene expression 24 h following drug treatment were variable. Juvenile drug exposure increased preference for nicotine when tested in adulthood.

Conclusions

Early-life MPH?+?FLX, or cocaine exposure similarly disrupts the ERK pathway, a signaling cascade implicated in motivation and mood regulation, and increases sensitivity for nicotine in adulthood.     

The effect of chronic amphetamine treatment on cocaine-induced facilitation of intracranial self-stimulation in rats

Rationale

Chronic amphetamine treatment reduces cocaine self-administration in pre-clinical and clinical settings, and amphetamine has been proposed as a candidate medication for treatment of cocaine abuse.

Objective

The objective of the present study was to investigate whether chronic amphetamine treatment can decrease abuse-related cocaine effects in an assay of intracranial self-stimulation (ICSS).

Methods

Thirteen adult male Sprague-Dawley rats were equipped with intracranial electrodes targeting the medial forebrain bundle and trained to lever press for pulses of brain stimulation in a “frequency-rate” ICSS procedure. Cocaine (10 mg/kg) was administered before (day 0), during (days 7 and 14), and after (posttreatment days 1 and 3) 2 weeks of continuous treatment with either amphetamine (0.32 mg/kg/h, n?=?7) or saline (n?=?6) via osmotic pump.

Results

Prior to treatment, cocaine facilitated ICSS in all rats. Saline treatment had no effect on baseline ICSS or cocaine-induced facilitation of ICSS at any time. Conversely, amphetamine produced a sustained though submaximal facilitation of baseline ICSS, and cocaine produced little additional facilitation of ICSS during amphetamine treatment. Termination of amphetamine treatment produced a depression of baseline ICSS and recovery of cocaine-induced facilitation of ICSS.

Conclusions

These data suggest that chronic amphetamine treatment blunts expression of abuse-related cocaine effects on ICSS in rats.     

CB1 antagonism: interference with affective properties of acute naloxone-precipitated morphine withdrawal in rats

Rationale

Modulation of the endocannabinoid system has been found to interfere with opiate withdrawal. The potential of activation and blockade of the endocannabinoid system to prevent the aversive-affective state of naloxone-precipitated morphine withdrawal (MWD) was investigated in a one-trial conditioned place aversion (CPA) paradigm.

Objective

CPA provides a sensitive measure of the motivational effects of acute MWD. The potential of the fatty acid amide hydrolase (FAAH) inhibitors, URB597 and PF-3845, the CB₁ antagonist/inverse agonist, AM251, and the neutral CB₁ antagonists, AM4113 and AM6527 (oral), to interfere with establishment of a MWD-induced CPA was investigated. As well, the potential of AM251 and AM4113 to interfere with reinstatement of a previously established MWD-induced CPA was investigated.

Materials and methods

Using a one-trial place conditioning paradigm, rats were administered naloxone (1 mg/kg, subcutaneous (sc)) 24 h after receiving a high dose of morphine (20 mg/kg, sc) and were placed on the conditioning floor. To determine the effect of each pretreatment drug on the establishment of the MWD-induced CPA, URB597 (0.3 mg/kg, intraperitoneally (ip)), PF-3845 (10 mg/kg, ip), AM251 (1 or 2.5 mg/kg, ip), AM4113 (1 or 2.5 mg/kg, ip), and AM6527 (5 mg/kg, oral) were administered prior to conditioning.

Results

AM251 (2.5, but not 1 mg/k), AM4113, and AM6527, but not URB597 or PF-3845, interfered with the establishment of the MWD-induced CPA. AM251 and AM4113 did not prevent reinstatement of the CPA.

Conclusions

Neutral antagonism of the CB₁ receptor reduces the aversive affective properties of morphine withdrawal.     

Feeding condition and the relative contribution of different dopamine receptor subtypes to the discriminative stimulus effects of cocaine in rats

Rationale

The contribution of dopamine receptor subtypes in mediating the discriminative stimulus effects of cocaine is not fully established. Many drug discrimination studies use food to maintain responding, necessitating food restriction, which can alter drug effects.

Objective

This study established stimulus control with cocaine (10 mg/kg) in free-feeding and food-restricted rats responding under a schedule of stimulus shock termination (SST) and in food-restricted rats responding under a schedule of food presentation to examine whether feeding condition or the reinforcer used to maintain responding impacts the effects of cocaine.

Method

Dopamine receptor agonists and antagonists were examined for their ability to mimic or attenuate, respectively, the effects of cocaine.

Results

Apomorphine, quinpirole, and lisuride occasioned >90 % responding on the cocaine-associated lever in free-feeding rats responding under a schedule of SST; apomorphine, but not quinpirole or lisuride, occasioned >90 % responding on the cocaine lever in food-restricted rats responding under a schedule of SST. In food-restricted rats responding for food these drugs occasioned little cocaine lever responding and were comparatively more potent in decreasing responding. In free-feeding rats, the effects of cocaine were attenuated by the D₂/D₃ receptor antagonist raclopride and the D₃ receptor-selective antagonist PG01037. In food-restricted rats, raclopride and the D₂ receptor-selective antagonist L-741,626 attenuated the effects of cocaine. Raclopride antagonized quinpirole in all groups while PG01037 antagonized quinpirole only in free-feeding rats.

Conclusion

These results demonstrate significant differences in the discriminative stimulus of cocaine that are due to feeding conditions and not to the use of different reinforcers across procedures.     

Pharmacological activation of kappa opioid receptors: aversive effects in adolescent and adult male rats

Rationale

The dynorphin (DYN)/kappa opioid receptor (KOR) system is involved in the dysphoric properties of drugs of abuse. Given that adolescents show reduced sensitivity to aversive effects of many drugs, alterations in the DYN/KOR system may contribute to the prevalence of drug use during adolescence.

Objectives

The present study was designed to assess dysphoric properties of a selective kappa agonist, U62,066, in adolescent and adult rats using both conditioned taste aversion (CTA) and conditioned place aversion (CPA) paradigms.

Methods

For CTA, water-restricted rats were administered U62,066 following 30 min access to a saccharin solution, with subsequent saccharin consumption used to index aversion. For CPA, animals were allowed access to both compartments of a two-compartment chamber for a 15-min pre- and post-conditioning test. For conditioning, subjects were administered U62,066 prior to confinement to one side of the chamber and saline prior to confinement to the other side for a total of four pairings.

Results

Overall, adolescents displayed reduced sensitivity to the kappa agonist relative to adults. Adults demonstrated taste aversions to the 0.2 and 0.3 mg/kg doses of U62,066, whereas adolescents did not display aversions to any tested doses. Adults demonstrated a place aversion to the 0.1 and 0.2 mg/kg dose of U62,066 when paired with the preferred side of the conditioning chamber. Adolescents did not display aversions to any of the doses tested.

Conclusions

Reduced sensitivity to DYN/KOR system activation during adolescence may be a contributing factor to the age-typical insensitivity to aversive properties of drugs commonly abused by adolescents.     

Altered cerebellar and prefrontal cortex function in rhesus monkeys that previously self-administered cocaine

Rationale

Differences in brain function in cocaine users can occur even when frank deficits are not apparent, indicating neuroadaptive consequences of use. Using monkeys to investigate altered metabolic activity following chronic cocaine self-administration allows an assessment of altered function due to cocaine use, without confounding pre-existing differences or polysubstance use often present in clinical studies.

Objectives

To evaluate alterations in metabolic function during a working memory task in the prefrontal cortex and the cerebellum following 1 year of chronic cocaine self-administration followed by a 20 month drug-free period.

Methods

Fluorodeoxyglucose (¹⁸F) PET imaging was used to evaluate changes in relative regional metabolic activity associated with a delayed match to sample working memory task. Chronic cocaine animals were compared to a control group, and region of interest analyses focused on the dorsolateral prefrontal cortex (DLPFC) and cerebellum.

Results

Despite no differences in task performance, in the cocaine group, the cerebellum showed greater metabolic activity during the working memory task (relative to the control task) compared to the control group. There was also a trend toward a significant difference between the groups in DLPFC activity (p?=?0.054), with the cocaine group exhibiting lower DLPFC metabolic activity during the delay task (relative to the control task) than the control group.

Conclusion

The results support clinical indications of increased cerebellar activity associated with chronic cocaine exposure. Consistent with evidence of functional interactions between cerebellum and prefrontal cortex, these changes may serve to compensate for potential impairments in functionality of DLPFC.     

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.     

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.