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.     

Responding for conditioned reinforcement in C57BL/6 and CD-1 mice,and Sprague-Dawley rats: Effects of methylphenidate and amphetamine

Rationale

Characterization of responding for conditioned reinforcement in mice is important to implement genetic tools in examining the neurobiological mechanisms underlying reward-related learning and incentive motivation.

Methods

Inbred C57BL/6 mice, outbred CD-1 mice, and outbred Sprague–Dawley rats underwent Pavlovian conditioning in which a conditioned stimulus (CS) was paired with saccharin. Subsequently, subjects were allowed to respond for that CS in tests of responding for conditioned reinforcement. Experiments measured the effects of methylphenidate (MPH) and amphetamine (AMPH) on lever pressing for conditioned reinforcement in mice and rats. We further examined the stability of responding for conditioned reinforcement in mice after repeated testing and the extinction of this behaviour following omission of the reinforcer. We also determined whether the CS exhibited reinforcing properties if it was not paired with saccharin.

Results

C57BL/6 and CD-1 mice learned to respond for a conditioned reinforcer similarly to rats, and the behaviour was stable over time. MPH increased responding in CD-1 mice and rats, but not in C57BL/6 mice. AMPH only increased responding in rats. Responding was reduced following omission of the conditioned reinforcer, and responding was only established when the CS was paired with saccharin.

Conclusions

These experiments characterize a conditioned reinforcement test which produces stable responding in two different mouse backgrounds. These findings also show that dopaminergic psychomotor stimulants can differently affect rats and mice in tests of responding for conditioned reinforcement.     

The effects of amphetamine sensitization on conditioned inhibition during a Pavlovian–instrumental transfer task in rats

Rationale

Evidence has implicated the endogenous opioids, in particular μ-opioid receptors, in emotional behavior and regulation of reward circuits, especially in the context of heroin addiction and hedonic responses to ingestive rewards. The μ-opioid receptor antagonist naltrexone (NTX) has been reported to be effective in preventing relapse to alcoholism and in reducing alcohol and cocaine craving during abstinence.

Objectives

The aim of the present experiments was to investigate the effects of a novel selective μ-opioid receptor antagonist GSK1521498 on cocaine and heroin seeking and the primary reinforcement of drug self-administration behavior.

Methods

Rats were first trained to self-administer cocaine or heroin and then to seek the drugs over prolonged periods of time under a second-order schedule of reinforcement, in which responding is maintained by contingent presentation of a drug-associated conditioned reinforcer. On a stable baseline, animals were treated with either GSK1521498 (0.1, 1, 3 mg/kg; IP) or NTX (0.1, 1, 3 mg/kg; SC) before each test session.

Results

Cocaine seeking was dose-dependently decreased following GSK1521498 treatment. However, the same treatment had no effect on cocaine self-administration under a continuous reinforcement schedule. Treatment with NTX had a less pronounced but similar effect. GSK1521498, but not NTX, dose-dependently reduced heroin seeking both before and after infusion of the drug although both increased heroin self-administration under continuous reinforcement.

Conclusions

These data suggest that GSK1521498, by reducing opioid receptor signaling at the μ-opioid receptor, may have therapeutic potential to reduce the propensity to seek cocaine or heroin and, additionally, to diminish the consequence of an initial relapse to heroin taking.     

Effects of acute withdrawal on ethanol-induced conditioned place preference in DBA/2J mice

Rationale

Reexposure to ethanol during acute withdrawal might facilitate the transition to alcoholism by enhancing the rewarding effect of ethanol.

Objective

The conditioned place preference (CPP) procedure was used to test whether ethanol reward is enhanced during acute withdrawal.

Methods

DBA/2J mice were exposed to an unbiased one-compartment CPP procedure. Ethanol (0.75, 1.0, or 1.5 g/kg IP) was paired with a distinctive floor cue (CS+), whereas saline was paired with a different floor cue (CS?). The withdrawal (W) group received CS+ trials during acute withdrawal produced by a large dose of ethanol (4 g/kg) given 8 h before each trial. The no-withdrawal (NW) group did not experience acute withdrawal during conditioning trials but was matched for acute withdrawal experience. Floor preference was tested in the absence of ethanol or acute withdrawal.

Results

All groups eventually showed a dose-dependent preference for the ethanol-paired cue, but development of CPP was generally more rapid and stable in the W groups than in the NW groups. Acute withdrawal suppressed the normal activating effect of ethanol during CS+ trials, but there were no group differences in test activity.

Conclusions

Acute withdrawal enhanced ethanol’s rewarding effect as indexed by CPP. Since this effect depended on ethanol exposure during acute withdrawal, the enhancement of ethanol reward was likely mediated by the alleviation of acute withdrawal, i.e., negative reinforcement. Enhancement of ethanol reward during acute withdrawal may be a key component in the shift from episodic to chronic ethanol consumption that characterizes alcoholism.     

The effects of nicotine exposure during Pavlovian conditioning in rats on several measures of incentive motivation for a conditioned stimulus paired with water

Rationale

Nicotine enhances approach toward and operant responding for conditioned stimuli (CSs), but the effect of exposure during different phases of Pavlovian incentive learning on these measures remains to be determined.

Objectives

These studies examined the effects of administering nicotine early, late or throughout Pavlovian conditioning trials on discriminated approach behavior, nicotine-enhanced responding for conditioned reinforcement, extinction, and the reinstatement of responding for conditioned reinforcement. We also tested the effect of nicotine on approach to a lever-CS in a Pavlovian autoshaping procedure and for this CS to serve as a conditioned reinforcer.

Methods

Thirsty rats were exposed to 13 conditioning sessions where a light/tone CS was paired with the delivery of water. Nicotine was administered either prior to the first or last seven sessions, or throughout the entire conditioning procedure. Responding for conditioned reinforcement, extinction, and the reinstatement of responding by the stimulus and nicotine were compared across exposure groups. Separately, the effects of nicotine on conditioned approach toward a lever-CS during autoshaping, and responding for that CS as a conditioned reinforcer, were examined.

Results

Nicotine exposure was necessary for nicotine-enhanced responding for conditioned reinforcement and the ability for nicotine and the stimulus to additively reinstate responding on the reinforced lever. Nicotine increased contacts with a lever-CS during autoshaping, and removal of nicotine abolished this effect. Prior nicotine exposure was necessary for nicotine-enhanced responding reinforced by the lever.

Conclusions

Enhancements in the motivating properties of CSs by nicotine occur independently from duration and timing effects of nicotine exposure during conditioning.     

The GABAB receptor agonist baclofen administered into the median and dorsal raphe nuclei is rewarding as shown by intracranial self-administration and conditioned place preference in rats

Rationale

The midbrain raphe regions have long been implicated in affective processes and disorders. There is increasing evidence to suggest that the median (MR) and dorsal raphe nuclei (DR) tonically inhibit reward-related processes.

Objectives

Stimulation of GABA_B receptors in the midbrain raphe nuclei is known to inhibit local neurons, especially serotonergic neurons. We sought to determine if injections of the GABA_B receptor agonist baclofen into the MR or DR are rewarding, using intracranial self-administration and conditioned place preference.

Results

Rats quickly learned to lever press for infusions of baclofen (0.1–2.5 mM) into the MR, but not the ventral tegmental area or central linear nucleus. Rats increased lever pressing associated with intra-DR baclofen infusions, but not readily. Baclofen self-administration into the MR or DR was attenuated by coadministration of the GABA_B receptor antagonist SCH 50911 (1 mM) or systemic pretreatment with the dopamine receptor antagonist SCH 23390 (0.025 mg/kg, i.p.). In addition, intra-DR and intra-MR injections of baclofen induced conditioned place preference; injection into DR was more effective.

Conclusions

Baclofen injections into the midbrain raphe nuclei are rewarding. Baclofen was more readily self-administered into the MR than into the DR, while baclofen injections into the DR more readily induced conditioned place preference than those into the MR. These sites may be differentially involved in aspects of reward. These findings suggest that MR or DR neurons containing GABA_B receptors are involved in tonic inhibitory control over reward processes.     

Comparison of the conditioned reinforcing properties of a safety signal and appetitive stimulus: effects of d-amphetamine and anxiolytics

Rationale

Safety signals providing relief are hypothesised to possess conditioned reinforcing properties, supporting the acquisition of a new response (AnR) as seen with appetitive stimuli. Such responding should also be sensitive to the rate-increasing effects of d-amphetamine and to the anxiolytics 8-OH-DPAT and diazepam.

Objectives

This study tests whether safety signals have conditioned reinforcing properties similar to those of stimuli-predicting reward.

Methods

Rats received Pavlovian conditioning with either appetitive stimuli (CS+) or safety signals (conditioned inhibitors, CIs) plus truly random control (TRC) stimuli. The appetitive group received a CS + paired with a sucrose pellet and the safety signal group, a stimulus paired with shock omission. Stimuli were tested using an AnR procedure and following systemic d-amphetamine, the 5HT-1A agonist 8-OH-DPAT and the benzodiazepine diazepam in a counterbalanced design.

Results

Effective conditioning selectively reduced contextual freezing during CI presentation in the safety signal group and increased food magazine responses (with respect to context and TRC) during CS + presentation in the appetitive group. The appetitive stimulus strongly supported AnR but the safety signal did not. Systemic d-amphetamine significantly potentiated lever pressing in the appetitive group but for the safety signal group, it either reduced it or had no effect, dependent on food deprivation state. 8-OH-DPAT and diazepam had no effect on responding in either group.

Conclusions

The safety signal did not support AnR and, therefore, did not exhibit conditioned reinforcing properties. Furthermore, d-amphetamine decreased responding when the safety signal was presented as a consequence, whilst increasing responding with appetitive-conditioned reinforcement. These results are discussed in terms of implications for opponent motivational theory.     

Ethanol seeking triggered by environmental context is attenuated by blocking dopamine D1 receptors in the nucleus accumbens core and shell in rats

Rationale

Conditioned behavioral responses to discrete drug-associated cues can be modulated by the environmental context in which those cues are experienced, a process that may facilitate relapse in humans. Rodent models of drug self-administration have been adapted to reveal the capacity of contexts to trigger drug seeking, thereby enabling neurobiological investigations of this effect.

Objectives

We tested the hypothesis that dopamine transmission in the nucleus accumbens, a neural structure that mediates reinforcement, is necessary for context-induced reinstatement of responding for ethanol-associated cues.

Methods

Rats pressed one lever (active) for oral ethanol (0.1 ml; 10% v/v) in operant conditioning chambers distinguished by specific visual, olfactory, and tactile contextual stimuli. Ethanol delivery was paired with a discrete (4 s) light-noise stimulus. Responses on a second lever (inactive) were not reinforced. Behavior was then extinguished by withholding ethanol but not the discrete stimulus in a different context. Reinstatement, expressed as elevated responding for the discrete stimulus without ethanol delivery, was tested by placing rats into the prior self-administration context after administration of saline or the dopamine D1 receptor antagonist, SCH 23390 (0.006, 0.06, and 0.6 μg/side), into the nucleus accumbens core or shell.

Results

Compared with extinction responding, active lever pressing in saline-pretreated rats was enhanced by placement into the prior ethanol self-administration context. SCH 23390 dose-dependently reduced reinstatement after infusion into the core or shell.

Conclusion

These findings suggest a critical role for dopamine acting via D1 receptors in the nucleus accumbens in the reinstatement of responding for ethanol cues triggered by placement into an ethanol-associated context.     

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.     

Effects of repeated MDMA administration on the motivation for palatable food and extinction of operant responding in mice

Rationale

Repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) produces mainly dopaminergic neurotoxicity in mice. However, the consequences of this exposure on the behavioural responses related to natural reinforcing stimuli are still largely unknown.

Objectives

We examined whether repeated treatment with neurotoxic and non-neurotoxic doses of MDMA could exert acute and long-lasting effects on the motivation of mice to obtain a highly palatable food and on the extinction and reinstatement of food-seeking behaviour. Food-deprived mice were first trained to acquire stable responding on fixed ratio (FR) schedules of reinforcement and then treated twice daily with saline, 3 or 30 mg/kg MDMA during four consecutive days.

Results

The high dose of MDMA impaired instrumental responding on the first and third day of treatment, whilst no residual effects were apparent on FR5 responding at any of the doses studied 24 h after treatment withdrawal. Breaking points were decreased in mice treated with both doses of MDMA. This decrease in motivation for palatable food was not due to unspecific locomotor or coordination deficits. A resistance to extinction was observed only with the highest dose of MDMA, whilst all mice showed similar reinstatement of palatable food-seeking behaviour irrespective of previous treatment. Autoradiography of [³H]-mazindol binding revealed a decrease in striatal dopamine transporter binding only in mice treated with the highest dose of MDMA.

Conclusions

This study demonstrates that repeated treatment with MDMA decreases the incentive motivation for a palatable food reward and that long-lasting MDMA-induced dopaminergic neurotoxicity increases the resistance to extinction of responding in the absence of reward.     

Amphetamine-induced enhancement of responding for conditioned reward in rats: interactions with repeated testing

Rationale

The mesolimbic dopamine system underlies the ability of reward-related stimuli to control operant behavior. Previous work has shown that amphetamine potentiates operant responding for conditioned rewards (CRs).

Objectives

Here, we asked whether the profile of this amphetamine-produced potentiation changes with repeated CR presentation, i.e., as the CR is being extinguished.

Methods

Amphetamine (0?C1.0?mg/kg, i.p.), administered over four daily sessions using a Latin square design, dose-dependently increased lever pressing for a ??lights-off?? stimulus previously paired with food in rats.

Results

The amphetamine-produced enhancement of responding for CR was significantly modulated with repeated CR exposure: it was strongest on day?1 and became less pronounced in subsequent sessions whereas the CR effect persisted. In further experiments, rats receiving LiCl devaluation of the primary reward failed to show a significant reduction in the amphetamine-produced enhancement of responding for CR.

Conclusions

The nature of the dissociable effects of amphetamine on responding for CR versus the CR effect itself remains to be elucidated.     

Deletion of the GABAA α2-subunit does not alter self administration of cocaine or reinstatement of cocaine seeking

Rationale

GABA_A receptors containing α2-subunits are highly represented in brain areas that are involved in motivation and reward, and have been associated with addiction to several drugs, including cocaine. We have shown previously that a deletion of the α2-subunit results in an absence of sensitisation to cocaine.

Objective

We investigated the reinforcing properties of cocaine in GABA_A α2-subunit knockout (KO) mice using an intravenous self-administration procedure.

Methods

α2-subunit wildtype (WT), heterozygous (HT) and KO mice were trained to lever press for a 30 % condensed milk solution. After implantation with a jugular catheter, mice were trained to lever press for cocaine (0.5 mg/kg/infusion) during ten daily sessions. Responding was extinguished and the mice tested for cue- and cocaine-primed reinstatement. Separate groups of mice were trained to respond for decreasing doses of cocaine (0.25, 0.125, 0.06 and 0.03 mg/kg).

Results

No differences were found in acquisition of lever pressing for milk. All genotypes acquired self-administration of cocaine and did not differ in rates of self-administration, dose dependency or reinstatement. However, whilst WT and HT mice showed a dose-dependent increase in lever pressing during the cue presentation, KO mice did not.

Conclusions

Despite a reported absence of sensitisation, motivation to obtain cocaine remains unchanged in KO and HT mice. Reinstatement of cocaine seeking by cocaine and cocaine-paired cues is also unaffected. We postulate that whilst not directly involved in reward perception, the α2-subunit may be involved in modulating the “energising” aspect of cocaine’s effects on reward-seeking.     

The effects of AMPA receptor blockade in the prelimbic cortex on systemic and ventral tegmental area opiate reward sensitivity

Rationale

The medial prefrontal cortex (mPFC) is a key neural region involved in opiate-related reward memory processing. AMPA receptor transmission in the mPFC modulates opiate-related reward memory processing, and chronic opiate exposure is associated with alterations in intra-mPFC AMPA receptor function.

Objective

The objectives of this study were to examine how pharmacological blockade of AMPA receptor transmission in the prelimbic (PLC) division of the mPFC may modulate opiate reward memory acquisition and whether opiate exposure state may modulate the functional role of intra-PLC AMPA receptor transmission during opiate reward learning.

Methods

Using an unbiased conditioned place preference (CPP) procedure in rats, we performed discrete, bilateral intra-PLC microinfusions of the AMPA receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione, prior to behavioral morphine CPP conditioning, using sub-reward threshold conditioning doses of either systemic (0.05 mg/kg; i.p.) or intra-ventral tegmental area (VTA) morphine (250 ng/0.5 μl).

Results

We show that, in both opiate-naïve and opiate-dependent states, intra-PLC blockade of AMPA receptor transmission, but not the infralimbic cortex, increases the behavioral reward magnitude of systemic or intra-VTA morphine. This effect is dependent on dopamine (DA)ergic signaling because pre-administration of cis-(Z)-flupenthixol-dihydrochloride (α-flu), a broad-spectrum dopamine receptor antagonist, blocked the morphine-reward potentiating effects of AMPA receptor blockade.

Conclusions

These findings suggest a critical role for intra-PLC AMPA receptor transmission in the processing of opiate reward signaling. Furthermore, blockade of AMPA transmission specifically within the PLC is capable of switching opiate reward processing to a DA-dependent reward system, independently of previous opiate exposure history.     

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.     

Cues predicting drug or food reward restore morphine-induced place conditioning in mice lacking delta opioid receptors

Rationale

The exact role of delta opioid receptors in drug-induced conditioned place preference (CPP) remains debated. Under classical experimental conditions, morphine-induced CPP is decreased in mice lacking delta opioid receptors (Oprd1 ^?/?). Morphine self-administration, however, is maintained, suggesting that drug-context association rather than drug reward is deficient in these animals.

Objectives

This study further examined the role of delta opioid receptors in mediating drug-cue associations, which are necessary for the expression of morphine-induced CPP.

Methods

We first identified experimental conditions under which Oprd1 ^?/? mice are able to express CPP to morphine (5, 10 or 20 mg/kg) in a drug-free state and observed that, in this paradigm, CPP was dependent on circadian time conditions. We then took advantage of this particularity to assess the ability of various cues (internal or discrete), predicting either drug or food reward, to restore CPP induced by morphine (10 mg/kg) in Oprd1 ^?/? mice in conditions under which they normally fail to express CPP.

Results

We found that presentation of circadian, drug or auditory cues, predicting morphine or food reward, restored morphine CPP in Oprd1 ^?/? mice, which then performed as well as control mice.

Conclusions

This study reveals that, in contrast to spatial cues, internal or discrete morphine-predicting stimuli permit full expression of morphine CPP in Oprd1 ^?/? mice. Delta receptors, therefore, appear to play a crucial role in modulating spatial contextual cue-related responses. This activity may be critical when context gains control over behavior, as is the case for context-induced relapse in drug abuse.     

Delay discounting of food and remifentanil in rhesus monkeys

Rationale

Drug abuse can be conceptualized as choice between drug and nondrug reinforcers in which drug choice is excessive; factors impacting drug taking can be examined using procedures in which subjects choose between drug and an alternative reinforcer.

Objective

This experiment examined the effects of delayed reinforcement on choice between food and the mu-opioid receptor agonist remifentanil.

Methods

Rhesus monkeys responded under a concurrent fixed-ratio 5, fixed-ratio 5 schedule in which responding on one lever delivered one food pellet and responding on another lever delivered an i.v. infusion.

Results

With no delay, monkeys responded predominantly for food rather than saline or small doses of remifentanil; as the dose of remifentanil increased (0.1–1.0 μg/kg/infusion), monkeys responded more for drug. Delaying delivery (30–240 s) of 0.32 and not 1.0 μg/kg/infusion of remifentanil (food delivered immediately) decreased responding for drug and increased responding for food, resulting in a rightward shift in the remifentanil dose–effect curve. Delaying delivery of food (60–240 s) when doses of remifentanil smaller than 0.32 μg/kg/infusion (but not saline) were available decreased responding for food and increased responding for drug, resulting in a leftward shift in the remifentanil dose–effect curve.

Conclusion

These results provide evidence that delaying the delivery of a mu-opioid receptor agonist reduces its potency as a positive reinforcer; more importantly, delaying the delivery of an alternative nondrug reinforcer (e.g., food) enhances the reinforcing potency of the agonist. Thus, understanding the factors that control substance abuse requires examination of contingencies for both drug and nondrug reinforcers.     

Hindbrain orexin 1 receptors influence palatable food intake, operant responding for food, and food-conditioned place preference in rats

Rationale

Brain orexin 1 receptors (OX1Rs) are involved in food-motivated behavior. Most research has focused on forebrain OX1R populations, but hindbrain OX1Rs affect feeding. We hypothesized that hindbrain OX1Rs affect the reward value of food.

Objectives

We examined the effects of hindbrain OX1R stimulation or blockade on motivation for food, palatable high-fat (HF) food intake, and food-conditioned place preference.

Methods

Rats trained to lever press for sucrose on a progressive ratio (PR) schedule received fourth intracerebroventricular (icv) injections of vehicle, orexin-A (0.1–1 nmol), or the OX1R antagonist SB334867 (10–20 nmol) before operant test sessions. Effects of these treatments on HF food intake during daily 1-h tests were assessed with fourth icv and nucleus of the solitary tract (NTS) injections. We conditioned a place preference by pairing HF food with one side of a two-sided chamber and then examined the effect of 20 nmol fourth icv SB334867 on the expression of that preference.

Results

In ad lib fed rats on the PR schedule, fourth icv orexin-A significantly increased responding and breakpoint relative to the vehicle. In 24-h food-deprived rats, fourth icv SB334867 significantly decreased responding and breakpoint. Orexin-A delivered to the fourth ventricle (0.1 nmol) or NTS (0.01 nmol) increased HF diet intake. Fourth icv SB334867 did not affect HF food intake, but SB334867 delivered either fourth icv (20 nmol) or intra-NTS (5–10 nmol) suppressed chow intake. Expression of HF food-conditioned place preference was inhibited by fourth icv SB334867.

Conclusions

Hindbrain OX1R activity affects food-motivated operant behavior and may play a role in responding to cues that predict palatable food.     

Synergistic interaction between caloric restriction and amphetamine in food-unrelated approach behavior of rats

Rationale

Approach behavior is regulated by the brain integrating information about environment and body state. Psychoactive drugs interact with this process.

Objectives

We examined the extent to which caloric (i.e., food) restriction, amphetamine (AMPH) and lithium interact in potentiating locomotor activity and responding reinforced by visual stimulus (VS), a reward unrelated to energy homeostasis.

Methods

Rats either had ad libitum access to food or received daily rations that maintained 85–90 % of their original body weights. Leverpressing turned on a cue light for 1 s and turned off house light for 5 s. AMPH and lithium were administered through intraperitoneal injections and diet, respectively.

Results

Food restriction or AMPH (1 mg/kg) alone had little effect on VS-reinforced responding; however, the combination of the two conditions markedly potentiated VS-reinforced responding (fourfold). Food restriction lasting 7 days or longer was needed to augment AMPH's effect on VS-reinforced responding. AMPH (0.3–3 mg/kg) potentiated locomotor activity similarly between food-restricted and ad libitum groups. Repeated injections of AMPH-sensitized locomotor activity, but not VS-reinforced responding. In addition, while chronic lithium treatments (0.2 % lithium carbonate chow) reduced VS-reinforced responding, chronic lithium further augmented AMPH-potentiated VS-reinforced responding.

Conclusions

Food restriction interacts with psychoactive drugs to potentiate goal-directed responding unrelated to food seeking in a much more powerful manner than previously thought. The novel finding that lithium can augment a psychostimulant effect of AMPH suggests caution when combining lithium and psychostimulant drugs in clinical settings.     

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.