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The most intractable feature of drug addiction is the high rate of relapse, even following extended periods of abstinence from drug-taking. Evidence suggests that allowing rats extended access to cocaine self-administration leads to behavioral characteristics in these animals that are consistent with the development of addiction in humans. In the current study, rats were allowed to self-administer cocaine over a total of 22 daily sessions, the final seven of which were long-access (LgA) sessions of 6 h duration. Assessments of reinstatement of drug-seeking behavior were made following reintroduction to the drug-taking environment and noncontingent priming with either conditioned stimulus (CS) or cocaine in both extinguished and abstinent subject groups. Three separate groups of rats were treated with either saline or D-serine (100 mg/kg i.p.) administered 2 h prior to, or immediately following, each extinction training session. Saline-treated LgA rats were resistant to the effects of extinction training to reduce noncontingent priming of reinstatement of drug-seeking behavior with either CS or cocaine. In contrast, treatment with D-serine either before or immediately following the sessions resulted in a significant enhancement in the ability of extinction training to reduce cocaine-primed reinstatement of drug-seeking behavior. These results suggest that D-serine can act to enhance the consolidation of extinction learning in LgA rats, and is therefore a promising adjunctive agent along with behavioral therapy for the treatment of cocaine addiction., (Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

This study investigated the extent to which hydromorphone (HYD) choice and behavioral economic demand differed during experimental analogs of Unemployment (Drug Only: HYD and no money alternative), Employment (Drug or Money: HYD and $4 alternative), and Punishment (Drug Only+Money Loss: HYD only and $4 subtracted for each HYD choice), in the context of anticipated high vs. low post-session drug availability (HYD 24 mg vs. placebo). Eleven heroin-dependent, buprenorphine-stabilized (8 mg/day) volunteers first sampled two HYD doses (0 and 24 mg IM in randomized, counterbalanced order, labeled Drug A [session 1] and Drug B [session 2]). In each of the final six sessions, volunteers were given access to a 12-trial choice progressive ratio (PR) task and could work to receive HYD unit doses (2mg each); cumulative dose units earned were administered in a bolus injection after the work session. Before the PR task, volunteers were told which HYD dose (Drug A or B) would be available 3h after the PR-contingent injection. Relative to Unemployment (Drug Only), Employment (Drug or Money) and Punishment (Drug Only+Money Loss) each significantly suppressed HYD seeking (e.g., breakpoints). Employment and Punishment also reduced HYD behavioral economic demand, but via different mechanisms: Employment increased HYD price-elasticity, whereas Punishment decreased HYD demand intensity. Adjusting for the initial level difference (i.e., normalized demand), Employment significantly decreased P(max) (i.e., lower "essential value" of HYD) and O(max) (maximum HYD responding) compared to Punishment or Unemployment. These effects were not significantly altered by post-session drug availability., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

A distributed limbic-corticostriatal circuitry is implicated in cue-induced drug craving and relapse. Exposure to drug-paired cues not only precipitates relapse, but also triggers the reactivation and reconsolidation of the cue-drug memory. However, the limbic cortical-striatal circuitry underlying drug memory reconsolidation is unclear. The aim of this study was to investigate the involvement of the nucleus accumbens core and the basolateral amygdala in the reconsolidation of a cocaine-conditioned stimulus-evoked memory. Antisense oligodeoxynucleotides (ASO) were infused into each structure to knock down the expression of the immediate-early gene zif268, which is known to be required for memory reconsolidation. Control infusions used missense oligodeoxynucleotides (MSO). The effects of zif268 knockdown were measured in two complementary paradigms widely used to assess the impact of drug-paired CSs upon drug seeking: the acquisition of a new instrumental response with conditioned reinforcement and conditioned place preference. The results show that both intranucleus accumbens core and intrabasolateral amygdala zif268 ASO infusions at memory reactivation impaired the reconsolidation of the memory underlying a cocaine-conditioned place preference. However, knockdown of zif268 in the nucleus accumbens at memory reactivation had no effect on the memory underlying the conditioned reinforcing properties of the cocaine-paired CS measured subsequently, and this is in contrast to the marked impairment observed previously following intrabasolateral amygdala zif268 ASO infusions. These results suggest that both the basolateral amygdala and nucleus accumbens core are key structures within limbic cortical-striatal circuitry where reconsolidation of a cue-drug memory occurs. However reconsolidation of memory representations formed during Pavlovian conditioning are differentially localized in each site.

Background: Acute and chronic stress reinstates drug-seeking behavior. Current animal models show that these effects are contingent (temporally, contextually, or both) on the drug-conditioning environment. To date, no paradigm exists to model the common human situation in which stressors that are distinct from the experience of drugs can lead to relapse., Methods: Rats were allowed to self-administer cocaine or saline over 8 days. They then underwent extinction training, during which responding was not reinforced with drug infusions. After 16 days of extinction, rats were submitted to a brief cold swim stress and then tested for seeking behavior (responding not reinforced with drug infusions) for 4 days., Results: All rats developed self-administration behavior. Following extinction, cold swim stress induced reinstatement of drug-seeking behavior in cocaine-trained rats, an effect that was still present 3 days after stress exposure., Conclusions: This study indicates that cold swim stress can have long-term effects on drug-seeking behavior and may provide us with a suitable model to study the latent effects of stress on relapse to drug abuse., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Oral naltrexone effectively antagonizes heroin, but patient noncompliance limits its utility; sustained-release preparations may overcome this. Few data are available on optimal blood naltrexone levels for preventing craving and/or return to heroin use. This study assesses various risk factors, including blood naltrexone level, for heroin craving and relapse to illicit opioids., Methods: Heroin-dependent persons from a randomized controlled trial of oral versus implant naltrexone were followed up for 6 months. Thirty-four participants received 50 mg oral naltrexone daily, plus placebo implant; thirty-five participants received a single dose of 2.3 g naltrexone implant, plus daily oral placebo tablets., Results: Compared to oral naltrexone patients, implant naltrexone patients were significantly less likely to use any opioids and had one-fifth the risk of using heroin > or = weekly. Risk of > or = weekly heroin use increased by 2.5 times at blood naltrexone concentration < .5 ng/mL compared with > or = .5 ng/mL, with 3 ng/mL associated with very low risk of use. Craving remained near "floor" levels for implant patients but rebounded to higher levels among oral patients. Lower craving scores (< or = 20/70) predicted lower relapse risk. Noncompliance with daily oral formula, higher baseline craving, longer history of use, and being younger predicted higher craving at follow-up., Conclusions: Implant naltrexone was better associated with reduced heroin craving and relapse than oral naltrexone. Effective treatment was achieved at blood naltrexone levels of 1 ng/mL to 3 ng/mL, with higher levels associated with greater efficacy. Craving assessment may be valuable in predicting relapse risk allowing timely intervention., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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 role for glutamatergic signaling in the nucleus accumbens (NA) in both the expression and extinction of cocaine seeking has been suggested. The effects of extinction following cocaine self-administration on the expression and synaptosomal distribution of GluR1 and NMDAR1 glutamate receptor subunits in the NA shell and core and the dorsolateral striatum were examined. Rats self-administered cocaine or had access to saline for 14 days followed by a period of extinction training, home-cage exposure, or placement in the self-administration chambers with levers retracted in the absence of discrete cues. Self-administration followed by home-cage exposure reduced GluR1 expression in the NA shell and NMDAR1 expression in the dorsolateral striatum without affecting expression in the NA core. These effects were not observed following extinction. Extinction training increased synaptosomal GluR1 in the NA shell and core and NMDAR1 in the dorsolateral striatum while decreasing synaptosomal NMDAR1 in the shell. Extinction but not home-cage exposure was associated with altered expression and synaptosomal content of the scaffolding proteins PICK1 and PSD95.Following extinction, synaptosomal PICK1 decreased in the dorsolateral striatum while total PICK1 expression was increased in the shell. The synaptosomal PSD95 was decreased in the NA shell, while total PSD95 expression was increased in the core. These data suggest that extinguished cocaine seeking is associated with changes in GluR1 and NMDAR1 expression and subcellular distribution that are region-specific and consist of both a reversal of cocaine-induced adaptations and emergent extinction-related alterations that include receptor subunit redistribution and may involve alterations in scaffolding proteins.

Addiction to drugs of abuse is a disorder that involves dysfunctions in motivational processes. Both the primary rewarding effects of drugs, as well as the acquired motivational properties of stimuli associated with drug-seeking and -taking, contribute to the perpetuation of dependence on drugs of abuse. Metabotropic glutamate (mGlu) receptors, which mediate slow glutamate neurotransmission, are located throughout limbic and cortical brain sites implicated in drug addiction. Preclinical evidence suggests that mGlu receptors play a crucial role in regulating behavioral effects of drugs of abuse relevant to drug addiction. Specifically, antagonists at excitatory postsynaptic mGlu5 receptors decrease drug self-administration without affecting motor behaviors, cognition or the reward value of natural rewards, while agonists at inhibitory presynaptic mGlu2/3 receptor agonists prevent reinstatement to drug-seeking and -taking after a period of abstinence. These findings have increased our understanding of the neuropathological processes associated with aspects of dependence on drugs of abuse and have provided new targets for pharmacological approaches to the treatment of dysfunctions in motivational processes characterizing the various phases of drug addiction.