Attenuating Nicotine Reinforcement and Relapse by Enhancing Endogenous Brain Levels of Kynurenic Acid in Rats and Squirrel Monkeys.

The currently available antismoking medications have limited efficacy and often fail to prevent relapse. Thus, there is a pressing need for newer, more effective treatment strategies. Recently, we demonstrated that enhancing endogenous levels of kynurenic acid (KYNA, a neuroinhibitory product of tryptophan metabolism) counteracts the rewarding effects of cannabinoids by acting as a negative allosteric modulator of α7 nicotinic receptors (α7nAChRs). As the effects of KYNA on cannabinoid reward involve nicotinic receptors, in the present study we used rat and squirrel monkey models of reward and relapse to examine the possibility that enhancing KYNA can counteract the effects of nicotine. To assess specificity, we also examined models of cocaine reward and relapse in monkeys. KYNA levels were enhanced by administering the kynurenine 3-monooxygenase (KMO) inhibitor, Ro 61-8048. Treatment with Ro 61-8048 decreased nicotine self-administration in rats and monkeys, but did not affect cocaine self-administration. In rats, Ro 61-8048 reduced the ability of nicotine to induce dopamine release in the nucleus accumbens shell, a brain area believed to underlie nicotine reward. Perhaps most importantly, Ro 61-8048 prevented relapse-like behavior when abstinent rats or monkeys were reexposed to nicotine and/or cues that had previously been associated with nicotine. Ro 61-8048 was also effective in monkey models of cocaine relapse. All of these effects of Ro 61-8048 in monkeys, but not in rats, were reversed by pretreatment with a positive allosteric modulator of α7nAChRs. These findings suggest that KMO inhibition may be a promising new approach for the treatment of nicotine addiction.

Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse.

Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration dose-response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell--consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement.

Nicotine-seeking reinstatement is reduced by inhibition of instrumental memory reconsolidation.

The reinforcing properties of nicotine play a major role in instrumental conditioning to nicotine taking in smokers. Retrieval of nicotine-related memories may promote relapse to nicotine seeking after prolonged abstinence. Once consolidated, memories are stable, but they return to a labile phase, called reconsolidation, after their retrieval. The aim of our study was to investigate whether it was possible to interfere with the reconsolidation of instrumental nicotine-related memories by acting at glutamatergic receptors [N-methyl-D-aspartate receptors (NMDARs)] to prevent relapse to nicotine-seeking behaviour in the rat. We assessed whether the NMDAR antagonist MK-801, administered before or after nicotine-related instrumental memory retrieval, can reduce reinstatement of nicotine-seeking behaviour in rats previously trained to nicotine self-administration. Following a period of forced abstinence, MK-801 (0.1 mg/kg intraperitoneally) was administered 30 min before or 1 h after the re-exposure to 20 lever presses without any contingency in the training context to retrieve instrumental memory. MK-801 administered after, but not before, retrieval inhibited reinstatement compared with vehicle controls and groups without retrieval of instrumental memory. Interestingly, a retrieval factor effect was observed as an increase of reinstatement in vehicle-treated groups, suggesting a behavioural outcome of the occurrence of instrumental memory reconsolidation. Our findings suggest that, by acting on NMDARs, it is possible to reduce the reinstatement of nicotine-seeking behaviour through inhibition of instrumental nicotine-related memory reconsolidation.

The effect of postretrieval extinction of nicotine pavlovian memories in rats trained to self-administer nicotine.

INTRODUCTION: Retrieval (reactivation) of smoking-related memories is a potent trigger of relapse among ex-smokers, and manipulation of smoking-related memories is considered to be a promising target for therapeutic intervention. Recent studies have shown that postreactivation extinction attenuates drug-related memories and relapse to drug-seeking both in rodents and in humans. We investigated the effect of postreactivation extinction in a rat model of relapse to nicotine-seeking. METHODS: Rats were trained to self-administer nicotine in context A (CxA). Pressing the active lever resulted in the nicotine infusion paired with a cue-light (CS). Nicotine-related Pavlovian memories were then reactivated via presentation of 3 non-contingent CS. We then extinguished nicotine-related memories in a distinct context (CxB) followed 24hr later by the assessment of renewal of responding in CxA. RESULTS: Postreactivation extinction, applied 1 but not 6hr after reactivation, induced a significant reduction of the rate of responding on renewal compared to responding during nicotine self-administration, whereas no such effect of CS-Extinction was observed in No-Reactivation group. However, between-group comparisons of responding during renewal did not show any significant difference. CONCLUSIONS: Current results show that the reactivation of nicotine-related Pavlovian memories may reduce the effect of renewal to exert nicotine-seeking. However, it appears that this effect is small in size and is not significantly different from CS-Extinction alone.

Post-retrieval extinction as reconsolidation interference: methodological issues or boundary conditions?

Memories that are emotionally arousing generally promote the survival of species; however, the systems that modulate emotional learning can go awry, resulting in pathological conditions such as post-traumatic stress disorders, phobias, and addiction. Understanding the conditions under which emotional memories can be targeted is a major research focus as the potential to translate these methods into clinical populations carries important implications. It has been demonstrated that both fear and drug-related memories can be destabilised at their retrieval and require reconsolidation to be maintained. Therefore, memory reconsolidation offers a potential target period during which the aberrant memories underlying psychiatric disorders can be disrupted. Monfils et al. (Science 324:951-955, 2009) have shown for the first time that safe information provided through an extinction session after retrieval (during the reconsolidation window) may update the original memory trace and prevent the return of fear in rats. In recent years, several authors have then tested the effect of post-retrieval extinction on reconsolidation of either fear or drug-related memories in both laboratory animals and humans. In this article, we review the literature on post-reactivation extinction, discuss the differences across studies on the methodological ground, and review the potential boundary conditions that may explain existing discrepancies and limit the potential application of post-reactivation extinction approaches.

Acetylcholinesterase inhibitors partially generalize to nicotine discriminative stimulus effect in rats.

Acetylcholinesterase inhibitors (AChE-Is), galantamine, physostigmine and tacrine, enhance central levels of synaptic acetylcholine. Galantamine and physostigmine, but not tacrine, exhibit allosteric potentiation ligand (APL) properties on nicotinic acetylcholine receptors. The purpose of this study was to investigate whether AChE-Is with nicotinic acetylcholine receptor-positive allosteric modulator properties generalize to the discriminative stimulus effect of nicotine in rats. A two-lever operant conditioning paradigm was used in which rats were trained to discriminate nicotine (0.2 mg/kg/ml intraperitoneally) from saline. After training, generalization tests were carried out with galantamine (1, 3 or 5 mg/kg intraperitoneally), physostigmine (0.05, 0.1 or 0.2 mg/kg subcutaneously) or tacrine (0.625, 1.25 or 2.5 mg/kg subcutaneously) given as a single presession administration. Galantamine, physostigmine or tacrine produced a partial generalization of 62.2%, 55.1% or 43.6% , respectively, on the nicotine-appropriate lever compared with 100% partial generalization induced by the nicotine-training dose. High doses of galantamine, physostigmine or tacrine produced small but significant decreases in operant response rate, suggesting a possible underestimation of the degree of generalization. Our study showed that these three AChE-Is partially generalized to the nicotine stimulus without a significant distinction between AChE-Is with or without APL properties. These findings suggest that the APL property is not necessary for inducing nicotine-like effects in vivo in this behavioural paradigm.