Enhancing cognition by affecting memory reconsolidation

Fully consolidated associative memories can undergo a retrieval-dependent reconsolidation process, which allows for the updating and strengthening of the original association. Limiting, or so-called boundary, conditions determine whether a particular retrieval event triggers reconsolidation. Manipulating memories at reconsolidation may offer an opportunity to improve cognitive capacities in humans by increasing memory persistence, specificity and accuracy. Also, preventing the reconsolidation of maladaptive memories that characterize some neuropsychiatric disorders, such as post-traumatic stress disorder or drug addiction may offer a novel approach to treatment. Here we review recent advances in understanding and manipulating memory reconsolidation in both animals and humans, and discuss the potential of such interventions in cognitive enhancement.This work was supported by a UK Medical Research Council Programme Grant (G1002231) to B.J.E. and A.L.M. and was conducted in the Department of Psychology, University of Cambridge, and the Behavioural and Clinical Neuroscience Institute (BCNI), an initiative jointly funded by the MRC and the Wellcome Trust.This is the author accepted manuscript. It first appeared at http://www.sciencedirect.com/science/article/pii/S2352154615000273#

Reconsolidation of appetitive memories for both natural and drug reinforcement is dependent on B-adrenergic receptors

We have investigated the neurochemical mechanisms of memory reconsolidation and, in particular, the functional requirement for intracellular mechanisms initiated by beta-adrenergic signaling. We show that propranolol, given in conjunction with a memory reactivation session, can specifically disrupt the conditioned reinforcing properties of a previously appetitively reinforced conditioned stimulus (CS), whether the stimulus had been associated with self-administered cocaine or with sucrose. These data show that memories for both drug and nondrug CS-US associations are dependent on beta-adrenergic receptor-mediated signaling for their reconsolidation, with implications for the potential development of a novel treatment for drug addiction and some forms of obesity

In search of predictive endophenotypes in addiction: insights from preclinical research.

Drug addiction is widely recognized to afflict some but not all individuals by virtue of underlying risk markers and traits involving multifaceted interactions between polygenic and external factors. Remarkably, only a small proportion of individuals exposed to licit and illicit drugs develop compulsive drug-seeking behavior, maintained in the face of adverse consequences and associated detrimental patterns of drug intake involving extended and repeated bouts of binge intoxication, withdrawal and relapse. As a consequence, research has increasingly endeavored to identify distinctive neurobehavioral mechanisms and endophenotypes that predispose individuals to compulsive drug use. However, research in active drug users is hampered by the difficulty in categorizing putatively causal behavioral traits prior to the initiation of drug use. By contrast, research in experimental animals is often hindered by the validity of approaches used to investigate the neural and psychological mechanisms of compulsive drug-seeking habits in humans. Herein, we survey and discuss the principal findings emanating from preclinical animal research on addiction and highlight how specific behavioral endophenotypes of presumed genetic origin (e.g. trait anxiety, novelty preference and impulsivity) differentially contribute to compulsive forms of drug seeking and taking and, in particular, how these differentiate between different classes of stimulant and non-stimulant drugs of abuse.The authors acknowledge funding support from the UK Medical Research Council (grants G9536855; G0701500; G0802729), the Newton-Cambridge Trust and the Wellcome Trust (grant WT109738MA). The Behavioural and Clinical Neuroscience Institute at Cambridge University is supported by a core award from the Medical Research Council (G1000183) and Wellcome Trust (093875/Z/10/Z).This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/gbb.1226

The persistence of maladaptive memory: addiction, drug memories and anti-relapse treatments

Addiction is a chronic, relapsing disorder, characterised by the long-term propensity of addicted individuals to relapse. A major factor that obstructs the attainment of abstinence is the persistence of maladaptive drug-associated memories, which can maintain drug-seeking and taking behaviour and promote unconscious relapse of these habits. Thus, addiction can be conceptualised as a disorder of aberrant learning of the formation of strong instrumental memories linking actions to drug-seeking and taking outcomes that ultimately are expressed as persistent stimulus-response habits; of previously neutral environmental stimuli that become associated with drug highs (and/or withdrawal states) through pavlovian conditioning, and of the subsequent interactions between pavlovian and instrumental memories to influence relapse behaviour. Understanding the psychological, neurobiological and molecular basis of these drug memories may produce new methods of pro-abstinence, anti-relapse treatments for addiction.This work was supported by a UK Medical Research Council grant (no. 9536855) to BJE, and was conducted in the Behavioural and Clinical Neuroscience Institute, funded by a joint award from the MRC and the Wellcome Trust

Decrease of cocaine, but not heroin, self-administration and relapse by the tyrosine kinase inhibitor masitinib in male Sprague Dawley rats.

RATIONALE: Accumulating evidence shows that cocaine, and also heroin, influence several tyrosine kinases, expressed in neurons and in non-neuronal populations such as microglia, astrocytes and mast-cells. Drug-induced activation of mast cells both triggers inflammatory processes in the brain mediated by the glial cells they activate, and facilitates histamine release which may directly influence the dopamine system. Thus, by triggering the activation and degranulation of mast cells dependent on the tyrosine kinase c-kit and Fyn, the latter being also involved in NMDA-dependent synaptic plasticity, cocaine and heroin may indirectly influence the neural mechanisms that mediate their reinforcing properties. Masitinib, a novel tyrosine kinase inhibitor with high selectivity for c-Kit, Fyn and Lyn, may alter the aberrant consequences of the activation of these tyrosine kinases by cocaine and heroin. OBJECTIVE: We investigated in rats the effect of a chronic oral treatment with masitinib (20 mg/kg) on the reinforcing and motivational properties of self-administered cocaine (250 μg/infusion) and heroin (40 μg/infusion). METHODS: Three different cohorts of rats were trained instrumentally to respond for cocaine, heroin or food under continuous reinforcement. In each group, we assessed the influence of chronic daily treatment with masitinib on the maintenance of instrumental responding and intake and the motivation for the reinforcer. Thus, masitinib and vehicle-treated rats were challenged to adapt to high behavioural demand, to respond under a progressive ratio schedule of reinforcement and to reinstate instrumental responding after extinction and/or abstinence. RESULTS: Masitinib selectively decreased cocaine intake, the motivation for cocaine and the subsequent propensity to respond for cocaine under extinction, while having no effect on instrumental responding for heroin or food. CONCLUSION: The present findings suggest masitinib, a drug with proven efficacy in CNS disorders, could represent a novel treatment for cocaine addiction provided its influence on the reinforcing and incentive properties of the drug is confirmed

Com afronta la policia de la Generalitat - Mossos d'Esquadra (PGME) la prevenció dels extremismes violents

The hippocampus and amygdala are thought to be functionally distinct components of different learning and memory systems. This functional dissociation has been particularly apparent in pavlovian fear conditioning, where the integrity of the hippocampus is necessary for contextual conditioning, and of the amygdala for discrete cue conditioning. Their respective roles in appetitive conditioning, however, remain equivocal mainly due to the lack of agreement concerning the operational definition of a 'context'. The present study used a novel procedure to measure appetitive conditioning to spatial context or to a discrete cue. Following selective excitotoxic lesions of the hippocampus (HPC) or basolateral amygdala (BLA), rats were initially trained to acquire discrete CS-sucrose conditioning in a Y-maze apparatus with three topographically identical chambers, the chambers discriminated only on the basis of path integration. The same group of animals then underwent 'place/contextual conditioning' where the CS presented in a chamber assigned as the positive chamber was paired with sucrose, but the same CS presented in either of the other two chambers was not. Thus, spatial context was the only cue that the animal could use to retrieve the value of the CS. HPC lesions impaired the acquisition of conditioned place preference but facilitated the acquisition of cue conditioning, while BLA lesions had the opposite effect, retarding the acquisition of cue conditioning but leaving the acquisition of conditioned place preference intact. Here we provide strong support for the notion that the HPC and BLA subserve complementary and competing roles in appetitive cue and contextual conditioning

Evidence for a Long-Lasting Compulsive Alcohol Seeking Phenotype in Rats

Excessive drinking to intoxication is the major behavioral characteristic of those addicted to alcohol but it is not the only one. Indeed, individuals addicted to alcohol also crave alcoholic beverages and spend time and put much effort into compulsively seeking alcohol, before eventually drinking large amounts. Unlike this excessive drinking, for which treatments exist, compulsive alcohol seeking is therefore another key feature of the persistence of alcohol addiction since it leads to relapse and for which there are few effective treatments. Here we provide novel evidence for the existence in rats of an individual vulnerability to switch from controlled to compulsive, punishment-resistant alcohol seeking. Alcohol-preferring rats given access to alcohol under an intermittent 2-bottle choice procedure to establish their alcohol-preferring phenotype were subsequently trained instrumentally to seek and take alcohol on a chained schedule of reinforcement. When stable seeking-taking performance had been established, completion of cycles of seeking responses resulted unpredictably either in punishment (0.45 mA foot-shock) or the opportunity to make a taking response for access to alcohol. Compulsive alcohol seeking, maintained in the face of the risk of punishment, emerged in only a subset of rats with a predisposition to prefer and drink alcohol, and was maintained for almost a year. We show further that a selective and potent μ-opioid receptor antagonist (GSK1521498) reduced both alcohol seeking and alcohol intake in compulsive and non-compulsive rats, indicating its therapeutic potential to promote abstinence and prevent relapse in individuals addicted to alcohol.The present study was funded by a Medical Research Council Programme Grant (no. G1002231) and by GlaxoSmithKline (GSK), which has a commercial interest in GSK1521498. The production of the P rats was funded by the R24 Alcohol Research Resource Award grant (R24 AA015512) from NIAAA