Drug Cues, Conditioned Reinforcement, and Drug Seeking: The Sequelae of a Collaborative Venture With Athina Markou.

Athina Markou spent a research period in my laboratory, then in the Department of Anatomy in Cambridge University, in 1991 to help us establish a cocaine-seeking procedure. Thus we embarked on developing a second-order schedule of intravenous cocaine reinforcement to investigate the neural basis of the pronounced effects of cocaine-associated conditioned stimuli on cocaine seeking. This brief review summarizes the fundamental aspects of cocaine seeking measured using this approach and the importance of the methodology in enabling us to define the neural mechanisms and circuitry underlying conditioned reinforcement and cocaine, heroin, and alcohol seeking. The shift over time and experience of control over drug seeking from a limbic cortical-ventral striatal circuit underlying goal-directed drug seeking to a dorsal striatal system mediating habitual drug seeking are also summarized. The theoretical implications of these data are discussed, thereby revealing the ways in which the outcomes of a collaboration can endure

From the ventral to the dorsal striatum: Devolving views of their roles in drug addiction

AbstractWe revisit our hypothesis that drug addiction can be viewed as the endpoint of a series of transitions from initial voluntarily drug use to habitual, and ultimately compulsive drug use. We especially focus on the transitions in striatal control over drug seeking behaviour that underlie these transitions since functional heterogeneity of the striatum was a key area of Ann Kelley's research interests and one in which she made enormous contributions. We also discuss the hypothesis in light of recent data that the emergence of a compulsive drug seeking habit both reflects a shift to dorsal striatal control over behaviour and impaired prefontal cortical inhibitory control mechanisms. We further discuss aspects of the vulnerability to compulsive drug use and in particular the impact of impulsivity. In writing this review we acknowledge the untimely death of an outstanding scientist and a dear personal friend

Differential vulnerability to the punishment of cocaine related behaviours: effects of locus of punishment, cocaine taking history and alternative reinforcer availability.

BACKGROUND: The availability of alternative reinforcement has been shown to reduce drug use, but it remains unclear whether it facilitates a reduction or cessation of drug seeking or taking. OBJECTIVES: We compared the effects of punishment of cocaine seeking or taking behaviour after brief or extended cocaine-taking histories when behavioural reallocation was facilitated or not by making available an alternative ingestive reinforcer (sucrose). METHODS: In the first experiment, punishment of either seeking or taking responses was introduced immediately after training on the seeking-taking chained schedule. In the second experiment, punishment of cocaine seeking was introduced after 12 additional days of either 1 or 6 h daily access to cocaine self-administration. In both experiments, beginning 1 week before the introduction of punishment, a subset of rats had concurrent nose poke access to sucrose while seeking or taking cocaine. RESULTS: The presence of an alternative source of reinforcement markedly facilitated behavioural reallocation from punished cocaine taking after acquisition. It also facilitated punishment-induced suppression of cocaine seeking after an extensive cocaine self-administration history likely by prompting goal-directed motivational control over drug use. However, a significant proportion of rats were deemed compulsive-maintaining drug use after an extensive cocaine history despite the presence of abstinence-promoting positive and negative incentives. CONCLUSION: Making available an alternative reinforcer facilitates disengagement from punished cocaine use through at least two different processes but remains ineffective in a subpopulation of vulnerable animals, which continued to seek cocaine despite the aversive consequence of punishment and the presence of the alternative positive reinforcer.This work was supported by the United Kingdom Medical Research Council (MRC) Grant to BJE (G9536855) and was conducted within the MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute. The authors declare no conflicts of interest.This is the final published version, which can also be found on the publisher's website here: http://download.springer.com/static/pdf/914/art%253A10.1007%252Fs00213-014-3648-5.pdf?auth66=1404987650_ca63ac8614a2994c56b0f619563ee6af&ext=.pd

A Novel Retrieval-Dependent Memory Process Revealed by the Arrest of ERK1/2 Activation in the Basolateral Amygdala.

Fully consolidated fear memories can be maintained or inhibited by retrieval-dependent mechanisms depending on the degree of re-exposure to fear cues. Short exposures promote memory maintenance through reconsolidation, and long exposures promote inhibition through extinction. Little is known about the neural mechanisms by which increasing cue exposure overrides reconsolidation and instead triggers extinction. Using auditory fear conditioning in male rats, we analyzed the role of a molecular mechanism common to reconsolidation and extinction of fear, ERK1/2 activation within the basolateral amygdala (BLA), after intermediate conditioned stimulus (CS) exposure events. We show that an intermediate re-exposure (four CS presentations) failed to activate ERK1/2 in the BLA, suggesting the absence of reconsolidation or extinction mechanisms. Supporting this hypothesis, pharmacologically inhibiting the BLA ERK1/2-dependent signaling pathway in conjunction with four CS presentations had no effect on fear expression, and the NMDA receptor partial agonist d-cycloserine, which enhanced extinction and ERK1/2 activation in partial extinction protocols (seven CSs), had no behavioral or molecular effect when given in association with four CS presentations. These molecular and behavioral data reveal a novel retrieval-dependent memory phase occurring along the transition between conditioned fear maintenance and inhibition. CS-dependent molecular events in the BLA may arrest reconsolidation intracellular signaling mechanism in an extinction-independent manner. These findings are critical for understanding the molecular underpinnings of fear memory persistence after retrieval both in health and disease.SIGNIFICANCE STATEMENT Consolidated fear memories can be altered by retrieval-dependent mechanisms. Whereas a brief conditioned stimulus (CS) exposure promotes fear memory maintenance through reconsolidation, a prolonged exposure engages extinction and fear inhibition. The nature of this transition and whether an intermediate degree of CS exposure engages reconsolidation or extinction is unknown. We show that an intermediate cue exposure session (four CSs) produces the arrest of ERK1/2 activation in the basolateral amygdala, a common mechanism for reconsolidation and extinction. Amnestic or hypermnestic treatments given in association with four CSs had no behavioral or molecular effects, respectively. This evidence reveals a novel retrieval-dependent memory phase. Intermediate degrees of CS exposure fail to trigger reconsolidation or extinction, leaving the original memory in an insensitive state

Addictive behaviour in experimental animals: prospects for translation.

Since the introduction of intravenous drug self-administration methodology over 50 years ago, experimental investigation of addictive behaviour has delivered an enormous body of data on the neural, psychological and molecular mechanisms of drug reward and reinforcement and the neuroadaptations to chronic use. Whether or not these behavioural and molecular studies are viewed as modelling the underpinnings of addiction in humans, the discussion presented here highlights two areas-the impact of drug-associated conditioned stimuli-or drug cues-on drug seeking and relapse, and compulsive cocaine seeking. The degree to which these findings translate to the clinical state of addiction is considered in terms of the underlying neural circuitry and also the ways in which this understanding has helped develop new treatments for addiction. The psychological and neural mechanisms underlying drug memory reconsolidation and extinction established in animal experiments show particular promise in delivering new treatments for relapse prevention to the clinic.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'

Reconsolidation and extinction are dissociable and mutually exclusive processes: behavioral and molecular evidence.

Memory persistence is critically influenced by retrieval. In rats, a single presentation of a conditioned fear stimulus induces memory reconsolidation and fear memory persistence, while repeated fear cue presentations result in loss of fear through extinction. These two opposite behavioral outcomes are operationally linked by the number of cue presentations at memory retrieval. However, the behavioral properties and mechanistic determinants of the transition have not yet been explored; in particular, whether reconsolidation and extinction processes coexist or are mutually exclusive, depending on the exposure to non-reinforced retrieval events. We characterized both behaviorally and molecularly the transition from reconsolidation to extinction of conditioned fear and showed that an increase in calcineurin (CaN) in the basolateral amygdala (BLA) supports the shift from fear maintenance to fear inhibition. Gradually increasing the extent of retrieval induces a gradual decrease in freezing responses to the conditioned stimulus and a gradual increase in amygdala CaN level. This newly synthesized CaN is required for the extinction, but not the reconsolidation, of conditioned fear. During the transition from reconsolidation to extinction, we have revealed an insensitive state of the fear memory where NMDA-type glutamate receptor agonist and antagonist drugs are unable either to modulate CaN levels in the BLA or alter the reconsolidation or extinction processes. Together, our data indicate both that reconsolidation and extinction are mutually exclusive processes and also reveal the presence of a transitional, or "limbo," state of the original memory between these two alternative outcomes of fear memory retrieval, when neither process is engaged.This research was supported by aUK Medical Research Council Programme Grant (no. 9536855) to B.J.E., and was conducted in the Department of Psychology and the Medical Research Council/Wellcome Trust Behavioural and Clinical Neuroscience Institute. E.M. was supported by a Royal Society Newton International Fellowship. A.L.M. was partly supported by the Ferreras-Willetts Fellowship in Neuroscience at Downing College, Cambridge University.This is the final version of the article. It first appeared from Society for Neuroscience via http://dx.doi.org/10.1523/JNEUROSCI.4001-13.2014

Cellular imaging of zif268 Expression in the hippocampus and amygdala during contextual and cued fear memory retrieval: selective activation of hippocampal CA1 neurons during the recall of contextual memories

The neuroanatomical and molecular basis of fear memory retrieval was studied by analyzing the expression of the plasticity-associated immediate early gene zif268. Cellular quantitative in situ hybridization revealed that zif268 is expressed within specific regions of the hippocampus and amygdala during fear memory retrieval. Within the hippocampus, increased expression of zif268 was observed within CA1 neurons, but not dentate gyrus neurons, during the retrieval of contextual, but not cued, fear associations. In contrast, zif268 expression was increased within neurons of the amygdala (lateral, basal, and central nuclei) during the retrieval of both contextual and cued fear memories. These results demonstrate activation of hippocampal CA1 neurons in contextual fear memory retrieval that was not merely a correlate of the behavioral expression of fear itself, because it was limited to the retrieval of contextual, and not cued, fear memories. Further studies revealed that the selective increase in hippocampal CA1 zif268 expression seen after contextual fear memory retrieval was limited to the retrieval of recent (24 hr) but not older (28 d) memories. These experiments represent the first demonstration that zif268 expression in specific neuronal populations is associated with memory retrieval and suggest that this gene may contribute to plasticity and reconsolidation accompanying the retrieval process