Morphine state-dependent learning: interactions with α2-adrenoceptors and acute stress

Homayoun, Houman; Khavandgar, Simin; Mr, Zarrindast

doi:10.1097/00008877-200302000-00004

Cited by 57 publications

(35 citation statements)

References 60 publications

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“…Each 500-s-long daily session consisted of trials separated by intertrial intervals (ITIs) of variable duration, averaging 15 s. During the 8 d of training, selected groups of mice were exposed to stress before each daily session. On training days 3, 6 and 8, different groups of mice were treated with adrenergic alpha-2 receptor drugs clonidine and yohimbine, which affect brain norepinephrine levels 28 . During the 5 d of recall, we asked whether mouse performance was most influenced by current stress or by memories of stress experienced during training.…”

Section: Resultsmentioning

confidence: 99%

Stress, genotype and norepinephrine in the prediction of mouse behavior using reinforcement learning

2009

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Individual behavioral performance during learning is known to be affected by modulatory factors, such as stress and motivation, and by genetic predispositions that influence sensitivity to these factors. Despite numerous studies, no integrative framework is available that could predict how a given animal would perform a certain learning task in a realistic situation. We found that a simple reinforcement learning model can predict mouse behavior in a hole-box conditioning task if model metaparameters are dynamically controlled on the basis of the mouse's genotype and phenotype, stress conditions, recent performance feedback and pharmacological manipulations of adrenergic alpha-2 receptors. We find that stress and motivation affect behavioral performance by altering the exploration-exploitation balance in a genotype-dependent manner. Our results also provide computational insights into how an inverted U-shape relation between stress/arousal/norepinephrine levels and behavioral performance could be explained through changes in task performance accuracy and future reward discounting.Animal behavior is guided by rewards that can be received in different situations and by modulatory factors such as stress and motivation. Acute stress can have positive or negative effects on learning and memory that depend on stressor properties (timing, duration and relation with the task) and on the predispositions of stressed individuals [1][2][3] . These effects are thought to be mediated through the modulation of synaptic plasticity by stress hormones and neuromodulators, such as glucocorticoids and norepinephrine [4][5][6][7] . However, their role in high-level processes such as learning, action selection and future reward discounting is not well understood. In addition to stress, genotype 8 , affective traits 9 , motivation 10 and recent performance feedback 11 also influence individual performance, but it may be difficult and inefficient to explicitly model each factor to accurately predict animal behavior.A number of models have related neuromodulatory systems to cognitive processes and to statistical quantities characterizing the environment 12,13 . Although such models provide insights into potential mechanisms, alone they are often unable to accurately predict animal behavior in a realistic situation as a result of the diversity of the modulatory factors affecting it. Here, we propose a method that can, in principle, quantify the influence of arbitrary modulatory factors on behavior as control parameters of a general behavioral model and that is exemplified here for the case of stress and genetic strain in mice.In modeling reward-based behavioral learning, approaches based on the theory of reinforcement learning 14 have been the most successful. They have been applied to explain experimental data in animal conditioning 10 , human decision-making 15 and addiction 16 . However, the modulatory role of stress and affective traits has not yet been considered. In reinforcement learning, modeled animals occupy different states cor...

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Section: Resultsmentioning

confidence: 99%

Stress, genotype and norepinephrine in the prediction of mouse behavior using reinforcement learning

2009

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“…In animals, clonidine has been found to produce memory impairments in several learning paradigms ranging from shuttle box (Hawkins and Monti, 1979;Homayoun et al, 2003) to avoidance tasks (Galeotti et al, 2004;Genkova-Papasova and Lazarova-Bakurova, 1988;Genkova-Papazova et al, 1997) and to cue detection (Smith and Aston-Jones, 2011;Brown et al, 2012). Some studies in humans have also reported memory impairments associated with clonidine administration in healthy subjects (Riekkinen et al, 1999;Hall et al, 2001) and in Alzheimer's disease patients (Jakala et al, 1999a, b).…”

Section: Dosage and Number Of Treatmentsmentioning

confidence: 99%

“…Additionally, a few open-label studies have shown beneficial effects of clonidine in treating some PTSD symptoms (Kinzie and Leung, 1989;Harmon and Riggs, 1996;Ziegenhorn et al, 2009), but none of these studies used clonidine specifically in combination with traumatic memory retrieval. In animal models, the use of clonidine has been found to produce memory impairments in step-down (GenkovaPapasova and Lazarova-Bakurova, 1988;Genkova-Papazova et al, 1997), shuttle box (Hawkins and Monti, 1979;Homayoun et al, 2003), and passive avoidance tasks (Galeotti et al, 2004); however, the use of clonidine to block memory reconsolidation has yet to be investigated.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of Reconsolidation Blockade by Clonidine as a Potential Novel Treatment for Posttraumatic Stress Disorder

Gamache

Pitman

Nader

2012

Neuropsychopharmacol

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Exposure to traumatic events can lead to posttraumatic stress disorder (PTSD). Current PTSD treatments typically only produce partial improvement. Hence, there is a need for preclinical research to identify new candidate drugs and to develop novel therapeutic approaches. Animal studies have indicated that fear memories can be weakened by blocking restabilization after retrieval, a process known as reconsolidation. Furthermore, evidence suggests that there are important alterations of the noradrenergic system in PTSD, and hence it may be of interest to study drugs that target this pathway. Here, we investigated the efficacy of clonidine, an a 2 -adrenoreceptor agonist, to block reconsolidation in an animal model of persistent traumatic memories. Using an auditory fear conditioning paradigm in rats, we tested the efficacy of clonidine to weaken fear memory retention when administered systemically after retrieval. We evaluated dosage, number of treatments, and specificity in reconsolidation blockade. We found that postretrieval administration of clonidine disrupts fear-related memories in a dose-dependent manner and that two treatments are sufficient for maximal memory impairment. Furthermore, we determined that this effect is long lasting and specific to reconsolidation processes as shown by the selectivity to affect reactivated memories and the absence of spontaneous recovery and of postreactivation short-term memory impairment. Our results demonstrate the efficacy of systemic administration of clonidine following retrieval to persistently disrupt fear memory retention through reconsolidation blockade. This study provides important preclinical parameters for future therapeutic strategies involving clonidine to block reconsolidation as a novel treatment for PTSD symptoms.

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“…Our results are consistent with studies showing that clonidine has detrimental effects on memory. In animals, clonidine has been found to produce memory impairments in several learning paradigms ranging from shuttle box (Hawkins and Monti, 1979;Homayoun et al, 2003) to avoidance tasks (Galeotti et al, 2004;Genkova-Papasova and Lazarova-Bakurova, 1988;Genkova-Papazova et al, 1997) and to cue detection (Smith and Aston-Jones, 2011;Brown et al, 2012). Some studies in humans have also reported memory impairments associated with clonidine administration in healthy subjects (Riekkinen et al, 1999;Hall et al, 2001) and in Alzheimer's disease patients (Jakala et al, 1999a, b).…”

Section: Dosage and Number Of Treatmentsmentioning

confidence: 99%

“…Additionally, a few open-label studies have shown beneficial effects of clonidine in treating some PTSD symptoms (Kinzie and Leung, 1989;Harmon and Riggs, 1996;Ziegenhorn et al, 2009), but none of these studies used clonidine specifically in combination with traumatic memory retrieval. In animal models, the use of clonidine has been found to produce memory impairments in step-down (GenkovaPapasova and Lazarova-Bakurova, 1988; Genkova-Papazova et al, 1997), shuttle box (Hawkins and Monti, 1979;Homayoun et al, 2003), and passive avoidance tasks (Galeotti et al, 2004); however, the use of clonidine to block memory reconsolidation has yet to be investigated.…”

Section: Introductionmentioning

confidence: 99%

Developing Memory Reconsolidation Blockers as Novel PTSD Treatments

Pitman¹,

Bolshakov²,

Brunet³

et al. 2012

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERMassachusetts General Hospital, Boston, MA, 02114 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES Note: The previous report was deemed unacceptable for the following reason. "There is no data in the body of this report and data in the appended manuscript are not cited in the body of the report to support key research accomplishments. In a revised report, please summarize the data from the previous year. The appended publication can be used as supporting material as long as figures are referenced in the body of the progress report." The following revised report now contains data in the body of the report, which are indicated by yellow highlighting.14. ABSTRACT-The aim of this project is to develop post-reactivation (PR) pharmacologic interventions that may serve as novel treatments for posttraumatic stress disorder (PTSD). The underlying theory is that candidate drugs, when given following the reactivation of a conditioned fear response in animals, or a traumatic memory in humans, will reduce the strength of the conditioned response or traumatic memory. We plan to test such drugs, either alone or in combination, for their possible reconsolidation-blocking properties in a hierarchy of experiments. Drugs that show promise at a given stage of investigation will be advanced to the next stage. In Stage I, we will evaluate the ability of candidate drugs to reduce freezing in a Pavlovian cue-conditioned fear task in rats. In Stage II, we will evaluate the ability of candidate drugs to reverse fear conditioning-induced synaptic enhancement in rat amygdala slices using whole-cell electrophysiologic recording. In Stage III, we will test the ability of a single session of PR candidate drug to reduce subsequent psychophysiologic responding during script-driven imagery of the traumatic event in trauma-exposed human subjects. In Stage IV, we will test the ability of a series of PR candidate drug therapy sessions to reduce symptoms in PTSD patients.

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Morphine state-dependent learning: interactions with α2-adrenoceptors and acute stress

Cited by 57 publications

References 60 publications

Stress, genotype and norepinephrine in the prediction of mouse behavior using reinforcement learning

Stress, genotype and norepinephrine in the prediction of mouse behavior using reinforcement learning

Preclinical Evaluation of Reconsolidation Blockade by Clonidine as a Potential Novel Treatment for Posttraumatic Stress Disorder

Developing Memory Reconsolidation Blockers as Novel PTSD Treatments

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