Rationale A significant obstacle to an improved understanding of pathological dissociative and ps... more Rationale A significant obstacle to an improved understanding of pathological dissociative and psychosis-like states is the lack of readily implemented pharmacological models of these experiences. Ketamine has dissociative and psychotomimetic effects but can be difficult to use outside of medical and clinical-research facilities. Alternatively, nitrous oxide (N2O) — like ketamine, a dissociative anaesthetic and NMDAR antagonist — has numerous properties that make it an attractive alternative for modelling dissociation and psychosis. However, development and testing of such pharmacological models relies on well-characterized measurement instruments. Objectives To examine the factor structures of the Clinician Administered Dissociative States Scale (CADSS) and Psychotomimetic States Inventory (PSI) administered during N2O inhalation in healthy volunteers. Methods Secondary analyses of data pooled from three previous N2O studies with healthy volunteers. Results Effect sizes for N2O-ind...
Maladaptive reward memories (MRMs) are involved in the development and maintenance of acquired ov... more Maladaptive reward memories (MRMs) are involved in the development and maintenance of acquired overconsumption disorders, such as harmful alcohol and drug use. The process of memory reconsolidation - where stored memories become briefly labile upon retrieval - may offer a means to disrupt MRMs and prevent relapse. However, reliable means for pharmacologically weakening MRMs in humans remain elusive. Here we demonstrate that the N-methyl D-aspartate (NMDA) antagonist ketamine is able to disrupt MRMs in hazardous drinkers when administered immediately after their retrieval. MRM retrieval + ketamine (RET + KET) effectively reduced the reinforcing effects of alcohol and long-term drinking levels, compared to ketamine or retrieval alone. Blood concentrations of ketamine and its metabolites during the critical ‘reconsolidation window’ predicted beneficial changes only following MRM reactivation. Pharmacological reconsolidation interference may provide a means to rapidly rewrite maladaptiv...
The COVID-19 pandemic has introduced a number of challenges to laboratory-based experimental stud... more The COVID-19 pandemic has introduced a number of challenges to laboratory-based experimental studies. Following testing of the first participant in the current study, we found that one of the challenges was the discomfort associated with long duration of direct participant-researcher contact within a closed (though ventilated) environment. Despite efforts to minimise such contact, it became clear that to further reduce risks of infection, additional steps were needed to abbreviate the protocol. Considering the secondary nature of the hypotheses related to inhibitory control, and the long duration of the inhibitory control task, we decided to remove this task from the protocol. The addendum reflects removal of this task. The description below has been updated to remove any references to inhibitory control that were present in the original registration (submitted 14/07/2021). Stressful experiences initiate a cascade of hormonal and neural processes, leading to the strengthening of mem...
The Coronavirus pandemic has exposed millions of people to unprecedented levels of stress, either... more The Coronavirus pandemic has exposed millions of people to unprecedented levels of stress, either through threat of infection or mitigation efforts. While this may put individuals at elevated risk of anxiety and traumatic stress, these diagnostic categories aim to capture symptoms associated with exposure to episodic 'traumas' as opposed to extended stressors. The latter may increase low-level, diffuse symptoms associated with 'adjustment disorder' (Zelviene and Kazlauskas 2018), the onset of which reflects failure to adapt to, and preoccupation with, a stressor and its consequences. This is assessed using the Adjustment Disorder-New Module 20 (ADNM-20) questionnaire (Einsle, Kollner et al. 2010), which additionally measures avoidance, depressive mood, anxiety and irritability. Hence, the ADNM-20 questionnaire is an ideal tool to identify at-risk individuals in the present context. High quality randomised controlled trials of interventions for AD are currently lackin...
BackgroundPharmacological treatments targeting the neuroendocrine stress response may hold specia... more BackgroundPharmacological treatments targeting the neuroendocrine stress response may hold special promise in secondary prevention of posttraumatic stress disorder (PTSD). However, findings from clinical trials have been inconsistent and the efficacy of specific drugs, their temporal window of efficacy, effective doses and the characteristics of likely treatment responders remain unclear.MethodUsing an experimental human model of distressing involuntary memory formation, we compare the effects of two drugs that have theoretical or empirical support as secondary preventive agents in PTSD. Eighty-eight healthy women (average age: 23.5 years) received oral propranolol (80 mg), hydrocortisone (30 mg), or matched placebo immediately after viewing a ‘trauma film’. They then completed daily, time-stamped intrusion diaries for 1 week, at the end of which, voluntary memory was tested.ResultsWhile neither drug affected voluntary memory for the trauma narrative, propranolol treatment was assoc...
Addiction is a disorder of motivational learning and memory. Maladaptive motivational memories li... more Addiction is a disorder of motivational learning and memory. Maladaptive motivational memories linking drug-associated stimuli to drug seeking are formed over hundreds of reinforcement trials and accompanied by aberrant neuroadaptation in the mesocorticolimbic reward system. Such memories are resistant to extinction. However, the discovery of retrieval-dependent memory plasticity has opened up the possibility of permanent modification of established (long-term) memories during 'reconsolidation'. Here, we investigate whether reappraisal of maladaptive alcohol cognitions performed after procedures designed to destabilize alcohol memory networks affected subsequent alcohol memory, craving, drinking and attentional bias. Forty-seven at-risk drinkers attended two sessions. On the first lab session, participants underwent one of two prediction error-generating procedures in which outcome expectancies were violated while retrieving alcohol memories (omission and value prediction er...
1. Whole-cell recordings were made from cerebellar granule cells cultured in high-K+ medium to in... more 1. Whole-cell recordings were made from cerebellar granule cells cultured in high-K+ medium to induce expression of Ca(2+)-permeable AMPA receptors. Current-voltage (I-V) plots of agonist-evoked responses showed varying degrees of inward rectification, but became linear within 5-10 min. 2. Recombinant Ca(2+)-permeable kainate receptors, composed of GluR6(Q)/KA-2 subunits, exhibited rectifying whole-cell I-V plots that became linear in outside-out patches. 3. Loss of rectification in granule cells was prevented by including 100 microM spermine in the pipette; the degree of rectification was then correlated with Ca2+ permeability. 4. Spermine also prevented loss of rectification in patches containing GluR6(Q)/KA-2 receptors (IC50, 1.7 microM). 5. We suggest that spermine, or a similar cellular constituent, may act as a cytoplasmic factor conferring inward rectification on Ca(2+)-permeable non-NMDA receptors, and that 'washout' of this factor underlies the observed loss of rectification.
Publisher Summary Neurotransmitter receptors mediate signal transduction at the postsynaptic memb... more Publisher Summary Neurotransmitter receptors mediate signal transduction at the postsynaptic membrane of chemical synapses in the nervous system. The major excitatory and inhibitory neurotransmitter receptors in the brain are ligandgated ion channels. These receptors directly bind neurotransmitters, resulting in the opening of an intrinsic ion channel. The predominant ligand-gated ion channels in the nervous system are the nicotinic acetylcholine receptor, the glutamate receptors, the γ-aminobutyric acid (GABA A ) receptors and the glycine receptors. Biochemical and electrophysiologic studies of these receptors have demonstrated that they are multiply phosphorylated by a variety of protein kinases. Phosphorylation of these receptors regulates many functional properties, including desensitization, open channel probability, open time, and subcellular targeting. Because of the central role of ligand-gated ion channels in synaptic transmission, protein phosphorylation of these receptors is a major mechanism in the regulation of synaptic transmission and may underlie many forms of synaptic plasticity. This chapter reviews a variety of techniques to examine the role of protein phosphorylation in the regulation of ligand-gated ion channel function. The chapter also reviews general strategies and methods for characterizing the phosphorylation state of ligand-gated ion channels, identifying phosphorylation sites on these channels, and analyzing the physiologic consequences of channel phosphorylation.
Rationale A significant obstacle to an improved understanding of pathological dissociative and ps... more Rationale A significant obstacle to an improved understanding of pathological dissociative and psychosis-like states is the lack of readily implemented pharmacological models of these experiences. Ketamine has dissociative and psychotomimetic effects but can be difficult to use outside of medical and clinical-research facilities. Alternatively, nitrous oxide (N2O) — like ketamine, a dissociative anaesthetic and NMDAR antagonist — has numerous properties that make it an attractive alternative for modelling dissociation and psychosis. However, development and testing of such pharmacological models relies on well-characterized measurement instruments. Objectives To examine the factor structures of the Clinician Administered Dissociative States Scale (CADSS) and Psychotomimetic States Inventory (PSI) administered during N2O inhalation in healthy volunteers. Methods Secondary analyses of data pooled from three previous N2O studies with healthy volunteers. Results Effect sizes for N2O-ind...
Maladaptive reward memories (MRMs) are involved in the development and maintenance of acquired ov... more Maladaptive reward memories (MRMs) are involved in the development and maintenance of acquired overconsumption disorders, such as harmful alcohol and drug use. The process of memory reconsolidation - where stored memories become briefly labile upon retrieval - may offer a means to disrupt MRMs and prevent relapse. However, reliable means for pharmacologically weakening MRMs in humans remain elusive. Here we demonstrate that the N-methyl D-aspartate (NMDA) antagonist ketamine is able to disrupt MRMs in hazardous drinkers when administered immediately after their retrieval. MRM retrieval + ketamine (RET + KET) effectively reduced the reinforcing effects of alcohol and long-term drinking levels, compared to ketamine or retrieval alone. Blood concentrations of ketamine and its metabolites during the critical ‘reconsolidation window’ predicted beneficial changes only following MRM reactivation. Pharmacological reconsolidation interference may provide a means to rapidly rewrite maladaptiv...
The COVID-19 pandemic has introduced a number of challenges to laboratory-based experimental stud... more The COVID-19 pandemic has introduced a number of challenges to laboratory-based experimental studies. Following testing of the first participant in the current study, we found that one of the challenges was the discomfort associated with long duration of direct participant-researcher contact within a closed (though ventilated) environment. Despite efforts to minimise such contact, it became clear that to further reduce risks of infection, additional steps were needed to abbreviate the protocol. Considering the secondary nature of the hypotheses related to inhibitory control, and the long duration of the inhibitory control task, we decided to remove this task from the protocol. The addendum reflects removal of this task. The description below has been updated to remove any references to inhibitory control that were present in the original registration (submitted 14/07/2021). Stressful experiences initiate a cascade of hormonal and neural processes, leading to the strengthening of mem...
The Coronavirus pandemic has exposed millions of people to unprecedented levels of stress, either... more The Coronavirus pandemic has exposed millions of people to unprecedented levels of stress, either through threat of infection or mitigation efforts. While this may put individuals at elevated risk of anxiety and traumatic stress, these diagnostic categories aim to capture symptoms associated with exposure to episodic 'traumas' as opposed to extended stressors. The latter may increase low-level, diffuse symptoms associated with 'adjustment disorder' (Zelviene and Kazlauskas 2018), the onset of which reflects failure to adapt to, and preoccupation with, a stressor and its consequences. This is assessed using the Adjustment Disorder-New Module 20 (ADNM-20) questionnaire (Einsle, Kollner et al. 2010), which additionally measures avoidance, depressive mood, anxiety and irritability. Hence, the ADNM-20 questionnaire is an ideal tool to identify at-risk individuals in the present context. High quality randomised controlled trials of interventions for AD are currently lackin...
BackgroundPharmacological treatments targeting the neuroendocrine stress response may hold specia... more BackgroundPharmacological treatments targeting the neuroendocrine stress response may hold special promise in secondary prevention of posttraumatic stress disorder (PTSD). However, findings from clinical trials have been inconsistent and the efficacy of specific drugs, their temporal window of efficacy, effective doses and the characteristics of likely treatment responders remain unclear.MethodUsing an experimental human model of distressing involuntary memory formation, we compare the effects of two drugs that have theoretical or empirical support as secondary preventive agents in PTSD. Eighty-eight healthy women (average age: 23.5 years) received oral propranolol (80 mg), hydrocortisone (30 mg), or matched placebo immediately after viewing a ‘trauma film’. They then completed daily, time-stamped intrusion diaries for 1 week, at the end of which, voluntary memory was tested.ResultsWhile neither drug affected voluntary memory for the trauma narrative, propranolol treatment was assoc...
Addiction is a disorder of motivational learning and memory. Maladaptive motivational memories li... more Addiction is a disorder of motivational learning and memory. Maladaptive motivational memories linking drug-associated stimuli to drug seeking are formed over hundreds of reinforcement trials and accompanied by aberrant neuroadaptation in the mesocorticolimbic reward system. Such memories are resistant to extinction. However, the discovery of retrieval-dependent memory plasticity has opened up the possibility of permanent modification of established (long-term) memories during 'reconsolidation'. Here, we investigate whether reappraisal of maladaptive alcohol cognitions performed after procedures designed to destabilize alcohol memory networks affected subsequent alcohol memory, craving, drinking and attentional bias. Forty-seven at-risk drinkers attended two sessions. On the first lab session, participants underwent one of two prediction error-generating procedures in which outcome expectancies were violated while retrieving alcohol memories (omission and value prediction er...
1. Whole-cell recordings were made from cerebellar granule cells cultured in high-K+ medium to in... more 1. Whole-cell recordings were made from cerebellar granule cells cultured in high-K+ medium to induce expression of Ca(2+)-permeable AMPA receptors. Current-voltage (I-V) plots of agonist-evoked responses showed varying degrees of inward rectification, but became linear within 5-10 min. 2. Recombinant Ca(2+)-permeable kainate receptors, composed of GluR6(Q)/KA-2 subunits, exhibited rectifying whole-cell I-V plots that became linear in outside-out patches. 3. Loss of rectification in granule cells was prevented by including 100 microM spermine in the pipette; the degree of rectification was then correlated with Ca2+ permeability. 4. Spermine also prevented loss of rectification in patches containing GluR6(Q)/KA-2 receptors (IC50, 1.7 microM). 5. We suggest that spermine, or a similar cellular constituent, may act as a cytoplasmic factor conferring inward rectification on Ca(2+)-permeable non-NMDA receptors, and that 'washout' of this factor underlies the observed loss of rectification.
Publisher Summary Neurotransmitter receptors mediate signal transduction at the postsynaptic memb... more Publisher Summary Neurotransmitter receptors mediate signal transduction at the postsynaptic membrane of chemical synapses in the nervous system. The major excitatory and inhibitory neurotransmitter receptors in the brain are ligandgated ion channels. These receptors directly bind neurotransmitters, resulting in the opening of an intrinsic ion channel. The predominant ligand-gated ion channels in the nervous system are the nicotinic acetylcholine receptor, the glutamate receptors, the γ-aminobutyric acid (GABA A ) receptors and the glycine receptors. Biochemical and electrophysiologic studies of these receptors have demonstrated that they are multiply phosphorylated by a variety of protein kinases. Phosphorylation of these receptors regulates many functional properties, including desensitization, open channel probability, open time, and subcellular targeting. Because of the central role of ligand-gated ion channels in synaptic transmission, protein phosphorylation of these receptors is a major mechanism in the regulation of synaptic transmission and may underlie many forms of synaptic plasticity. This chapter reviews a variety of techniques to examine the role of protein phosphorylation in the regulation of ligand-gated ion channel function. The chapter also reviews general strategies and methods for characterizing the phosphorylation state of ligand-gated ion channels, identifying phosphorylation sites on these channels, and analyzing the physiologic consequences of channel phosphorylation.
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