Prof. Dr. Linda Simmler Department of Pharmaceutical Sciences Profiles & Affiliations OverviewResearch Publications Projects & Collaborations Projects & Collaborations OverviewResearch Publications Projects & Collaborations Profiles & Affiliations Projects & Collaborations 3 foundShow per page10 10 20 50 Psilocybin-induced synaptic plasticity: circuit mechanisms underlying the antidepressant potential of hallucinogens Research Project | 1 Project MembersPsilocybin induces hallucinations through its active metabolite psilocin, which acts as serotonin (5-HT) 2A receptor agonist. Although classified as drugs of abuse, psilocybin and other hallucinogens may be clinically used for several psychiatric disorders, including major depressive disorder. Preliminary clinical studies advocate administering single doses of psilocybin intermittently, based on the observation that a single dose induces long-lasting therapeutic effects. Neuronal plasticity may underlie these long-lasting effects. In humans, psilocybin acutely increases the activity of the prefrontal cortex, likely by facilitating thalamocortical signaling. This coincides with the localization of 5-HT 2A receptors, which are expressed in frontal cortex pyramidal cells postsynaptically and putatively in thalamic afferents on the presynaptic site. In rodent brain slices, 5-HT and various hallucinogens acutely increase synaptic strength of glutamate afferents onto cortical pyramidal neurons. Specific neuronal circuits and synapses that may be persistently changed after psilocybin have not been identified and we lack proof of causality for antidepressant efficacy. We will therefore examine synaptic plasticity in defined neuronal circuits as a mechanism underlying psilocybin's effect on anhedonia, a key symptom of depression. Further, we will investigate a simple, translational strategy to refine psilocybin pharmacotherapy. Akin to classical conditioning, pairing psilocybin treatment with a cue may allow recalling the therapeutic benefits through cue exposure when the initial drug effect wears off. This strategy could enhance the efficacy of psilocybin treatment sessions. This project builds on the hypotheses that psilocybin induces long-lasting forms of plasticity at thalamocortical synapses, which underlie its antidepressant-like effects, and that the potential therapeutic effect can be recalled through exposure to a drug-associated cue. We aim to identify neuronal circuits involved in psilocybin-induced long-term synaptic plasticity, establish psilocybin efficacy for antidepressant-like effects and elucidate the underlying mechanism, and provide evidence for recall of psilocybin effects through drug-cue conditioning that may be clinically translated. Optogenetics and whole-cell patch-clamp slice recordings will be used for celltype- and circuit-specific observations and manipulations. Behavioral testing of anhedonia in an anxiogenic environment will be applied, as this can report the antidepressant potential of a drug. This research will reveal the clinically relevant mode of action of psilocybin and provide blueprints for improved treatment strategies such as the supportive application of conditioned drug cues. Pharmacology and Toxicology of Amphetamine-type Substances Research Project | 4 Project MembersUse of amphetamine-type substances including MDMA (ecstasy), methylphenidate (Ritalin), and novel cathinone designer drugs is prevalent in our society. In particular, the pharmacology and toxicology of the cathinones is poorly known and will be characterized in this project. In addition, we investigate the pharmacological effects of MDMA and Ritalin with regard to effects on emotion recognition, empathy, and social behavior in humans. Social cognition (emotion recognition and empathy) is critical for human social interactions. MDMA produces subjective feelings of openness and closeness to others and is said to have "empathogenic" effect. However, it is unknown whether MDMA indeed improves affective perception and enhances emotional or cognitive empathy. Such effects are relevant with regart to the recreational use of MDMA but also to its potential therapeutic use in psychotherapy. Methylphenidate is widely used in the treatment of attention deficit hyperactivity disorder (ADHD). In addition, methylphenidate is also abused as a party drug and its use for cognitive enhancement as so-called 'smart drug' has become a focus of concern. Whether methylphenidate use affects social cognition is not known. However, it is possible that part of the therapeutic benefits of this amphetamine derives from enhanced face emotion recognition which has been shown to be impaired in children with ADHD. Our clinical studies will also produce important data on the pharmacological mechanism of action of amphetamines that will inform emergency physicians on how to treat intoxications with these drugs. Mechanism of action of MDMA (Ecstasy) Research Project | 7 Project MembersIn our main project: "Mechanism of action of MDMA (Ecstasy)" we investigate how MDMA acts in the brain using both in vitro techniques and studies in humans. In the in vitro studies we assess interactions of MDMA with serotonin-, dopamine-, and norepinephrine uptake carriers in cell assays. In humans, we assess the subjective and cardiovascular effects of MDMA after the administration of substances that selectively block potential sites of action of MDMA in the brain. 1 1 OverviewResearch Publications Projects & Collaborations
Projects & Collaborations 3 foundShow per page10 10 20 50 Psilocybin-induced synaptic plasticity: circuit mechanisms underlying the antidepressant potential of hallucinogens Research Project | 1 Project MembersPsilocybin induces hallucinations through its active metabolite psilocin, which acts as serotonin (5-HT) 2A receptor agonist. Although classified as drugs of abuse, psilocybin and other hallucinogens may be clinically used for several psychiatric disorders, including major depressive disorder. Preliminary clinical studies advocate administering single doses of psilocybin intermittently, based on the observation that a single dose induces long-lasting therapeutic effects. Neuronal plasticity may underlie these long-lasting effects. In humans, psilocybin acutely increases the activity of the prefrontal cortex, likely by facilitating thalamocortical signaling. This coincides with the localization of 5-HT 2A receptors, which are expressed in frontal cortex pyramidal cells postsynaptically and putatively in thalamic afferents on the presynaptic site. In rodent brain slices, 5-HT and various hallucinogens acutely increase synaptic strength of glutamate afferents onto cortical pyramidal neurons. Specific neuronal circuits and synapses that may be persistently changed after psilocybin have not been identified and we lack proof of causality for antidepressant efficacy. We will therefore examine synaptic plasticity in defined neuronal circuits as a mechanism underlying psilocybin's effect on anhedonia, a key symptom of depression. Further, we will investigate a simple, translational strategy to refine psilocybin pharmacotherapy. Akin to classical conditioning, pairing psilocybin treatment with a cue may allow recalling the therapeutic benefits through cue exposure when the initial drug effect wears off. This strategy could enhance the efficacy of psilocybin treatment sessions. This project builds on the hypotheses that psilocybin induces long-lasting forms of plasticity at thalamocortical synapses, which underlie its antidepressant-like effects, and that the potential therapeutic effect can be recalled through exposure to a drug-associated cue. We aim to identify neuronal circuits involved in psilocybin-induced long-term synaptic plasticity, establish psilocybin efficacy for antidepressant-like effects and elucidate the underlying mechanism, and provide evidence for recall of psilocybin effects through drug-cue conditioning that may be clinically translated. Optogenetics and whole-cell patch-clamp slice recordings will be used for celltype- and circuit-specific observations and manipulations. Behavioral testing of anhedonia in an anxiogenic environment will be applied, as this can report the antidepressant potential of a drug. This research will reveal the clinically relevant mode of action of psilocybin and provide blueprints for improved treatment strategies such as the supportive application of conditioned drug cues. Pharmacology and Toxicology of Amphetamine-type Substances Research Project | 4 Project MembersUse of amphetamine-type substances including MDMA (ecstasy), methylphenidate (Ritalin), and novel cathinone designer drugs is prevalent in our society. In particular, the pharmacology and toxicology of the cathinones is poorly known and will be characterized in this project. In addition, we investigate the pharmacological effects of MDMA and Ritalin with regard to effects on emotion recognition, empathy, and social behavior in humans. Social cognition (emotion recognition and empathy) is critical for human social interactions. MDMA produces subjective feelings of openness and closeness to others and is said to have "empathogenic" effect. However, it is unknown whether MDMA indeed improves affective perception and enhances emotional or cognitive empathy. Such effects are relevant with regart to the recreational use of MDMA but also to its potential therapeutic use in psychotherapy. Methylphenidate is widely used in the treatment of attention deficit hyperactivity disorder (ADHD). In addition, methylphenidate is also abused as a party drug and its use for cognitive enhancement as so-called 'smart drug' has become a focus of concern. Whether methylphenidate use affects social cognition is not known. However, it is possible that part of the therapeutic benefits of this amphetamine derives from enhanced face emotion recognition which has been shown to be impaired in children with ADHD. Our clinical studies will also produce important data on the pharmacological mechanism of action of amphetamines that will inform emergency physicians on how to treat intoxications with these drugs. Mechanism of action of MDMA (Ecstasy) Research Project | 7 Project MembersIn our main project: "Mechanism of action of MDMA (Ecstasy)" we investigate how MDMA acts in the brain using both in vitro techniques and studies in humans. In the in vitro studies we assess interactions of MDMA with serotonin-, dopamine-, and norepinephrine uptake carriers in cell assays. In humans, we assess the subjective and cardiovascular effects of MDMA after the administration of substances that selectively block potential sites of action of MDMA in the brain. 1 1
Psilocybin-induced synaptic plasticity: circuit mechanisms underlying the antidepressant potential of hallucinogens Research Project | 1 Project MembersPsilocybin induces hallucinations through its active metabolite psilocin, which acts as serotonin (5-HT) 2A receptor agonist. Although classified as drugs of abuse, psilocybin and other hallucinogens may be clinically used for several psychiatric disorders, including major depressive disorder. Preliminary clinical studies advocate administering single doses of psilocybin intermittently, based on the observation that a single dose induces long-lasting therapeutic effects. Neuronal plasticity may underlie these long-lasting effects. In humans, psilocybin acutely increases the activity of the prefrontal cortex, likely by facilitating thalamocortical signaling. This coincides with the localization of 5-HT 2A receptors, which are expressed in frontal cortex pyramidal cells postsynaptically and putatively in thalamic afferents on the presynaptic site. In rodent brain slices, 5-HT and various hallucinogens acutely increase synaptic strength of glutamate afferents onto cortical pyramidal neurons. Specific neuronal circuits and synapses that may be persistently changed after psilocybin have not been identified and we lack proof of causality for antidepressant efficacy. We will therefore examine synaptic plasticity in defined neuronal circuits as a mechanism underlying psilocybin's effect on anhedonia, a key symptom of depression. Further, we will investigate a simple, translational strategy to refine psilocybin pharmacotherapy. Akin to classical conditioning, pairing psilocybin treatment with a cue may allow recalling the therapeutic benefits through cue exposure when the initial drug effect wears off. This strategy could enhance the efficacy of psilocybin treatment sessions. This project builds on the hypotheses that psilocybin induces long-lasting forms of plasticity at thalamocortical synapses, which underlie its antidepressant-like effects, and that the potential therapeutic effect can be recalled through exposure to a drug-associated cue. We aim to identify neuronal circuits involved in psilocybin-induced long-term synaptic plasticity, establish psilocybin efficacy for antidepressant-like effects and elucidate the underlying mechanism, and provide evidence for recall of psilocybin effects through drug-cue conditioning that may be clinically translated. Optogenetics and whole-cell patch-clamp slice recordings will be used for celltype- and circuit-specific observations and manipulations. Behavioral testing of anhedonia in an anxiogenic environment will be applied, as this can report the antidepressant potential of a drug. This research will reveal the clinically relevant mode of action of psilocybin and provide blueprints for improved treatment strategies such as the supportive application of conditioned drug cues.
Pharmacology and Toxicology of Amphetamine-type Substances Research Project | 4 Project MembersUse of amphetamine-type substances including MDMA (ecstasy), methylphenidate (Ritalin), and novel cathinone designer drugs is prevalent in our society. In particular, the pharmacology and toxicology of the cathinones is poorly known and will be characterized in this project. In addition, we investigate the pharmacological effects of MDMA and Ritalin with regard to effects on emotion recognition, empathy, and social behavior in humans. Social cognition (emotion recognition and empathy) is critical for human social interactions. MDMA produces subjective feelings of openness and closeness to others and is said to have "empathogenic" effect. However, it is unknown whether MDMA indeed improves affective perception and enhances emotional or cognitive empathy. Such effects are relevant with regart to the recreational use of MDMA but also to its potential therapeutic use in psychotherapy. Methylphenidate is widely used in the treatment of attention deficit hyperactivity disorder (ADHD). In addition, methylphenidate is also abused as a party drug and its use for cognitive enhancement as so-called 'smart drug' has become a focus of concern. Whether methylphenidate use affects social cognition is not known. However, it is possible that part of the therapeutic benefits of this amphetamine derives from enhanced face emotion recognition which has been shown to be impaired in children with ADHD. Our clinical studies will also produce important data on the pharmacological mechanism of action of amphetamines that will inform emergency physicians on how to treat intoxications with these drugs.
Mechanism of action of MDMA (Ecstasy) Research Project | 7 Project MembersIn our main project: "Mechanism of action of MDMA (Ecstasy)" we investigate how MDMA acts in the brain using both in vitro techniques and studies in humans. In the in vitro studies we assess interactions of MDMA with serotonin-, dopamine-, and norepinephrine uptake carriers in cell assays. In humans, we assess the subjective and cardiovascular effects of MDMA after the administration of substances that selectively block potential sites of action of MDMA in the brain.
