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F X Vollenweider

Publications and source records attributed to F X Vollenweider.

32 records · Page 2Linked to original sources
PubMed1999

5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man--a PET study with [11C]raclopride.

The modulating effects of serotonin on dopamine neurotransmission are not well understood, particularly in acute psychotic states. Positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [11C]raclopride to D2-dopamine receptors in the striatum in healthy volunteers after placebo and a psychotomimetic dose of psilocybin (n = 7). Psilocybin is a potent indoleamine hallucinogen and a mixed 5-HT2A and 5-HT1A receptor agonist. Psilocybin administration (0.25 mg/kg p.o.) produced changes in mood, disturbances in thinking, illusions, elementary and complex visual hallucinations and impaired ego-functioning. Psilocybin significantly decreased [11C]raclopride receptor binding potential (BP) bilaterally in the caudate nucleus (19%) and putamen (20%) consistent with an increase in endogenous dopamine. Changes in [11C]raclopride BP in the ventral striatum correlated with depersonalization associated with euphoria. Together with previous reports of 5-HT receptor involvement in striatal dopamine release, it is concluded that stimulation of both 5-HT2A and 5-HT1A receptors may be important for the modulation of striatal dopamine release in acute psychoses. The present results indirectly support the hypothesis of a serotonin-dopamine dysbalance in schizophrenia and suggest that psilocybin is a valuable tool in the analysis of serotonin-dopamine interactions in acute psychotic states.

Adult↗
PubMed1998

Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action.

Psilocybin, an indoleamine hallucinogen, produces a psychosis-like syndrome in humans that resembles first episodes of schizophrenia. In healthy human volunteers, the psychotomimetic effects of psilocybin were blocked dose-dependently by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone, but were increased by the dopamine antagonist and typical antipsychotic haloperidol. These data are consistent with animal studies and provide the first evidence in humans that psilocybin-induced psychosis is due to serotonin-2A receptor activation, independently of dopamine stimulation. Thus, serotonin-2A overactivity may be involved in the pathophysiology of schizophrenia and serotonin-2A antagonism may contribute to therapeutic effects of antipsychotics.

Adult↗
PubMed1998

Effects of high amphetamine dose on mood and cerebral glucose metabolism in normal volunteers using positron emission tomography (PET).

The effects of high euphorigenic doses of D-amphetamine (0.9-1.0 mg/kg p.o.) on regional cerebral glucose metabolism (rCMRglu) and psychological measures were investigated in 10 healthy human volunteers using a within-subject design and [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) and a variety of psychological assessments. At the dose tested, D-amphetamine produced a mania-like syndrome concomitantly with a widespread increase in absolute cerebral metabolism, which was significant in the anterior cingulate cortex, caudate nucleus, putamen, and thalamus. An exploratory analysis revealed that: (1) certain aspects of this mania-like syndrome correlated positively with the metabolic changes seen in the frontal cortex, caudate nucleus and putamen; and (2) some of the amphetamine-induced changes in CMRglu correlated with D-amphetamine plasma levels. The present findings of cortical and subcortical increases in cerebral metabolism after D-amphetamine application in humans accord with previous studies in animals, demonstrating that relatively high doses of D-amphetamine (presumably at least 1 mg/kg) are needed to increase cerebral glucose metabolism.

Adult↗
PubMed1998

Psychological and cardiovascular effects and short-term sequelae of MDMA ("ecstasy") in MDMA-naïve healthy volunteers.

3, 4-methylenedioxymethamphetamine (MDMA, "Ecstasy") is a recreational drug reported to produce a different psychological profile than that of classic hallucinogens and stimulants. It has, therefore, been tentatively classified into a novel pharmacological class termed entactogens. This double-blind placebo-controlled study examined the effects of a typical recreational dose of MDMA (1.7 mg/kg) in 13 MDMA-naïve healthy volunteers. MDMA produced an effective state of enhanced mood, well-being, and increased emotional sensitiveness, little anxiety, but no hallucinations or panic reactions. Mild depersonalization and derealization phenomena occurred together with moderate thought disorder, first signs of loss of body control, and alterations in the meaning of percepts. Subjects also displayed changes in the sense of space and time, heightened sensory awareness, and increased psychomotor drive. MDMA did not impair selective attention as measured by the Stroop test. MDMA increased blood pressure moderately, with the exception of one subject who showed a transient hypertensive reaction. This severe increase in blood pressure indicates that the hypertensive effects of MDMA, even at recreational doses, should not be underestimated, particularly in subjects with latent cardiovascular problems. Most frequent acute somatic complaints during the MDMA challenge were jaw clenching, lack of appetite, impaired gait, and restless legs. Adverse sequelae during the following 24 hours included lack of energy and appetite, feelings of restlessness, insomnia, jaw clenching, occasional difficulty concentrating, and brooding. The present findings are consistent with the hypothesis that MDMA produces a different psychological profile than classic hallucinogens or psychostimulants.

Adult↗
PubMed1998

Advances and pathophysiological models of hallucinogenic drug actions in humans: a preamble to schizophrenia research.

Recent research into the pharmacological mechanism of hallucinogens (LSD, psilocybin) and dissociative anesthetics (PCP, ketamine) suggest that multiple neurotransmitter systems are involved in drug-induced and possibly also in naturally occurring psychoses. Specifically, animal models suggest that a dysbalance between serotonin, glutamate, and dopamine in the limbic cortico-striato-thalamic circuitry may be critical to psychotic symptom formation. To test this hypothesis, psychometric measures and metabolic PET investigations were performed (1) with FDG to elucidate the common neuronal substrates of different hallucinogens, (2) with specific receptor ligands before and after pretreatment with specific receptor antagonists to explore the putative interactions of hallucinogens with various neurotransmitter systems. Our data demonstrate that the neuronal substrate of normal and abnormal thought and behavior is associated with a distributed neuronal network and with multiple interactive neurotransmitter systems. The data also support the view that the hallucinogen challenge paradigm constitutes a powerful tool for elucidating the pathophysiology of neuropsychiatric disorders.

Anesthetics, Dissociative↗
PubMed1997

Determination of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man.

In order to investigate the pharmacokinetic properties of psilocybin (PY), the main psychoactive compound of Psilocybe mushrooms, high performance liquid chromatographic procedures with column-switching coupled with electrochemical detection (HPLC-ECD) for reliable quantitative determination of the PY metabolites psilocin (PI) and 4-hydroxyindole-3-acetic acid (4HIAA) in human plasma were established. Sample work-up includes protection of the highly unstable phenolic analytes with ascorbic acid, freeze-drying and in-vitro microdialysis. The data of two controlled clinical studies with healthy volunteers are presented. The subjects (N = 6 for both studies) received single oral PY doses of 0.224 +/- 0.02 mg/kg b.wt. (10-20 mg) and intravenous doses of 1 mg PY, respectively. Peak plasma levels of PI after oral administration of PY were measured after 105 +/- 37 min showing an average concentration of 8.2 +/- 2.8 ng PI/ml plasma. 4HIAA peak concentrations of 150 +/- 61 ng/ml plasma were found 113 +/- 41 min after ingestion of PY. After intravenous administration, a mean PI maximum plasma concentration of 12.9 +/- 5.6 ng/ml plasma was found 1.9 +/- 1.0 min after injection. The maximum plasma levels appearing within a very short period indicate a rapid dephosphorylation of PY also when administered systemically. 4HIAA was not detected after 1 mg of intravenous PY. Estimates for the absolute bioavailability of PI after oral administration of PY were 52.7 +/- 20% (N = 3).

Administration, Oral↗
PubMed1997

Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis.

The effects of the indolehallucinogen psilocybin, a mixed 5-HT2 and 5-HT1 agonist, on regional cerebral glucose metabolism were investigated in 10 healthy volunteers with PET and [F-18]-fluorodeoxyglucose (FDG) prior to and following a 15- or 20-mg dose of psilocybin. Psychotomimetic doses of psilocybin were found to produce a global increase in cerebral metabolic rate of glucose (CMRglu) with significant and most marked increases in the frontomedial and frontolateral cortex (24.3%), anterior cingulate (24.9%), and temporomedial cortex (25.3%). Somewhat smaller increases of CMRglu were found in the basal ganglia (18.5%), and the smallest increases were found in the sensorimotor (14.7%) and occipital cortex (14.4%). The increases of CMRglu in the prefrontal cortex, anterior cingulate, temporomedial cortex, and putamen correlated positively with psychotic symptom formation, in particular with hallucinatory ego disintegration. The present data suggest that excessive 5-HT2 receptor activation results in a hyperfrontal metablic pattern that parallels comparable metabolic findings associated with acute psychotic episodes in chronic schizophrenics and contrasts with the hypofrontality in chronic schizophrenic patients.

Adult↗
PubMed1997

Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG).

To date, the ketamine/PCP model of psychosis has been proposed to be one of the best pharmacological models to mimic schizophrenic psychosis in healthy volunteers, since ketamine can induce both positive and negative symptoms of schizophrenia. At subanesthetic doses, ketamine has been reported to primarily block N-methyl-D-aspartate (NMDA) receptor complex giving support to a glutamate deficiency hypothesis in schizophrenia. Positron emission tomography was used to study ketamine-induced psychotic symptom formation in relation to cerebral metabolic alterations in healthy volunteers. Our study shows that NMDA receptor blockade results in a hyperfrontal metabolic pattern. Increased metabolic activity in the frontomedial and anterior cingulate cortex correlated positively with psychotic symptom formation, in particular with ego pathology. Analysis of correlations between syndrome scores and metabolic rate of glucose (CMRglu) or metabolic gradients (ratios) revealed that each psychopathological syndrome was associated with a number of metabolic alterations in cortical and subcortical brain regions, suggesting that not a single brain region, but distributed neuronal networks are involved in acute psychotic symptom formation.

Adult↗
PubMed1997

Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET).

Until recently, racemic ketamine (S-ketamine/R-ketamine = 50:50) has been used to study NMDA receptor hypofunction in relation to pathophysiological models of schizophrenia. Ketamine given to normal humans in subanesthetic doses produces a model psychosis including both positive and negative symptoms of schizophrenia. More recently it has been shown that at subanesthetic doses the pure (S)- and (R)-ketamine enantiomeres interact differently with the NMDA and sigma receptor sites in human brain. It was found that (S)-ketamine binds with a 3-4 time higher affinity to the PCP binding site of the NMDA receptor than (R)-ketamine, and that at these concentrations (R)-ketamine interacts also weakly with the sigma receptor sites, where (S)-ketamine binds only negligibly. To further investigate the role of NMDA-receptor mediated neurotransmission in schizophrenic psychosis, the effects of pure (S)- and (R)-ketamine enantiomeres on brain energy metabolism in normal humans using positron emission tomography and [18F]fluorodeoxyglucose (FDG) are reported here. Psychotomimetic doses of (S)-ketamine increased cerebral metabolic rates of glucose (CMRglu) markedly in the frontal cortex including the anterior cingulate, parietal and left sensorimotor cortex, and in the thalamus. The metabolic changes in the frontal and left temporal cortex correlated with ego-disintegration and hallucinatory phenomena. Equimolar doses of (R)-ketamine tended to decrease CMRglu across brain regions and significantly suppressed CMRglu in the temporomedial cortex and left insula. (R)-ketamine did not produce psychotic symptoms, but a state of relaxation. The (S)-ketamine-induced metabolic hyperfrontality appears to parallel similar metabolic findings in acute psychotic schizophrenic patients and encourages further investigations of glutamatergic disturbances in schizophrenia.

Adult↗
PubMed1995

Development of a gas chromatography-mass spectrometry method for determination of ketamine in plasma and its application to human samples.

A sensitive and precise gas chromatography-mass spectrometry method with selected ion monitoring has been developed for identification and quantification of the phencyclidine derivative ketamine in human plasma. The assay is based on an alkaline extraction from aqueous to organic solvent from plasma and an efficient gas chromatographic separation on a DB-5 capillary column. The analytical procedure has a coefficient of variation of 0.7-6.2% and from 1.3 to 8.7% within-day and from day-to-day analysis, respectively. The low level of sensitivity was 10 ng/ml. It was used to measure low plasma concentrations in volunteers during ketamine-induced experimental psychosis. The method is not enantio selective.

Adult↗
PubMed1990

Effect of climbing fiber deprivation on release of endogenous aspartate, glutamate, and homocysteate in slices of rat cerebellar hemispheres and vermis.

Aspartate (Asp) and/or glutamate (Glu) have been proposed as putative excitatory transmitters released from synaptic terminals of the olivo-cerebellar climbing fiber afferents to the Purkinje cells. Investigations of the climbing fiber transmitter(s) separately for hemispheres and vermis were performed to examine whether the current controversy over the role of Asp as a neurotransmitter in the climbing fibers may be due to topographic differences. K(+)-induced Ca2(+)-dependent release of endogenous substances was investigated in slices of cerebellar hemisphere and vermis of control rats and those deprived of climbing fibers by 3-acetylpyridine (3-AP) treatment. A release of Asp and Glu, as well as a small but significant release of homocysteic acid (HCA) was confirmed in control rats. Climbing fiber deprivation by 3-AP treatment reduced the stimulated release of Asp by 48% in slices of cerebellar hemispheres, but not in vermis. Climbing fiber deprivation completely abolished the release of HCA in both hemispheres and vermis. The release of HCA, Asp, and Glu from slices of control and climbing fiber-deprived rats evoked by 50 mM K+ was greater than 90% Ca2(+)-dependent. These results support the hypothesis that Asp is a transmitter candidate of the climbing fibers projecting to the cerebellar hemispheres, but not to the vermis, and provide the first evidence that HCA can be linked to a specific pathway.

Animals↗
PubMedDate not supplied

Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans.

Administration of the N-methyl-D-aspartate (NMDA) antagonist S-ketamine in normals produces a psychosis-like syndrome including several positive and negative symptoms of schizophrenic disorders (Abi-Saab WM, D'Souza DC, Moghaddam B, Krystal JH. The NMDA antagonist model for schizophrenia: promise and pitfalls. Pharmacopsychiatry 1998;31:104-109). Given the clinical efficacy of dopamine (DA) D2 receptor antagonists in the treatment of positive symptoms, it is conceivable that S-ketamine-induced psychotic symptoms are partially due to a secondary activation of dopaminergic systems. To date, animal and human studies of the effects of NMDA antagonists on striatal DA levels have been inconsistent. The present study used positron emission tomography (PET) to determine whether a psychotomimetic dose of S-ketamine decreases the in vivo binding of [11C]raclopride to striatal DA D2 receptors in humans (n = 8). S-ketamine elicited a psychosis-like syndrome, including alterations in mood, cognitive disturbances, hallucinations and ego-disorders. S-ketamine decreased [11C]raclopride binding potential (BP) significantly in the ventral striatum (-17.5%) followed by the caudate nucleus (-14.3%) and putamen (-13.6%), indicating an increase in striatal DA concentration. The change in raclopride BP in the ventral striatum correlated with heightened mood ranging from euphoria to grandiosity. These results provide evidence that the glutamatergic NMDA receptor may contribute to psychotic symptom formation via modulation of the DA system.

Adult↗