Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, th...
We used the MembStruk computational procedure to predict the three-dimensional (3D) structure for the serotonin 5-HT(2C) G-protein-coupled receptor (GPCR). Using this structure, we used the MSCDock computational procedure to predict the 3D structures for bound ligand-protein complexes for agonists such as serotonin and antagonists such as ritanserin, metergo...
N,N-dipropyltryptamine (DPT) is a synthetic tryptamine hallucinogen which has been used psychotherapeutically in humans, but has been studied preclinically only rarely. In the present studies, DPT was tested in a drug-elicited head-twitch assay in mice, and in rats trained to discriminate lysergic acid diethylamide (LSD), N,N-dimethyl-4-phosphoryloxytryptami...
Although psilocybin has been trained in the rat as a discriminative stimulus, little is known of the pharmacological receptors essential for stimulus control. In the present investigation rats were trained with psilocybin and tests were then conducted employing a series of other hallucinogens and presumed antagonists. An intermediate degree of antagonism of ...
Activation of 5-HT(2A) receptors is thought to mediate the hallucinogenic effects of LSD. Nevertheless, in a previous report we provided evidence that a delayed temporal phase of the behavioral pharmacology of LSD is mediated by D(2)-like dopamine receptor stimulation. In this study rats were trained to discriminate LSD with either a 30 min preinjection time...
Schizophrenia patients exhibit impairments in prepulse inhibition (PPI) of the startle response. Hallucinogenic 5-HT(2A) receptor agonists are used for animal models of schizophrenia because they mimic some symptoms of schizophrenia in humans and induce PPI deficits in animals. Nevertheless, one report indicates that the 5-HT(2A) receptor agonist psilocybin ...
Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT(2A) receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural...
BackgroundAnecdotal reports suggest that psychedelic agents may relieve symptoms of obsessive-compulsive disorder (OCD). This modified double-blind study investigated the safety, tolerability, and clinical effects of psilocybin, a potent 5-HT(1A) and 5-HT(2A/2C) agonist, in patients with OCD.MethodNine subjects with DSM-IV-defined OCD and no other current ma...
Hallucinogenic psilocybin is known to alter the subjective experience of time. However, there is no study that systematically investigated objective measures of time perception under psilocybin. Therefore, we studied dose-dependent effects of the serotonin (5-HT)2A/1A receptor agonist psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine) on temporal processin...
Increasing evidence suggests a link between attention, working memory, serotonin (5-HT), and prefrontal cortex activity. In an attempt to tease out the relationship between these elements, this study tested the effects of the hallucinogenic mixed 5-HT1A/2A receptor agonist psilocybin alone and after pretreatment with the 5-HT2A antagonist ketanserin. Eight h...
An SAR study of psilocybin and psilocin derivatives reveals that 1-methylpsilocin is a selective agonist at the h5-HT(2C) receptor. The corresponding phosphate derivative, 1-methylpsilocybin, shows efficacy in an animal model for obsessive-compulsive disorder, as does 4-fluoro-N,N-dimethyltryptamine. These results suggest a new area for development of novel ...
Binocular rivalry occurs when different images are presented simultaneously to corresponding points within the left and right eyes. Under these conditions, the observer's perception will alternate between the two perceptual alternatives. Motivated by the reported link between the rate of perceptual alternations, symptoms of psychosis and an incidental observ...
RationaleSerotonin (5-Hydroxytryptamine, 5-HT) receptors play an important role in perception, affect regulation and attention. Pharmacological challenge with the 5-HT(2A) agonist psilocybin (PY) is useful in studying the neurobiological basis of cognition and consciousness.ObjectiveInvestigation of dose-dependent effects of PY on psycho(patho)logical and ph...
Previously the NMDA (N-methyl-D-aspartate) receptor (NMDAR) antagonist ketamine was shown to disrupt generation of the auditory event-related potential (ERP) mismatch negativity (MMN) and the performance of an 'AX'-type continuous performance test (AX-CPT)--measures of auditory and visual context-dependent information processing--in a similar manner as obser...
RationaleAyahuasca, a South American psychotropic plant tea, combines the psychedelic agent and 5-HT(2A/2C) agonist N, N-dimethyltryptamine (DMT) with beta-carboline alkaloids showing monoamine oxidase-inhibiting properties. Current human research with psychedelics and entactogens has explored the possibility that drugs displaying agonist activity at the 5-H...
Psilocybin poisoning produces biphasic reactions composed of a schizophrenic phase and a panic attack-like phase. There is a time lag of several hours between phases, which may be considered an accumulation time in certain sites between the gut and the brain. So far as 5-hydroxytryptamine (5-HT) congeners are concerned, no sites are to be found except the am...
This review focuses on recent brain imaging and behavioral studies of sensory gating functions, which assess similarities between the effects of classic hallucinogens (eg, psilocybin), dissociative anesthetics (eg, ketamine), and entactogens (eg, 3,4-methylenedioxymethamphetamine [MDMA]) in humans. Serotonergic hallucinogens and psychotomimetic anesthetics p...
Increasing evidence from neuroimaging and behavioral studies suggests that functional disturbances within cortico-striato-thalamic pathways are critical to psychotic symptom formation in drug-induced and possibly also naturally occurring psychoses. Recent basic and clinical research with psychotomimetic drugs, such as the N-methyl-D-aspartate (NMDA) glutamat...
The action of P. cubensis mushroom extract, containing psilocybin (PCB) and psilocin, on spike activity of hippocampal CA1 pyramidal neurons was studied in in vitro rat brain slices. In 38 (76%) out of 50 investigated neurons spike activity was decreased, in 2 (4%) cells it increased. There was no response 10 (20%) neurons. Application of the extract caused ...
