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. (+info)
Increased exploratory activity and altered response to LSD in mice lacking the 5-HT(5A) receptor.
In order to determine the distribution and function of the 5-HT5A serotonin receptor subtype, we generated knockout mice lacking the 5-HT5A gene. Comparative autoradiography studies of brains of wild-type (wt) and 5-HT5A knockout (5A-KO) mice revealed the existence of binding sites with high affinity for [125I]LSD that correspond to 5-HT5A receptors and that are concentrated in the olfactory bulb, neocortex, and medial habenula. When exposed to novel environments, the 5A-KO mice displayed increased exploratory activity but no change in anxiety-related behaviors. In addition, the stimulatory effect of LSD on exploratory activity was attenuated in 5A-KO mice. These results suggest that 5-HT5A receptors modulate the activity of neural circuits involved specifically in exploratory behavior and suggest that some of the psychotropic effects of LSD may be mediated by 5-HT5A receptors. (+info)
Neurometabolic effects of psilocybin, 3,4-methylenedioxyethylamphetamine (MDE) and d-methamphetamine in healthy volunteers. A double-blind, placebo-controlled PET study with [18F]FDG.
The neurometabolic effects of the hallucinogen psilocybin (PSI; 0.2 mg/kg), the entactogen 3,4-methylenedioxyethylamphetamine (MDE; 2 mg/kg) and the stimulant d-methamphetamine (METH; 0.2-0.4 mg/kg) and the drugs' interactions with a prefrontal activation task were investigated in a double-blind, placebo-controlled human [F-18]fluorodeoxyglucoseFDG-positron emission tomographicPET study (each group: n = 8). Subjects underwent two scans (control: word repetition; activation word association) within 2-4 weeks. Psilocybin increased rMRGlu in distinct right hemispheric frontotemporal cortical regions, particularly in the anterior cingulate and decreased rMRGlu in the thalamus. Both MDE and METH induced cortical hypometabolism and cerebellar hypermetabolism. In the MDE group, cortical hypometabolism was more pronounced in frontal regions, with the exception of the right anterior cingulate, which tended to be hyperactive. Cognitive activation-related increases in left frontocortical regions were attenuated under all three psychoactive substances, but less so under MDE. Taking into account performance data and subjective reports on task difficulty, these effects may result from different mechanisms across the three groups. Our PSI data are in line with studies on acute schizophrenic patients suggesting frontal overactivity at rest, but diminished capacity to activate prefrontal regions upon cognitive demand. The MDE data support the hypothesis that entactogens constitute a distinct psychoactive substance class, which takes an intermediate position between stimulants and hallucinogens. (+info)
Analysis of illicit ecstasy tablets: implications for clinical management in the accident and emergency department.
OBJECTIVE: To examine the composition of illicitly manufactured "ecstasy" tablets sold on the UK drugs market. METHODS: Analysis by gas chromatography of 25 illicit ecstasy tablets handed in under amnesty to Leeds Addiction Unit. RESULTS: Illicitly manufactured ecstasy tablets contain a range of ingredients, of widely differing concentrations, and even tablets with the same brand name have variable concentrations of active ingredients. Concentrations of 3,4-methylenedioxymethamphetamine (MDMA) more popularly known as ecstasy, varied 70-fold between tablets. Nine tablets contained neither MDMA nor related analogues. CONCLUSIONS: These results have implications for emergency workers attending to those who have become casualties of the drug ecstasy. Those claiming to have ingested ecstasy may actually have taken other agents that require different clinical management. (+info)
Effects of sustained phencyclidine exposure on sensorimotor gating of startle in rats.
Phencyclidine (PCP), a non-competitive NMDA antagonist with actions at multiple other central nervous system receptors, can cause both acute and lasting psychoses in humans, and has also been used in cross-species models of psychosis. Acute exposure to PCP in rats produces behavioral changes, including a loss of prepulse inhibition (PPI) of the startle reflex, which parallels the loss of PPI observed in schizophrenia patients. Sustained exposure to PCP in rats produces neuropathological changes in several limbic regions and prolonged behavioral abnormalities that may parallel neuropsychological deficits in schizophrenia. It is unclear whether sustained PCP exposure will also produce a loss of prepulse inhibition which parallels the decrease observed in schizophrenia patients. In the present study, we examined changes in PPI during and after sustained PCP administration, using 5-day PCP exposure via subcutaneous osmotic minipumps, or 14-day PCP exposure via repeated intraperitoneal injections. In both forms of drug delivery, PPI was disrupted during, but not after, sustained drug exposure. PPI does not appear to be sensitive to neuropathological effects of sustained PCP exposure. (+info)
Noribogaine generalization to the ibogaine stimulus: correlation with noribogaine concentration in rat brain.
The discriminative stimulus effects of ibogaine and noribogaine in rats have been examined in relation to their concentrations in blood plasma and brain regions and to receptor systems through which they have been proposed to act. Rats were trained to discriminate ibogaine (10 mg/kg i.p.), the NMDA antagonist dizocilpine (0.08 mg/kg i.p.) or the kappa-opioid agonist U50,488 (5 mg/kg i.p.) from vehicle in a standard two-lever operant conditioning procedure with a tandem VI-FR schedule of food reinforcement. Only rats trained on ibogaine generalized to noribogaine, which was approximately twice as potent as the parent compound. Noribogaine was detected in plasma and brain after administration of ibogaine and noribogaine. At the ED50 doses for the discriminative effect, the estimated concentrations of noribogaine in plasma, cerebral cortex, and striatum were similar regardless of whether ibogaine or noribogaine was administered. The findings suggest that the metabolite noribogaine may be devoid of NMDA antagonist and kappa-opioid agonist discriminative effects and that it may play a major role in mediating the discriminative stimulus effect of ibogaine. (+info)
Cardiovascular and neuroendocrine effects and pharmacokinetics of 3, 4-methylenedioxymethamphetamine in humans.
The cardiovascular and neuroendocrine effects and pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") were assessed in a double-blind, randomized, crossover, and controlled (placebo and amphetamine) clinical trial. Eight men with experience in the recreational use of MDMA participated in four 10-h experimental sessions with a 1-week washout period. Single oral doses of 125 mg and 75 mg of MDMA, 40 mg of amphetamine, and placebo were given. Both MDMA doses significantly increased blood pressure (increases of 40 mm Hg in systolic blood pressure), heart rate (increases of 30 beats/min), and pupillary diameter (mydriasis) as compared with placebo. Oral temperature did not show significant changes in any drug-active condition. Plasma cortisol levels showed a statistically significant increase after MDMA administration. Prolactin levels only increased after high dose of MDMA. Cmax values for 125-mg and 75-mg MDMA doses were 236.4 and 130.9 ng/ml, and Tmax was observed at 2.4 and 1.8 h, respectively. Elimination half-life was 8.6 h and 7.7 h for high and low MDMA doses, respectively. Amphetamine half-life was 15 h. Between 8 and 9% of the doses of MDMA appeared in plasma in the form of 3,4-methylenedioxyamphetamine. The important cardiovascular effects observed after MDMA administration in laboratory conditions at rest (increases of 40 mm Hg in systolic blood pressure and 30 beats/min in pulse rate) could be relevant in terms of toxicity in real-life conditions (e.g., crowded places and physical activity). (+info)
Stereospecific analysis and enantiomeric disposition of 3, 4-methylenedioxymethamphetamine (Ecstasy) in humans.
BACKGROUND: Little is known concerning the enantioselective disposition of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) in humans. In addition, the potential of utilizing the stereochemical composition of an analyte in biological media for forensic purposes requires investigation. METHODS: The enantiomers of MDMA and its demethylated metabolite, 3,4-methylenedioxyamphetamine (MDA), present in plasma and urine extracts were derivatized with (-)-(R)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride and analyzed by gas chromatography-mass spectrometry and gas chromatography, respectively. The enantioselective disposition of MDMA and MDA was determined following oral administration of racemic MDMA (40 mg) to eight male volunteers. RESULTS: The plasma concentrations of (R)-MDMA exceeded those of the S-enantiomer [ratio R:S of the area under the curve (AUC), 2.4 +/- 0.3], and the plasma half-life of (R)-MDMA (5.8 +/- 2.2 h) was significantly longer than that of the S-enantiomer (3.6 +/- 0.9 h). The majority of the recovered material in urine was excreted within 24 h after dosing, with the recovery of (R)-MDMA (21.4% +/- 11.6%) being significantly greater than that of (S)-MDMA (9.3% +/- 4.9%), and with (S)- and (R)-MDA accounting for 1.4% +/- 0.5% and 1.0% +/- 0.3% of the dose, respectively. Mathematical modeling of plasma enantiomeric composition vs sampling time demonstrated the applicability of using stereochemical data for the prediction of time elapsed after drug administration. CONCLUSIONS: Analytical methods for determining the enantiomeric composition of MDMA and MDA in plasma and urine were developed. The disposition of MDMA in humans is stereoselective, with the more active S-enantiomer having a reduced AUC and shorter half-life than (R)-MDMA. The determination of stereochemical composition may be applicable for forensic purposes. (+info)