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PubMed1989

Disruption of FR-40 by 5-HT agonists. II. Effects of chronic phenelzine or isocarboxazid.

Effects of chronic treatment with the monoamine oxidase inhibitors phenelzine and isocarboxazid on disruption of FR-40 operant responses by 5-HT agonists have been studied. Three groups of rats that were trained in the FR-40 operant schedule showed marked disruption by 0.1 mg/kg IP lysergic acid diethylamide (LSD), 2 mg/kg IP quipazine (Q), 0.05 mg/kg SC 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT), and 1 mg/kg SC (m-trifluoromethyl-phenyl)piperazine (TFMPP), administered twice weekly in random order. Subsequently, one group received daily IP injection of phenelzine (5 and 10 mg/kg), the second group received 5 mg/kg IP of isocarboxazid, and the third group received vehicle (0.5% methyl cellulose) for 24 days (Period 1 and Period 2). For these periods and 12 days after discontinuing the MAOI treatments (Washout Period), test doses of 5-HT agonists were evaluated for their effects to decrease reinforcements (R) and increase pauses (P). No change in sensitivity to the LSD, Q and TFMPP effects on FR-40 behavior was observed in the vehicle-treated group. However, an attenuated effect of 8-OHDPAT was found in this group. In phenelzine- and isocarboxazid-treated rats the disruption of FR-40 responses by LSD and 8-OHDPAT were significantly reduced during Period 1, Period 2 and Washout Period. A significantly less effect on disruption in FR-40 responses by quipazine and TFMPP during Period 2 and the Washout Period was also seen. Since MAO inhibitors appear to down-regulate both 5-HT1 and 5-HT2 binding sites in brain, the attenuated effects of the 5-HT agonists were anticipated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

A behavioral comparison of Nexus, cathinone, BDB, and MDA.

The effects of 4-bromo-2,5-dimethoxyphenethylamine (Nexus), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyphenyl-2-butanamine (BDB), and cathinone were studied in the newly hatched chicken and compared to the effects of d-amphetamine and three hallucinogens in the same species. Cathinone, a psychomotor stimulant in man (6), produced effects that were qualitatively similar to effects seen after administration of d-amphetamine (i.e., distress vocalization, wing extension, inability to stand, and loss of righting reflex). BDB, a compound with unknown activity in man, and two known hallucinogens, Nexus (5) and MDA (1), produced effects in the chicken that are common to both stimulants and hallucinogens in this species. For example, both MDA and BDB produced abnormal body posture that was identical to that reported after administration of hallucinogens such as lysergic acid diethylamide (LSD) and harmine (11). Nexus, on the other hand, produced rigid penguin-like posture, an effect seen in the chicken after administration of another hallucinogen, mescaline (12). BDB also produced bursting forward movements, an effect commonly observed after LSD and harmine. Our findings suggest that the young chicken can be used as an alternative, nonmammalian, model for predicting classification of new compounds.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1986

Adrenergic and serotonergic regulation of skeletal muscle metabolism in the rat: specificity of the serotonin- and isoproterenol-stimulable adenylyl cyclase in sarcolemma.

The specificity and kinetics of rat sarcolemmal serotonin- and isoproterenol-stimulable adenylyl cyclases were studied. The stimulation of adenylyl cyclase by serotonin was less than that by isoproterenol and required low concentrations of ATP (0.1 mM), 10 microM GTP, and free Mg ion concentrations of 10-20 microM. The isoproterenol-stimulated activity was readily detectable over a much wider range of MgCl2 (1.0-5.0 mM) and ATP (0.1-3.0 mM). (+/-)-Oxprenolol and l(-)-propranolol inhibited isoproterenol stimulation with KB values of 6.3 X 10(-9) M and 1.9 X 10(-9) M, respectively. Interference by (+/-)-cyproheptadine, (+/-)-methysergide and d(+)-propranolol was not strictly competitive. However, these were much more potent inhibitors of serotonin stimulation than were oxprenolol and l-propranolol. The concentrations of antagonists producing 50% inhibition (IC50) of the maximal adenylyl cyclase stimulation by serotonin were compared to the IC50 obtained with isoproterenol; the ratios were 0.02 for oxprenolol, 0.50 for l-propranolol, 295 for d-propranolol, 2438 for cyproheptadine, 578 for methysergide and greater than 125,000 for lysergic acid diethylamide (LSD). These data indicate that rat skeletal muscle adenylyl is stimulated by discrete serotonergic and adrenergic receptors, and that there may be distinct conditions for optional stimulation.

Adenylyl Cyclases↗
PubMed2005

Screening the receptorome for plant-based psychoactive compounds.

Throughout time, humans have used psychoactive plants and plant-derived products for spiritual, therapeutic and recreational purposes. Furthermore, the investigation of psychoactive plants such as Cannabis sativa (marijuana), Nicotiana tabacum (tobacco) and analogues of psychoactive plant derivatives such as lysergic acid diethylamide (LSD) have provided insight into our understanding of neurochemical processes and diseases of the CNS. Currently, many of these compounds are being used to treat a variety of diseases, such as depression and anxiety in the case of Piper methysticum Kava Kava (Martin et al., 2002; Singh and Singh, 2002). G-protein coupled receptors (GPCRs) are the most common molecular target for both psychoactive drugs and pharmaceuticals. The "receptorome" (that portion of the genome encoding ligand reception) encompasses more than 8% of the human genome (Roth et al., 2004) and as such provides a large number of possible targets for psychoactive drug interactions. A systematic, comprehensive study is necessary to identify novel active psychoactive plant-based compounds and the molecular targets of known compounds. Herein we describe the development of a high throughput system (HTS) to screen psychoactive compounds against the receptorome and present two examples (Salvia divinorum, the "magic mint" hallucinogen and Banisteriopsis caapi, the main component of Ayahuasca, a psychoactive beverage) where HTS enabled the identification of the molecular target of each compound.

Animals↗
PubMed2004

Hallucinogens.

Hallucinogens (psychedelics) are psychoactive substances that powerfully alter perception, mood, and a host of cognitive processes. They are considered physiologically safe and do not produce dependence or addiction. Their origin predates written history, and they were employed by early cultures in a variety of sociocultural and ritual contexts. In the 1950s, after the virtually contemporaneous discovery of both serotonin (5-HT) and lysergic acid diethylamide (LSD-25), early brain research focused intensely on the possibility that LSD or other hallucinogens had a serotonergic basis of action and reinforced the idea that 5-HT was an important neurotransmitter in brain. These ideas were eventually proven, and today it is believed that hallucinogens stimulate 5-HT(2A) receptors, especially those expressed on neocortical pyramidal cells. Activation of 5-HT(2A) receptors also leads to increased cortical glutamate levels presumably by a presynaptic receptor-mediated release from thalamic afferents. These findings have led to comparisons of the effects of classical hallucinogens with certain aspects of acute psychosis and to a focus on thalamocortical interactions as key to understanding both the action of these substances and the neuroanatomical sites involved in altered states of consciousness (ASC). In vivo brain imaging in humans using [(18)F]fluorodeoxyglucose has shown that hallucinogens increase prefrontal cortical metabolism, and correlations have been developed between activity in specific brain areas and psychological elements of the ASC produced by hallucinogens. The 5-HT(2A) receptor clearly plays an essential role in cognitive processing, including working memory, and ligands for this receptor may be extremely useful tools for future cognitive neuroscience research. In addition, it appears entirely possible that utility may still emerge for the use of hallucinogens in treating alcoholism, substance abuse, and certain psychiatric disorders.

Alcoholism↗
PubMed2006

The mysterious trace amines: protean neuromodulators of synaptic transmission in mammalian brain.

The trace amines are a structurally related group of amines and their isomers synthesized in mammalian brain and peripheral nervous tissues. They are closely associated metabolically with the dopamine, noradrenaline and serotonin neurotransmitter systems in mammalian brain. Like dopamine, noradrenaline and serotonin the trace amines have been implicated in a vast array of human disorders of affect and cognition. The trace amines are unique as they are present in trace concentrations, exhibit high rates of metabolism and are distributed heterogeneously in mammalian brain. While some are synthesized in their parent amine neurotransmitter systems, there is also evidence to suggest other trace amines may comprise their own independent neurotransmitter systems. A substantial body of evidence suggests that the trace amines may play very significant roles in the coordination of biogenic amine-based synaptic physiology. At high concentrations, they have well-characterized presynaptic "amphetamine-like" effects on catecholamine and indolamine release, reuptake and biosynthesis; at lower concentrations, they possess postsynaptic modulatory effects that potentiate the activity of other neurotransmitters, particularly dopamine and serotonin. The trace amines also possess electrophysiological effects that are in opposition to these neurotransmitters, indicating to some researchers the existence of receptors specific for the trace amines. While binding sites or receptors for a few of the trace amines have been advanced, the absence of cloned receptor protein has impeded significant development of their detailed mechanistic roles in the coordination of catecholamine and indolamine synaptic physiology. The recent discovery and characterization of a family of mammalian G protein-coupled receptors responsive to trace amines such as beta-phenylethylamine, tyramine, and octopamine, including socially ingested psychotropic drugs such as amphetamine, 3,4-methylenedioxymethamphetamine, N,N-dimethyltryptamine, and lysergic acid diethylamide, have revitalized the field of scientific studies investigating trace amine synaptic physiology, and its association with major human disorders of affect and cognition.

Amines↗
PubMed1999

Modulation of the firing activity of rat serotonin and noradrenaline neurons by (+/-)pindolol.

BACKGROUND: (+/-)Pindolol is a beta-adrenergic/5-HT1A receptor antagonist used in combination with certain antidepressant drugs to accelerate the onset of the antidepressive response. METHODS: The aim of the present study was to assess, using an in vivo electrophysiologic paradigm, the effect of (+/-)pindolol on the spontaneous firing activity of rat dorsal raphe serotonin (5-HT) and locus coeruleus noradrenaline (NA) neurons. RESULTS: (+/-)Pindolol did not modify the firing activity of dorsal raphe 5-HT neurons at low doses (10 and 200 micrograms/kg, i.v.), but it prevented the suppressant effect of the 5-HT autoreceptor agonist lysergic acid diethylamide (LSD, 10 micrograms/kg, i.v.) but not that of the 5-HT1A receptor 8-hydroxy-N,N-dipropyl-aminotetralin (8-OHDPAT, 5 micrograms/kg, i.v.). At a higher dose (500 micrograms/kg, i.v.), (+/-)pindolol decreased 5-HT neuronal firing and this effect was reversed by the selective 5-HT1A receptor antagonist WAY 100635 (100 micrograms/kg, i.v.), suggesting that it could act as a partial 5-HT1A autoreceptor agonist. In the locus coeruleus, the high dose of (+/-)pindolol decreased the firing activity of NA neurons and this effect was reversed by the 5-HT2A receptor antagonist MDL 100907 (200 micrograms/kg, i.v.). Finally, both a lesion of NA neurons and the administration of MDL 100907 prevented the suppressant effect of (+/-)pindolol on the firing of 5-HT neurons. CONCLUSIONS: It is suggested that, at low doses, (+/-)pindolol acts as a somatodendritic 5-HT1A autoreceptor antagonist whereas at a higher dose, it decreases the tonic excitatory input from NA neurons to 5-HT neurons.

Action Potentials↗
PubMed2000

Fluoxetine prevents PCP- and MK801-induced HSP70 expression in injured limbic cortical neurons of rats.

BACKGROUND: N-Methyl-D-aspartate (NMDA) receptor antagonists, including phencyclidine (PCP) and dizocilpine (MK801), cause schizophrenialike psychosis in humans, and produce vacuolated neurons in the cingulate and retrosplenial cortices of the rat brain. Since psychotically depressed patients and schizophrenic depressed patients may require treatment with selective serotonin reuptake inhibitors (SSRIs), it is of interest to examine the relationship between SSRIs and NMDA antagonist neurotoxicity. METHODS: The neurotoxicity of PCP and MK801 was assessed using heat shock protein (HSP70) immunocytochemistry and HSP70 Western blots because HSP70 is expressed in the injured, vacuolated neurons. Female rats were given fluoxetine (0, 5, 10, and 20 mg/kg IP) followed 1 hour later by MK801 (1 mg/kg IP) or PCP (50 mg/kg IP). RESULTS: Pretreatment with fluoxetine (20 mg/kg IP) 1 hour before MK801 prevented the induction of HSP70 by MK801 in the cingulate and retrosplenial cortices. Pretreatment with fluoxetine (10 or 20 mg/kg IP) 1 hour before PCP also prevented the HSP70 induction by PCP. CONCLUSIONS: Fluoxetine prevents the neurotoxicity of NMDA receptor antagonists in rat brain. This suggests the possibility that SSRIs could modulate psychosis, and may provide a model for examining the link between the hallucinogenic properties of PCP and lysergic acid diethylamide.

Animals↗
PubMed2001

5-HT1A and 5-HT2 receptors differentially regulate the excitability of 5-HT-containing neurones of the guinea pig dorsal raphe nucleus in vitro.

We have used intracellular recording techniques to examine the effects of 5-hydroxytryptamine (5-HT, serotonin) on 5-HT-containing neurones of the guinea pig dorsal raphe nucleus in vitro. Bath-applied 5-HT (30-300 microM) had two opposing effects on the membrane excitability of these cells, reflecting the activation of distinct 5-HT receptor subtypes. As demonstrated previously in the rat, 5-HT evoked a hyperpolarization and inhibition of 5-HT neurones, which appeared to involve the activation of an inwardly rectifying K(+) conductance. This hyperpolarizing response was blocked by the 5-HT(1A) receptor-selective antagonist WAY-100635 (30-100 nM). In the presence of WAY-100635, 5-HT induced a previously unreported depolarizing, excitatory response of these cells, which was often associated with an increase in the apparent input resistance of the neurone, likely due to the suppression of a K(+) conductance. Like the hyperpolarizing response to 5-HT, this depolarization could be recorded in the presence of the Na(+) channel blocker tetrodotoxin. In addition, the response was not significantly attenuated by the alpha(1)-adrenoceptor antagonist prazosin (500 nM), indicating that it is not due to the release of noradrenaline, or to the direct activation of alpha(1)-adrenoceptors by 5-HT. The 5-HT(3) receptor antagonist granisetron (1 microM) and the 5-HT(4) receptor antagonist SB 204070 (100 nM) failed to reduce the depolarizing response to 5-HT; however, ketanserin (100 nM), mesulergine (100 nM) and lysergic acid diethylamide (1 microM) significantly reduced or abolished the depolarization, indicating that this effect of 5-HT is mediated by 5-HT(2) receptors.

Animals↗
PubMed2001

Human 5-HT(5) receptors: the 5-HT(5A) receptor is functional but the 5-HT(5B) receptor was lost during mammalian evolution.

We have isolated from a human genomic library the human 5-hydroxytryptamine 5-HT(5A) and 5-HT(5B) genes. The human 5-HT(5A) gene encodes a protein with similar characteristics to its mouse homologue. When expressed in monkey COS-7 cells, the human 5-HT(5A) receptor displayed a high affinity for tritiated 5-carbamidotryptamine ([3H]5-CT; K(D)=2.8 nM) and iodinated lysergic acid diethylamide ([125I]LSD; K(D)=187 pM). These binding sites displayed the following displacement profile: Ergotamine>Methiothepin>5-CT, Ritanserin>5-HT. Reverse transcriptase polymerase chain reaction (RT-PCR) experiments revealed the presence of human 5-HT(5A) mRNA in the central nervous system but not in peripheral organs. When expressed in Xenopus oocytes, the 5-HT(5A) receptor was able to couple to the inwardly rectifying K(+) channel, GIRK(1). In contrast to the human 5-HT(5A) gene and the mouse 5-HT(5B) gene, the human 5-HT(5B) gene does not encode a functional protein because its coding sequence is interrupted by stop codons. Our results suggest, therefore, that the 5-HT(5B) receptor has been lost during evolution after the divergence between rodents and primates. The 5-HT(5B) receptor is the first example of a brain-specific protein that is absent in human.

3T3 Cells↗
PubMed1998

Effect of the reversible monoamine oxidase-A inhibitor befloxatone on the rat 5-hydroxytryptamine neurotransmission.

The aim of the present study was to assess, using in vivo electrophysiological paradigms, the effect of sustained administration of the selective and reversible monoamine oxidase-A inhibitor beflotaxone on serotonin (5-hydroxytryptamine, 5-HT) neurotransmission. In male Sprague-Dawley rats with the osmotic minipumps in place, a treatment with befloxatone (0.75 mg/kg per day, s.c.) for 2 days decreased the spontaneous firing activity of dorsal raphe 5-HT neurons. The combination of befloxatone and the 5-HT1A/1B receptor antagonist (-)-pindolol (15 mg/kg per day, s.c.) for 2 days slightly increased the firing activity of 5-HT neurons, whereas a treatment with (-)-pindolol alone for 2 days did not modify this parameter. The suppressant effects on the firing activity of 5-HT neurons of the 5-HT autoreceptor agonist lysergic acid diethylamide (LSD), injected intravenously, and of both 5-HT and the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), applied by microiontophoresis, were attenuated in rats treated with befloxatone for 2 days, suggesting an early desensitization of the somatodendritic 5-HT1A receptors. The firing activity of 5-HT neurons was back to normal after a treatment for 21 days with befloxatone but the suppressant effects of LSD, 5-HT or 8-OH-DPAT was the same as in controls. In contrast, the suppressant effect of the alpha2-adrenoceptor agonist clonidine on the firing activity of 5-HT neurons was significantly attenuated after the treatment with befloxatone for 21 days. At the postsynaptic level, the administration of the selective 5-HT1A receptor antagonist (N-[2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide trihydroxychloride (WAY 100635, 100 microg/kg, i.v.) did not modify the firing activity of quisqualate-activated dorsal hippocampus CA3 pyramidal neurons in control rats. In contrast, in rats treated with befloxatone in combination with (-)-pindolol for 2 days as well as with befloxatone alone for 21 days, WAY 100635 significantly increased the firing of CA3 pyramidal neurons. In conclusion, these data suggest that when the firing activity of 5-HT neurons is normal in the presence of befloxatone, either after a two-day treatment together with (-)-pindolol or alone for 21 days, the tonic activation of postsynaptic 5-HT1A receptors is enhanced.

Afferent Pathways↗
PubMed1975

Thin-layer gel chromatography of dyed proteins.

Plasma chromatography as a method for ultratrace qualitative and quantitative detection of organic compounds is especially well suited for detection of gas chromatographic effluents. The optimum range of sample quantity is 10(-6) to 10(-12) g for detection and identification of a compound by use of its characteristic positive and negative mobility spectra. The type of reference mobility spectra produced by alkanes, aromatics, esters, halogenated compounds, nitrogenated compounds and organic acids have been previously reported. This study presents the reference mobility spectra produced for lysergic acid diethylamide (LSD), delta9-tetrahydrocannabinol (delta9-THC), digitoxigenin and several biochemical compounds of research significance. LSD and delta9-THC in a mixture can be detected and identified by plasma chromatography positive mobility spectra in quantities of 10(-7) g or less. All the compounds investigated in this study display strong MH+ ions along with other ions primarily of the type (M)NO+, (M)2H+. None of these compounds exhibits negative mobility spectra.

Chromatography, Gel↗
PubMed2003

Use of dynamically coated capillaries with added cyclodextrins for the analysis of opium using capillary electrophoresis.

A rapid, precise, accurate, and robust method using capillary electrophoresis (CE) with dynamically coated capillaries for the analysis of the major opium alkaloids in opium is presented. Dynamic coating of the capillary surface is accomplished using a commercially available reagent kit (polycation coating followed by polyanion coating). The addition of dual cyclodextrins (hydroxypropyl-beta-cyclodextrin and dimethyl-beta-cyclodextrin) to the run buffer imparts excellent selectivity for the opium alkaloids. For the determination of morphine, papaverine, codeine, noscapine and thebaine in opium gum and opium latex samples (using tetracaine as an internal standard) good agreement with values obtained by gradient high-performance liquid chromatography is obtained. Compared to the latter technique, CE affords better resolution with significantly faster analysis time (12 min versus 29 min). Dynamically coated capillaries, which give rise to a relatively high and robust electroosmotic flow (EOF) at the background electrolyte pH of 2.5, allow for rapid analysis and excellent migration time and peak area precision (RSDs < or = 0.12% and < or = 1.2%, respectively). Reproducible separations (relative migration times) for over 500 samples have been obtained on a single capillary. The nature of the injection solvent, the injection time and the contents of the waste vials have a profound effect on the pressure injection precision of the relatively hydrophobic solutes. The CE conditions reported in this study are also applicable to the analysis of lysergic acid diethylamide (LSD) exhibits.

Cyclodextrins↗
PubMed2003

Adsorption-desorption effects in ion trap mass spectrometry using in situ ionization.

Quadrupole mass spectrometers were compared for the GC-MS analysis of six molecules frequently encountered in analytical toxicology: diazepam, alprazolam, triazolam, LSD (lysergic acid diethylamide), trimethylsilylated LSD and trimethylsilylated buprenorphine. Experiments performed with ion trap detectors using in situ ionization led to important chromatographic peak tailing for the most polar compounds; it was assumed to result from adsorption-desorption of neutral molecules in the mass spectrometer. This study showed that the degree of peak tailing is correlated with analyte polarity, with materials coating ion trap surfaces and with analysis temperature and that this anomaly can be greatly reduced using passivated surfaces and a high temperature of analysis.

Adsorption↗
PubMed1998

Central distribution and function of 5-HT6 receptor subtype in the rat brain.

The purpose of the present study was to elucidate the distribution of 5-HT6 receptor mRNA and possible physiological functions of the 5-HT6 receptor subtype using antisense oligonucleotides (AOs) in rats. Continuous intracerebroventricular injection of AOs caused a 30% reduction in the number of [3H]-lysergic acid diethylamide binding sites. Conditioned fear stress-induced increase in 5-HT release from the prefrontal cortex was significantly inhibited by treatment with AOs. The present study suggests that 5-HT6 receptors may be functionally expressed in the brain, where one of the functions appears to be in the mediation of certain anxiety disorders.

Animals↗
PubMed1996

Alcohol and drug use in UK university students.

BACKGROUND: Alcohol and illicit drug use are increasing among school children and young adults in the UK. Such increases have also been noted among university students and there is a need for a large survey across different universities and faculties. We report such a survey. METHODS: Information about drinking, use of cannabis and other illicit drugs, other lifestyle variables, and subjective ratings of anxiety and depression was obtained by questionnaire in a cross-faculty sample of 3075 second-year university students (1610 men, 1447 women, 18 sex not stated) from ten UK universities. The questionnaire was personally administered during scheduled lecture hours and almost all the students participated. The sample reflected the interfaculty and sex distribution and the proportion of non-white students at UK universities. FINDINGS: 11% of the students were non-drinkers. Among drinkers, 61% of the men and 48% of the women exceeded "sensible" limits of 14 units per week for women and 21 for men. Hazardous drinking (> or = 36 units per week for women, > or = 51 for men) was reported by 15% of the drinkers. Binge drinking was declared by 28% of drinkers. 60% of the men and 55% of the women reported having used cannabis once or twice and 20% of the sample reported regular cannabis use (weekly or more often). Experience with other illicit drugs was reported by 33% of the sample, most commonly LSD (lysergic acid diethylamide), amphetamines, Ecstasy (methylenedioxymethamphetamine), and amyl/butyl nitrate which had each been used by 13-18% of students. 34% of these had used several drugs. Drug use had started at school in 46% of the sample; 13% began after entering university. The overwhelming reason given for taking alcohol or drugs was pleasure. Subjective ratings of anxiety on the hospital anxiety depression scale were high, and sleep difficulties were common, but neither related to alcohol or drug use. INTERPRETATION: There is a need for better education about alcohol, drugs, and general health in universities. Such education should include all faculties. It remains unclear whether university students' lifestyles are carried over into later life.

Adolescent↗
PubMed2004

Monoamine oxidase and head-twitch response in mice. Mechanisms of alpha-methylated substrate derivatives.

It is well known that head-twitch response (HTR) in mice represents hallucinations, since administration of lysergic acid diethylamide (LSD) produces hallucinations in humans, and the HTR in mice is induced by administration of LSD as a hallucinogen. The HTR is produced by excitation of 5-hydroxytryptamine (5-HT)2A receptors. In this paper, we review the mechanisms of HTR induced by various drugs such as 5-HT precursor, 5-HT receptor agonist, 5-HT releaser, hallucinogenic compounds, benzodiazepins and cannabinoid. The response induced by HTR-inducers is significantly enhanced by combined treatment with a non-selective form of monoamine oxidase (MAO) inhibitor. Thus, the relationship between MAO activity and HTR caused by these drugs (especially, alpha-methylated analogous compounds which 5-fluoro-alpha-methyltryptamine, 6-fluoro-alpha-methyltryptamine and p-hydroxyamphetamine) is presented in detail.

Animals↗
PubMed2000

Serotonin model of schizophrenia: emerging role of glutamate mechanisms.

The serotonin (5-HT) hypothesis of schizophrenia arose from early studies on interactions between the hallucinogenic drug LSD (D-lysergic acid diethylamide) and 5-HT in peripheral systems. More recent studies have shown that the two major classes of psychedelic hallucinogens, the indoleamines (e.g., LSD) and phenethylamines (e.g. , mescaline), produce their central effects through a common action upon 5-HT(2) receptors. This review focuses on two brain regions, the locus coeruleus and the cerebral cortex, where the actions of indoleamine and the phenethylamine hallucinogens have been shown to be mediated by 5-HT(2A) receptors; in each case, the hallucinogens (via 5-HT(2A) receptors) have been found to enhance glutamatergic transmission. In the prefrontal cortex, 5-HT(2A)-receptors stimulation increases the release of glutamate, as indicated by a marked increase in the frequency of excitatory postsynaptic potentials/currents (EPSPs/EPSCs) in the apical dendritic region of layer V pyramidal cells; this effect is blocked by inhibitory group II/III metabotropic glutamate agonists acting presynaptically and by an AMPA/kainate glutamate antagonist, acting postsynaptically at non-NMDA glutamate receptors. A major alternative drug model of schizophrenia, previously believed to be entirely distinct from that of the psychedelic hallucinogens, is based on the psychotomimetic properties of antagonists of the NMDA subtype of glutamate receptor (e.g., phencylidine and ketamine). However, recently it has been found that many of the effects of the NMDA antagonists may also (1) involve 5-HT(2A) receptors and (2) be mediated through excess activity at non-NMDA (i.e., AMPA/kainate) glutamate receptors. Moreover, pharmacological manipulations of glutamate transmission (e. g., by inhibitory metabotropic glutamate agonists) provide unexpected parallels between the actions of these two classes of drugs. Given an emerging recognition of the importance of alterations in glutamatergic transmission in the actions of both psychedelic hallucinogens an NMDA antagonists, this review concludes with of implications for the pathophysiology and therapy of schizophrenia.

Animals↗