(+)-N-Allylnormetazocine (NANM) binds to at least two sites in the mammalian central nervous system, a high-affinity, haloperidol-sensitive site and a lower-affinity site identified as the phencyclidine (PCP) receptor. The relevance of these sites to the discriminative stimulus properties of (+)-NANM was evaluated in rats trained to discriminate (+)-NANM from saline. Drugs with a high affinity...
3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"), an amphetamine analog, is a "designer drug" which is being increasingly abused. The potential neurotoxic hazard of MDMA in humans was assessed by examining the effects of repeated systemic administration of MDMA on selected neurochemical and behavioral measures in rhesus monkeys. In the first study, MDMA (2.5 or 10 mg/kg twice daily for 4...
The interactions of the indolealkylamine hallucinogen d-lysergic acid diethylamide (d-LSD) and two phenalkylamine hallucinogens, 2,5-dimethoxy-4-bromoamphetamine (DOB) and 2,5-dimethoxy-4-iodoamphetamine (DOI), with 5-hydroxytryptamine2 (5-HT2) receptors were analyzed in rat cortex using both radioligand binding techniques and biochemical measurements of phosphatidylinositol (PI) turnover....
The effects of methylenedioxymethamphetamine (0.63-10.0 mg/kg) and N-ethyl-methylenedioxyamphetamine (1.0-10.0 mg/kg) on locomotor and investigatory responses of rats were measured in the Behavioral Pattern Monitor system, a system designed to measure both the quantity and quality of behavioral activity. Horizontal locomotion was increased considerably by these compounds in a dose-related...
Similar to other amphetamine analogs 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"), a currently popular illicit drug, has been characterized recently as a serotonergic neurotoxin due to its ability to cause long-lasting deficits in markers of central serotonergic function in animals. Because the serotonergic toxicity associated with the MDMA analog methamphetamine has been linked...
Based on electrophysiological, radioligand binding, and behavioral studies in laboratory animals, it is generally believed that the psychotomimetic effects of the phenethylamine and indolealkylamine hallucinogens are mediated by central serotonin (5-HT) receptors, in particular the 5-HT-2 subtype. Agonist-stimulated phosphoinositide hydrolysis was utilized to determine the potency and efficacy...
The stimulus properties of 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and several related compounds were compared to those of (+)-lysergic acid diethylamide (LSD) and mescaline (3,4,5-trimethoxyphenylethylamine) in a two-lever, water-reinforced, drug discrimination task. In animals trained to discriminate LSD (0.08 mg/kg) from saline (n = 8), LSD-like...
The pharmacology and structure-activity relationship of phencyclidine (PCP)-like drugs (phencyclinoids) were studied using electroencephalographic (EEG), behavioral and receptor binding techniques. The effects of PCP, 1-phenylcyclohexylamine HCl, N-methyl-1-phenycyclohexylamine HCl, N-ethyl-1-phenylcyclohexylamine HCl, N-(s-butyl)-1-phenylcyclohexylamine HCL, 1-(1-phenylcyclo-hexyl)-pyrrolidine...
The behavioral effects of MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imin e], a proposed noncompetitive N-methyl-D-aspartate (NMDA) antagonist, were compared to those of phencyclidine (PCP). In pigeons, MK-801 produced PCP-like catalepsy (i.e., loss of righting without eye closure and without muscle relaxation) and PCP-like discriminative stimulus effects. In rats,...
The racemic mixture of 3,4-methylenedioxymethamphetamine (MDMA), which has been reported to produce selective destruction of serotonergic neurons in the central nervous system, was studied to determine its neuroendocrine and temperature effects and mechanism of action. MDMA elevated serum concentrations of corticosterone in doses ranging from 3 to 20 mg/kg administered i.p. Serum corticosterone...
This study demonstrates that the isomers of 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) are different in their ability to induce changes in serotonergic parameters and nigral concentrations of neurotensin-like immunoreactivity. With five successive doses (3.5 mg/kg) the d-MDA isomer was more potent than the l-MDA in its ability to decrease the concentrations...
Phencyclidine (PCP)-induced behaviors were compared with 5-methoxy-N,N-dimethyltryptamine (5-MeODMT)- and p-chloroamphetamine-induced behaviors in rats pretreated with ritanserin or 5,7-dihydroxytryptamine (5,7-DHT) in order to investigate whether PCP interacts with 5-hydroxytryptamine2 (5-HT2) receptors. Head-twitch and wet-dog shake induced by p-chloroamphetamine, a 5-HT releaser, and...
Dioxadrol exists in four isomeric forms. alpha-(+)-Dioxadrol (dexoxadrol) showed phencyclidine (PCP)-like activity in rhesus monkeys trained to discriminate s.c. administration of ketamine, but neither alpha-(-)-dioxadrol (levoxadrol) nor beta-(+/-)-dioxadrol showed such activity. In addition, response-contingent i.v. dexoxadrol maintained higher rates of responding than either levoxadrol or...
This study examines the effects of repeated systemic administration (20 mg/kg s.c., twice daily for 4 days) of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on levels of brain monoamines, their metabolites and on the density of monoamine uptake sites in various regions of rat brain. Marked reductions (30-60%) in the concentration of 5-hydroxyindoleacetic acid...
The present studies examined whether dependence could be induced by continuous i.v. infusion of phencyclidine (PCP) in rats as demonstrated by disruptions of operant behavior during withdrawal. Rats were trained to lever press for their daily food rations under fixed-ratio 30 schedules of reinforcement during four, daily, 0.5-hr sessions. In the first study, withdrawal from 10 days of PCP...
(+/-)-3,4-Methylenedioxymethylamphetamine (MDMA) was administered s.c. to rats (10, 20 or 40 mg/kg b. wt.) and guinea pigs (20 mg/kg) twice a day for 4 days, 2 weeks before decapitation. Norepinephrine, dopamine and serotonin (5-HT) levels were assayed in the hippocampus, hypothalamus, striatum and neocortex. In rats, MDMA produced dose-dependent reductions in 5-HT in all brain regions...
The neurochemical effects of the unique psychedelic agent, methylenedioxymethamphetamine (MDMA), indicate it may be a serotonergic neurotoxin related to agents such as p-chloroamphetamine. MDMA had a biphasic effect on cortical serotonin concentrations beginning with an acute depletion of the transmitter which reached a maximum between 3 and 6 hr after drug administration. This early phase of...
Metaphit, a derivative of phencyclidine (PCP), binds irreversibly to PCP sites and appears to act as an antagonist of PCP under some conditions and as a PCP-like agonist under other conditions. To describe further these conditions, the authors investigated the behavioral effects of metaphit by using different routes of administration, behavioral procedures and species. In pigeons, metaphit...
Representatives from several chemical classes known to share behavioral properties with phencyclidine [(1-phenylcyclohexyl)piperidine] (PCP) have been shown to antagonize the excitatory effects of N-methylaspartate on spinal neurons selectively. This study compared the abilities of several of these PCP-like drugs to inhibit N-methyl-D-aspartate (NMDA)-stimulated efflux of acetylcholine in rat...
Four monkeys (Cercopithecus aethiops) were trained to discriminate 0.06 mg/kg of lysergic acid diethylamide (LSD) from saline in a two-key task in which correct responding was reinforced with food under a fixed ratio 32 schedule. The ED50 of LSD was 0.011 mg/kg. The nonhallucinogenic ergot, lisuride, and the hallucinogen, 5-methoxy-N,N-dimethyltryptamine, substituted completely for LSD (ED50...
Phencyclidine [(l-phenylcyclohexyl) piperidine] (PCP) is known to increase the basal efflux of striatal dopamine (DA) in vitro and to enhance haloperidol (HAL)-induced striatal DA metabolism in vivo. This study compared these activities of PCP to several representatives of the arylcyloalkylamine, benzomorphan and substituted dioxolane classes whose behavioral similarities to PCP have been well...
Previous studies from our laboratory have demonstrated that there are a number of important dissociations between the effects of hallucinogenic drugs on the activity of serotonin-containing dorsal raphe neurons and behavior in freely moving cats. In the present study, we extended this analysis to serotonergic units in the nucleus centralis superior (NCS) and nucleus raphe pallidus (RPA)....
Slices of rat hypothalamus prelabeled with [3H]-5-hydroxytryptamine ([3H]-5-HT) were superfused and the release of the labeled transmitter was elicited either by electrical stimulation or by fenfluramine. Whereas the electrically stimulated release of [3H]-5-HT was completely abolished by removing calcium from the superfusion medium, the fenfluramine-induced release of [3H]-5-HT was...
5-Methoxy-N,N-dimethyltryptamine (20-200 microgram/kg) inhibits phrenic and sympathetic neural discharges and depresses blood pressure. The effects occur within seconds after injection. Complete recovery occurs, on the average, after 20 min. The inhibition of phrenic nerve discharges is prevented during hypercapnia and hyperthermia and reversed during 50 Hz electrical stimulation of the carotid...
In blood platelets of rabbits, the shape change-inducing effect of D-lysergic acid diethylamide (D-LSD) has been compared with the D-LSD-binding. D-LSD, but not L-LSD, caused a shape change reaction (EC50 1.3 x 10(-9) M) which was inhibited by various 5-HT antagonists (methergoline and neuroleptic drugs), butaclamol showing marked stereospecificity. Strong inhibitors of 5 HT uptake were only...