The behavioral effects of L-methionine and related compounds in rats and mice.

Several groups of investigators have reported that the administration of L-methionine, with or without a monoamine oxidase inhibitor, induced an acute florid psychotic reaction in 40 percent of schizophrenics tested. The mode of action of L-methionine in brain is unknown, but may be via one or more of three mechanisms: the excess methionine (i) may lead to the production by transmethylation of some psychotomimetic methylated derivative of dopamine or serotonin, or (ii) could result in an increase in the levels of a metabolite of methionine (e.g., homocysteine, cystathionine, or cysteine), or (iii) may effect the cellular uptake of other amino acids. In order to test the first two hypotheses, L-methionine, betaine (another metyl group donor), L-methionine plus L-serine, L-cysteine, L-serine, and saline (as a control) were studied on the sleep-wake cycles of random-bred Swiss mice and on the avoidance behavior or rats. L-methionine plus L-histidine, L-methionine plus nicotinamide, L-histidine, and nicotinamide were also tested in the mice. Daily injections of 250 mg/kg of these compounds were administered for at least 21 consecutive days. Schedule performance in the rat and the sleep-wake cycles of the mice were monitored during this period and compared to controls. L-Methionine induced behavioral and sleep cycle disturbances which were removed by the simultaneous administration of L-serine but not by the addition of L-histidine or nicotinamide. These data suggest that the disruption may be due to an increase in the levels of one of the metabolities of methionine, homocysteine, rather than to an increase in the number of available methyl groups.

Ontogeny of N,N-dimethyltryptamine and related indolealkylamine levels in neonatal rats.

The present study deals with the measurement of the brain levels of the two potent hallucinogens N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (OMB), the biogenic amine tryptamine (TA), and its condensation product 1,2,3,4-tetrahydro-beta-carboline (THBC) in rats of various ages. Using gas chromatography-mass spectrometry with isotope dilution, we detected DMT, OMB, and THBC in neonatal rats from birth. DMT levels remained low until days 12 and 17 at which time they increased significantly and then returned to the initial low levels for all subsequent ages. The levels of OMB were higher than those measured for DMT with the highest levels being observed at days 12 and 17, and also on day 31. However, the levels for OMB showed much more variation. Although elevated levels of DMT and OMB have been correlated with stress, there are no known functions for these compounds. TA levels remained below detection limits until day 19. THBC levels were observed to be highest on days 22 and 31. The role that THBC plays in mammalian tissues is not known.

Structure-activity relationships in potentially hallucinogenic N,N-dialkyltryptamines substituted in the benzene moiety.

A series of N,N-dialkyltryptamines with methylthio or methylenedioxy substituents in the 4, 5, and 6 positions and methyl or isopropyl on the side-chain nitrogen has been synthesized. The behavioral pharmacology of these compounds showed them to possess Bovet-Gatti profiles characteristic of hallucinogens, and the 5-methylthio congener was the most potent. Binding studies at [3H]LSD and [3H]5-HT sites demonstrated that no single structural feature correlated with binding or behavioral changes and suggest a complex mode of action for these potential hallucinogenic agents.

Structure-activity relationships for hallucinogenic N,N-dialkyltryptamines: photoelectron spectra and serotonin receptor affinities of methylthio and methylenedioxy derivatives.

Serotonin receptor affinity and photelectron spectral data were obtained on a number of substituted N,N-dimethyltryptamines. Evidence is presented that electron-donating substituents in the 5-position lead to enhanced behavioral disruption activity and serotonin receptor affinity as compared to unsubstituted N,N-dimethyltryptamine and analogues substituted in the 4- or 6-position. Some correlation was found between ionization potentials and behavioral activity, which may have implications concerning the mechanism of receptor binding.

Stereospecific actions of 2,5-dimethoxy-4-methylamphetamine (DOM) on colonic temperature in the rat at various ambient temperatures.

The R(-) and S(+)-isomers of 2,5-dimethoxy-4-methylamphetamine (DOM) produce a dose-dependent hypothermia in rats kept in the cold (6 degrees C). 2 This hypothermia was linearly dependent upon ambient temperature and the R(-)-isomer was considerably more potent than the S(+)-isomer. 3 A statistically significant tachyphylaxis was observed when R(-)-DOM was administered on two successive days. The response seven days after the second injection was similar to that on the first day of injection. 4 The hypothermia induced by R(-) and S(+)-DOM was antagonized by methysergide but not by p-chlorophenylalanine (PCPA) or pimozide. Methysergide, PCPA or pimozide alone did not elicit hypothermia at the doses used. The results indicate that R(-) and S(+)-DOM act at post-synaptic 5-hydroxytryptamine receptors.

In vivo metabolism of alpha,alpha,beta,beta-tetradeutero-N, N-dimethyltryptamine in rodent brain.

The metabolism of alpha,alpha,beta,beta- tetradeutero -N,N -dimethyltryptamine ( D4DMT ) in rat brain in vivo as a function of time and dose was examined. Quantification of D4DMT and its respective deutero-metabolites was accomplished using gas chromatographic/mass spectrometric/selected ion monitoring/isotope dilution techniques. The results of this study indicate that D4DMT is metabolized to the corresponding deutero-N-methyltryptamine, tryptamine, 1,2,3,4-tetrahydro-beta-carboline, and 2-methyl-1, 2,3,4-tetrahydro-beta-carboline in rat brain. The subcellular distribution of D4DMT and the aforementioned metabolites is also reported.

Comparison of the brain levels of N,N-dimethyltryptamine and alpha, alpha, beta, beta-tetradeutero-N-N-dimethyltryptamine following intraperitoneal injection. The in vivo kinetic isotope effect.

A comparison of the brain levels (microgram/g wet weight of tissue) of the hallucinogen N,N-dimethyltryptamine (DMT) and its deuterated analog alpha, alpha, beta, beta-tetradeutero-DMT (D4DMT) as a function of time and dose is reported. It was observed that the presence of deuterium in the alpha- and beta-positions of the ethylamine side-chain led to a potentiation of the level of DMT in brain. Strikingly different dynamics of uptake and clearance were also noted. We propose that these results are due to primary kinetic isotope effect, illustrating the importance of the alpha-position in the metabolism of DMT.

Biphasic effects of 3-quinuclidinyl benzilate on spontaneous motor activity in mice.

Dose-response relationships for onset, duration, and magnitude of 3-quinuclidinyl benzilate (QNB) on spontaneous motor activity (SMA) were studied in mice. QNB was administered SC immediately before 2-h test sessions in dose levels differing by a factor of 0.5 log (range 0.1-10.0 mg/kg). For the total activity session of 2 h, QNB had a biphasic effect on SMA; at a low dose (0.1 mg/kg) it decreased, and at moderate to higher doses (0.3-10.0 mg/kg) it increased SMA in a dose-related fashion. The onset and duration of the significant decreasing or increasing effects were also dose dependent; at the low dose (0.1 mg/kg) it depressed SMA from 5 to 35 min postinjection, at moderate doses (0.3 and 1.0 mg/kg) it enhanced SMA from 5 to 45 min and 5 to 70 min, respectively, postinjection. At the higher doses (3.0 and 10.0 mg/kg) it increased SMA within 5 min and lasted for 100 and 120 min, respectively. The increase in SMA for the dose range from moderate to high doses of QNB (0.3-10.0 mg/kg) was linear with dose. In general, QNB appears to produce a biphasic effect on SMA responding in mice.

Effects of 3-quinuclidinyl benzilate on fixed-ratio responding and open field behavior in the rat.

The effects of 3-quinuclidinyl benzilate (QNB) in the rat were evaluated on a fixed-ratio (FR) schedule of water reinforcement and on open field behavior in a novel environment. QNB had a biphasic effect on FR-20 responding: at a low dose (0.01 mg/kg SC) it increased, and at moderate to higher doses (0.05-1.0 mg/kg SC) it decreased bar pressing in a dose-dependent manner. The effect of QNB on the multiple indices of open field activity showed that at the low dose (0.01 mg/kg SC) it depressed spontaneous motor activity (SMA), while at higher doses (0.5 and 1.0 mg/kg SC) it enhanced SMA: rearing and forelimb flicks were unaffected at low doses and increased at higher doses. In general, QNB appears to produce differential effects on operant responding and open field activity.

The effects of cholinergic agents on morphine-induced circling behavior in the intact mouse.

The effects of morphine on locomotor activity in mice was studied. It was shown that morphine in this species induces circling, a dose-dependent, stereotyped behavior. At high doses of morphine, mice engaged virtually exclusively in circling uninterrupted by other activities. The effect was modified by muscarinic agents. Blockade of muscarinic receptors with atropine potentiated circling while the muscarinic agonist, oxotremorine, attenuated it. The mixed muscarinic/nicotinic cholinergic agonist, physostigmine, had no effect on this behavior.

The schedule dependent effects of 3-quinuclidinyl benzilate on operant behavior in the rat.

The effects of 3-quinuclidinyl benzilate (QNB) on performance maintained by a fixed-ratio 20 (FR-20) or a differential-reinforcement-of-low-rate 20 sec. (DRL-20) schedule for water reinforcement were studied in rats. Graded doses of QNB (range 0.0125-0.2 mg/kg) were administered IP immediately prior to 30 min test sessions. QNB had a biphasic effect on FR responding: at a low dose (0.0125 mg/kg) it increased, while at higher doses (0.05-0.2 mg/kg) it decreased mean response rate in a linear, dose-dependent, manner. QNB had only a monotonic effect on DRL responding; doses of 0.05-0.2 mg/kg increased the mean response rate and decreased reinforcement rate in a dose-related fashion. The ED50's for loss of reinforcement were identical (0.07 mg/kg) for both schedules. The findings indicate that QNB may exert rate dependent effects.

Facilitation of an operant task in the rat following injection of whole brain extract.

It has been shown that the administration of trained donor brain extract to naive rats results in facilitation of performance on the same task. In the present study a group of food deprived rats was trained to press a lever for food on a continuous schedule of reinforcement until they reached criterion. The animals were then sacrificed, their brains excised, homogenized and the small proteins (m.w. less than 3500) extracted. A group of untrained rats was also sacrificed and their brains extracted. Three groups of rats were used as recipients, receiving either trained donor or untrained donor brain extract or saline. The animals were tested individually for one-hour sessions at 18, 42 and 66 hours after the injection. The number of bar presses made by each rat was noted and the group mean plus or minus the standard deviation were calculated for each session. The results of a one-way analysis of variance showed that the group which received trained donor brain extract performed at a higher rate than either control group. These data suggest that some factor, (specific or non-specific), associated with the task has been transferred.

The sedative effects of nicotinamide on gerbil wheel-running activity.

The activity of 5 groups of gerbils was monitored over 22 days. 3 of the groups received daily injections of nicotinamide (125, 250 or 500 mg/kg) and a 4th group received saline. The 5th group was untreated. The results indicated that both the 250 and 500 mg/kg nicotinamide administrations greatly reduced the activity levels of the gerbils.

Family therapists, community, and civic renewal.

In this article, we review family therapy's history regarding community concerns and broader societal issues; offer a model of levels of therapists' involvement with communities and community systems; and propose that family therapists join the citizen activation movement by becoming catalytic partners with families in communities. We call for a new kind of community practice that is driven less by therapist-defined problems and professional expertise, and more by community-defined problems and families' own expertise.