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Tolerance and cross tolerance to the antinociceptive effect of equipotent doses of morphine (10 mug/kg) and mescaline (100 mug/kg) are shown in the rabbit after their repeated intracerebroventricular administration. The recording of the electrical activity of different brain areas indicates that a partial tolerance also develops to the EEG effects in animals undergoing chronic treatment with mescaline. The comparison of certain of the mescaline-induced effects with those of morphine suggests that some biochemical and neural patterns are common to the 2 drugs.

The action of mescaline on mice innate behaviour was studied. In the first experiment the drug modified the innate behaviour of mice. The dose-effect curve was obtained by the second. The results pointed out that, in the range of doses examined, there was one for which the disruptive action of mescaline reach the maximum so that mice behaviour became completely casual.

Mescaline, in concentrations of 5 x 10(-4) and 1 x 10(-3) M, produced negative chronotropic and positive inotropic responses in isolated, spontaneously beating rat atria. In tissues driven at a constant rate, the inotropic response was diminished greatly, indicating that the increment in the force of contraction was secondary to the reduction in rate. These chronotropic and inotropic responses were not altered consistently by pretreatment with the histamine antagonists chlorpheniramine and metiamide.

Pigeons (N=4) were trained to discriminate between the effects induced by intramuscular (IM) injections of d-LSD and saline using a discrete-trial discrimination paradigm (choice between left and right hand key) in a conventional operant box. The solutions were administered IM 15 min prior to the sessions. A FR 15 schedule was in operation to produce food. Which of the two keys was correct on a given training session depended upon whether LSD or saline had been given. Three of the birds were trained and maintained with a dose of 40 microgram/kg of LSD and the fourth pigeon finally was maintained on 50 microgram/kg of LSD. The dose resulting in 50% LSD appropriate responding (ED50) was 18 microgram/kg and the median time-interval for the decay of the LSD stimulus (40 microgram/kg) was 84 min. Tests with psilocybin (ED50=0.55 mg/kg) and N,N-dimethyltryptamine (ED50=5.7 mg/kg) resulted in responding appropriate for the LSD training condition. Mescaline injections above 10 mg/kg severely suppressed responding. The few responses emitted after tests with 15 and 20 mg/kg of mescaline were directed to the LSD associated key. Tests with BOL (0.1 to 3 mg/kg) as well as three other psychotropic drugs (delta 9-tetrahydrocannabinol, morphine and, pentobarbital) did not result in responding above 50%) LSD appropriate responses. As a possible antidote, methergoline, a pubetative antagonist of post-synaptic serotonin receptor sites, was administered 75 min prior to testing the cueing properties of LSD. No definitive role for a blocking effect of the LSD-cue is provided by the present data.

Mice were injected ip with either saline, l-methadone (2.5, 5, 20 mg/kg), perphenazine (1, 10, 15 mg/kg), or chlorprothixene (1.25, 2.5, 15 mg/kg) 30 min prior to mescaline-14C (25 mg/kg). Mescaline-induced behavioral changes such as agitation, excitement, slight increase in ventilation, and fright to sound stimuli were prevented by all doses of three drugs, and head-shaking, scratching, and locomotor-increasing effects by 5 and 20 mg/kg methadone and by all doses of both neuroleptics. Catalepticlike state and moderate to marked hypothermia induced by all doses of chlorprothixene, 10 and 15 mg/kg perphenazine, and 20 mg/kg methadone were not reversed by mescaline. Chlorprothixene (all doses), perphenazine (10, 15 mg/kg), and methadone (5, 20 mg/kg) caused marked retention of mescaline and its deaminated metabolite, 3, 4, 5-trimethoxyphenyl acetic acid in both brain and plasma. The fact that relatively higher doses of methadone than neuroleptics are needed to ensure effective antagonism to mescaline action tends to indicate a less specific interaction of the opiate with the neuroleptic/dopamine receptor proposed for central mescaline effects.

The sensitivity of some electrocortical potentials of rats to topically applied tetrodotoxin (TTX), manganese, lanthanum, calcium, mescaline and strychnine was followed from the age of 6 to 20 days and compared with that of adult animals. Sensitivity to TTX was relatively greater in the younger rats. In contrast, the blocking effect of Mn2+ or La3+ was small initially but increased with age. Similarly, the ability of mescaline or strychnine to give rise to giant spikes (dendritic action potentials) increased with maturation of the brain cortex. Finally, an increase in external calcium concentration depressed cortical potentials in the younger animals and had the usual increase of the mescaline or strychnine spikes in the older rats. It is concluded that the formation of calcium channels in dendritic membranes is part of the maturation process of cortical neurons and possibly related to the learning mechanisms. The depressant action of high external calcium during the first days of life was ascribed to an unspecific reduction in membrane permeability.

This experiment is related to the hypothesis of Bridger and of Wray that hallucinogens have facilitatory effects on animal behavior when stress is part of the experiment and have disruptive effects otherwise. Male Long-Evans rats were trained to high (above 89%), stable base line rates of shuttlebox avoidance, then given each of four treatments at 6-day intervals after returning to base line avoidance rates: 1. saline (1 ml i.p.), 2. saline+stressor, 3. mescaline hydrochloride (36.6 mg/kg i.p.), 4. mescaline (39.6 mg/kg i.p.)+stressor. Stress treatment was 1.0 mA footshock (1 sec duration) every 20-30 sec for 15 min between injection and session. Sessions (100 trials) began 20 min after injection. Treatments 1 and 2 had no effect on avoidance rate. Treatments 3 and 4 significantly decreased avoidance rate, with the latter causing significantly more decrease than the former. None of the treatments affected presession (5 min adaptation period) or intertrial crossings of the shuttlebox or latency on escape trials. These results suggest that exposure to a stressor, per se, is not the crucial factor causing hallucinogens to have facilitatory effects on animal behavior.

Acute parachlorophenylalanine (pCPA) pretreatment (150 mg/kg, i.p., 24 h beforehand) potentiated facilitatory effects of mescaline (39.6 mg/kg i.p.) on shuttlebox escape/avoidance in hooded rats, tested in two different situations: 1. during aquisition of avoidance behavior (Experiment 1); and 2. in stable pretrained poor avoiders (Experiment 2). pCPA alone did not influence avoidance behavior in either situation. Mescaline, with pCPA pretreatment, may be associated with long-term behavioral effects; all rats treated with this combination were later found to be poor avoiders, unable to achieve a stable baseline of good avoidance. pCPA significantly depleted brain norepinephrine and dopamine, as well as serotonin, measured after testing in the second situation.

Phencyclidine (PCP), lysergic acid diethylamide (LSD), and mescaline produced potent contractile responses on isolated basilar and middle cerebral arteries, where, in terms of potency, LSD greater than mescaline greater than PCP. All three drugs produced cerebrovasospasm in a concentration range which parallels that needed for their psychotomimetic and intoxicating actions. Specific receptors for PCP, which subserve contraction and differ from those for LSD and mescaline, are found in cerebral arteries. Concentrations of PCP that produced near-maximum contractile responses on cerebral arteries were similar to those in the blood and brain of human subjects who had died from PCP overdoses. A specific calcium antagonist, verapamil, readily prevented (and reversed) PCP-induced vasospasm. This study provides direct evidence for PCP receptors in cerebral blood vessels, the biologic action of which can be reversed by a calcium antagonist; the clinical use of the latter could prove invaluable in treating PCP-intoxicated victims.

The ability of serotonin2 (5-HT2) antagonists to block the excitatory effects of mescaline on the acoustic startle reflex were analyzed. Mescaline (20 mg/kg) caused a consistent increase in the amplitude of the acoustic startle reflex. This effect was blocked in a dose-related fashion by the 5-HT2 antagonist ritanserin (ED50 dose = 0.25 mg/kg IP). In contrast, even a high dose of ritanserin (2.0 mg/kg) did not block the excitatory effects of amphetamine on startle. Other 5-HT2 antagonists (ketanserin, cinanserin, LY 53857) also blocked mescaline's effect, whereas the 5-HT1 antagonist pindolol (5 mg/kg) did not. These results support the hypothesis that the behavioral effects of hallucinogens are mediated by agonist actions at 5-HT2 receptors.

The nature of the substituents and their contribution at different ring positions to the overall hallucinogenic activity in a series of phenylalkylamines (amphetamines) are studied by using Fujita-Ban additive model. The calculated activity contributions of substituents and of parent structure, respectively, are then utilized to predict the most potent compound in the series and to remove the uncertainties in the observed activity of some phenylalkylamines. The most potent compound predicted is 2,6-dimethoxy-4-bromophenylisopropylamine.

The characteristics of the behavioral effects of 2,5-dimethoxy-4-methylamphetamine (DOM or STP) were compared with those of mescaline and methamphetamine in rats and mice. DOM significantly increased locomotor activity in an open-field situation at 0.5-1.0 mg/kg i.p., but at doses above 5 mg/kg i.p. caused biphasic changes, i.e. an initial decrease followed by an increase in motility and exploratory behavior. This hyperactivity was not accompanied by simultaneous increase in rearing. Besides, DOM induced head twitches in rats as well as in mice at doses above 0.1 mg/kg i.p., and marked backward locomotion only in rats at doses larger than 5 mg/kg i.p. The occurrence of backward locomotion might be attributable to the initial decrease in general activity. Behavioral effects of DOM were different from those of either mescaline or methamphetamine although they resembled those of mescaline in some respects.

Motor impairment, especially ataxia, is often mentioned as a 'side effect' of doses of psychoactive drugs which depress animal behaviour; it is difficult to determine it accurately from visual observation, but relatively few attempts have been made to measure it objectively and quantitatively. Mescaline, in moderate to large doses, can induce biphasic--depressant followed by stimulant--effects on learnt and other performance of laboratory rodents. Motor impairment, using three doses, was accordingly measured during the depressant phase by two methods. An 'ataxia' test, involving analyses of footprints, showed few irregularities of gait splay due to mescaline, but the drug markedly reduced the length of steps ('stride') in a dose-related manner. In a 'tilt plane' test for general motor control, the animals' ability to cling to a tilted plane decreased with 25 mg/kg mescaline, at 30 and 40 minutes after administration. Deficits of this kind can be relevant to interpreting drug actions on forms of behaviour which involve movements for responding, and they also have interesting potential in their own right.

A group of six rats was trained to discriminate the effects of para-methoxyamphetamine (PMA; 3 mg/kg, 15 min pretreatment time) and saline in a two-lever choice task using a fixed ratio 10 schedule of water reinforcement. Stimulus control was assumed to be present when 80% or more of the first ten responses were appropriate for the treatment condition on each of five consecutive days. PMA established stimulus control in each of the subjects. The mean number of sessions prior to the onset of criterion performance was 19 (SE = 2, range = 14-24). A second group of ten rats was similarly trained with lysergic acid diethylamide (LSD; 0.1 mg/kg, 15 min pretreatment time) and saline. In rats trained with PMA, LSD yielded intermediate results, i.e., significantly different from both training conditions. Likewise, the response distribution was intermediate in nature when LSD-trained subjects were tested with PMA. Pizotyline did not antagonize PMA-induced stimulus control in rats trained with PMA and saline but did antagonize the intermediate responding produced by PMA in LSD-trained subjects. It is concluded that PMA-induced stimulus control does not depend upon activation of serotonergic receptors but that PMA does possess some LSD-like effects which are mediated serotonergically.

The modifications of behavior caused in the rat by a chronic oral administration of mescaline have been studied in three experimental situations. In the staircase maze mescaline accelerated the spontaneous decay on the conditioned reflex (memory decay) during the period without daily training. Only the results observed at 30 mg/kg/day of mescaline were statistically significant. In a T maze two lateral alleys closed by two swinging doors, 30 mg/kg/day of mescaline increased the time spent in opening the first door. When the two doors of the lateral alleys were closed with a latch, mescaline 30 mg/kg/day, caused an increase in the time spent by the rat in opening the doors. Mescaline caused an increase in food consumption. The increase at 30 mg/kg/day is statistically significant.

Tactile startle responding by male Sprague-Dawley rats given 60 presentations of air-puff stimuli (37.5 psi) was measured after the intraperitoneal administration of graded doses of hallucinogens and other psychoactive drugs. Among the drugs tested were the indoleamine-derived compounds, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine and psilocin, and the phenylethylamine-derived compounds, mescaline, 2,5-dimethoxy-4-methylamphetamine and a series of active and inactive congeners of 2,5-dimethoxy-4-methylamphetamine. All of the active phenylethylamines increased startle response magnitudes throughout the test session. This pattern of augmented startle suggests that these drugs increase reactivity. However, none of the indoleamine hallucinogens increased startle responding. Of the nonhallucinogenic drugs tested, only apomorphine increased startle responding, while clonidine significantly decreased it, and amphetamine, chlorimipramine, scopolamine and methysergide had no effect. In additional studies with LSD, it was found that LSD increased the response to only the first stimulus when more intense air-puffs were used (50 psi). Furthermore, when the number of stimuli was increased from 60 to 240 (1 hr) so that appreciable habituation was evident in controls, LSD impaired this habituation. Whereas the response magnitudes of the control group decreased by 70% across the session, the responses of LSD-treated rats decreased by only 32%. These results suggest that LSD and phenylethylamine-derived hallucinogens may differ in their effects on tactile startle responding.

One member of a pair of rats was administered either mescaline, lysergic acid diethylamide (LSD), pentobarbital, or ethanol intraperitoneally twenty minutes prior to exposure to footshock in the presence of an undrugged opponent. At high doses, all drugs elicited biting from the undrugged rat of sufficient intensity to produce injury to its drugged opponent. Low doses produced species-typical fighting behavior which consisted of striking each other with their forepaws while upright and failed to elicit biting. Biting attacks by the undrugged rat were highly correlated with ataxic behavior by the drugged rat. Conversely, species-typical aggressive behavior was highly correlated with behaviors such as boxing or upright threat posture. These results suggest that drug-induced ataxic behavior may disinhibit mechanisms that regulate intra-species behavior, thus producing behavior that is more typical of inter-species aggression.

Head-twitch induced by lysergic acid diethylamide, mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM) was significantly increased by medial raphe (m-R) lesions, but dorsal raphe (d-R) lesions did not produce any changes. Hallucinogen-induced head twitch was inhibited by methysergide and tended to be increased by PCPA. These results suggest that 5-HT receptors innervated with the ascending 5-HT pathway originating in the m-R play a vital role in the manifestation of hallucinogen-induced head-twitch. That is, increase of head-twitch is ascribed to supersensitivity of 5-HT receptors. On the other hand, DOM-induced backward locomotion was inhibited by m-R or both dorsal and medial raphe lesions and methysergide, and was reversed to forward locomotion, differently from the hallucinogen-induced head-twitch. A reversion of backward locomotion was not obtained with d-R lesions or PCPA treatment.

Male hooded rats were observed for 6 days following implantation with slow-release subcutaneous pellets containing LSD, mescaline, or control vehicle solution. In animals housed in isolation cages, continuous hallucinogen administration resulted in a gradual increase in head twitches and catatonic postures which peaked 3--4 days after pellet implantation and then declined. In animals housed in social colonies, there were also delayed increases in behavior following hallucinogen-pellet implantation, but these principally involved social behaviors such as fighting by mescaline-treated animals and social grooming by LSD-treated animals. This finding of gradual and cumulative effects of continuous hallucinogen administration contrasts with the usual finding of a rapid tolerance to hallucinogens following repeated injections.

Four members of a new class of psychotomimetic agents have been synthesized and evaluated in man. These compounds, which incorporate a beta-methoxy group onto a beta-phenethylamine sidechain, are the first reported psychotomimetics which are structural analogues of the neurotransmitter noradrenaline. These substances are more potent than the corresponding phenethylamines (lacking a beta-methoxy group) but less potent than the correspondingly substituted amphetamine derivatives.

The present investigation sought to determine whether drugs which produce markedly different perceptual effects in man, barbital and mescaline or LSD produce different stimuli in rats. In a standard 2 lever operant test chamber, rats received sweetened milk for correct responses according to a variable interval schedule. All sessions were preceded by 1 of 2 treatments; following Treatment A, only responses on Lever A were reinforced and, in a similar fashion, Lever B was correct following Treatment B. No responses were reinforced during the first 5 min of a daily 30 min session. It was found that barbital can serve as a discriminative stimulus when this drug is paired with saline. Previously, we had demonstrated that mescaline or LSD can serve as discriminative stimuli. When barbital was administered to animals trained to discriminate mescaline or LSD and saline, they made either random responses or responses appropriate to saline treatment. This observation suggests that the stimulus properties of barbital are difference from those of the hallucinogens. A subsequent demonstration of discriminated responding when barbital and mescaline or LSD were paired as discriminative stimuli supports this conclusion. The present results extend previous findings which suggest that the degree of similarity or difference of drug stimuli in rats is congruent with the degree of similarity or difference of perceptual drug effects in man.

The effects on a fixed ratio-40 (FR-40) operant behavior of intracerebroventricular (ICV) administration of the hallucinogens lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM), mescaline or the non-hallucinogenic LSD-analogue lisuride were compared with intraperitoneal (IP) administration. Infusion of LSD (8.5 to 34 micrograms) into the left lateral ventricle produced a dose-dependent decrease in reinforcers and an increase in 10-sec periods of non-responding (pause intervals). The time-course of LSD showed a shorter latency to onset after ICV than IP administration. The ED50 for doses increasing pause intervals by ICV administration was 15 micrograms. This disruption was greater than that produced by IP administration of equivalent doses of LSD (IP ED50: 19 micrograms). DOM (40 to 120 micrograms) infused into the lateral ventricle also produced a dose-dependent disruption of FR-40 behavior. ICV DOM also showed a rapid onset to peak effects, but a slower offset than LSD, and was 3 times more potent than systemic administration (ED50s: 58 micrograms ICV vs. 153 micrograms IP). Mescaline was much more potent in disrupting FR-40 behavior by the ICV route than by IP administration. The ICV ED50 for doses of mescaline increasing pause intervals was 74 micrograms, in contrast to an ED50 following systemic administration of 2251 micrograms, demonstrating a 30-fold difference in potency. Lisuride administered via the ICV route was no more potent than by IP administration with ED50s of 4 micrograms ICV and 4 micrograms IP. Lower doses of lisuride administered by both routes had a similar effect over time on pause intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasopressin and related peptides cause behavioral excitation after intracerebroventricular injection in mice. This behavioral excitation is characterized by excessive scratching and grooming behavior in the unrestrained animal and enhanced escape-directed activity in stressful situations. These effects of vasopressin were found to be blocked by the administration of analogs which act as competitive antagonists of the pressor-activity of vasopressin. The potencies of these analogs in suppressing the behavioral effect paralleled the pressor antagonist potencies. The antagonists did not cause the characteristic behavioral alterations by themselves, nor did they block grooming and/or scratching behavior induced by the structurally-unrelated substances, mescaline, bombesin and substance P. It is suggested that these antagonists provide useful tools for studying the role of endogenous vasopressin in behavior.

The midpontine decerebrate dog, immobilized with gallamine, was used to determine the changes in the transcallosally evoked potential (TEP) produced by intravenous infusions of various drugs. A total of 50 TEPs, recorded from the g. ectolateralis, was computer analyzed before, during and after administration of the drugs. Changes in the TEP were also correlated with changes in the EEG recorded from the g. ectolateralis. The EEG was analyzed by inspection and amplitude integration (electrogenesis). LSD (30 microng/kg) significantly depressed the TEP, and the effect persisted for at least 80 min. DMT (1 mg/kg) caused a significant and reversible increase in the amplitude of the TEP. LSD and DMT reduced the alpha activity of the EEG and enhanced the amplitude of the low-frequency waves. DMT produced a significant and LSD a marginal increase in electrogenesis. Tryptamine (10 and 20 mg/kg), mescaline (6 mg/kg), methoxamine (0.88 mg/kg) and apomorphine (5 mg/kg) had no significant effect on the TEP or EEG. These results suggest that depression of the TEP is not related to spinal reflex facilitation in the dog or hallucinogenic activity in man.

In experiments on mice (put in triads and tetrads) stable domination-subordination relations (DS) of predominantly despotic type were formed. The experiments were staged in specially designed communicating populational cages. Pharmacological evidence of inertness of DS relations in small groups of mice is presented. Critical factors of DS inertness are examined. It is shown that psychotropic drugs of different classes have difficult effect on the maintainance of DS inertness. Prolonged administration of psychotropic drugs suppressing the dominant's aggression may result in DS inversion.

The effect of zotepine, a new neuroleptic, on head-twitch induced by L-5-hydroxytryptophan (L-5HTP), mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM) in mice and rats was compared with that of known neuroleptics and the serotonin receptor blocker cyproheptadine. Among the neuroleptics tested, zotepine and haloperidol produced potent inhibitory effects on head-twitch induced by these three drugs. The results indicate that zotepine has a potent anti-hallucinogenic effect.

Rats were tested on a two-way avoidance acquisition with or without inescapable shock given 24 h prior to training. Mescaline given to nonshock rats disrupted acquisition in a dose-dependent fashion and tolerance developed to this disruption. Mescaline given to shock rats had no effect on acquisition even though levels of acquisition were the same for both shock and nonshock rats without drug. Moreover, subchronic treatment (5 days facilitated acquisition. These experiments demonstrate an interaction between shock, which presumably is a stressor, and mescaline. The data are consistent with the observation that when animals are exposed to presumptive stressors (e.g., shock, handling) hallucinogens can facilitate behavior, while in other situations, hallucinogens disrupt behavior.

1 Mice in small groups develop a despotic type of social hierarchy, a feature of which is to resist alteration through the medium of psychotropic drugs. This makes a rapid pharmacologically induced change in the social hierarchy impossible. 2 Patrolling the territory and a certain level of social interaction are both critical factors in maintaining the phenomenon of inertia in the social hierarchy. Psychotropic drugs (diazepam, droperidol and mescaline) altered both these factors to a varying degree and also displayed a differing ability to maintain the inertia of the social hierarchy. 3 A drug-induced alteration in the level of aggression in a subordinate mouse in a group of three does not cause an alteration in its social position. 4 Chronic administration of diazepam, droperidol or mescaline, all of which alter the level of aggression in different ways, can result in an inversion of the social hierarchy where a competitive rival is present in the group of mice. The rate of inversion of the social hierarchy depends on the type of pre-existing social hierarchy. 5 It is suggested that the ability of psychotropic drugs to maintain the inertia of the hierarchy be used as an index of their effect upon certain types of species-specific behaviour; in particular aggression.

Rats were trained to discriminate intraperitoneally administered mescaline from saline in a two-lever operant chamber for food reinforcement. Reward was contingent upon responses made greater than 15 sec apart (DRL-15) on the appropriate lever paired with either drug or saline administration. Following the establishment of discriminative response control by mescaline, the animals were tested for stimulus generalization produced by mescaline after: (a) blockade of periphreral and central serotonin (5-HT) receptors with cinanserin, methysergide, or cyproheptadine; (b) blockade of peripheral 5-HT receptors with xylamidine tosylate; and (c) depletion of brain 5-HT with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA). The results show that all three central 5-HT antagonists greatly reduced the discriminability of mescaline while the peripheral antagonist, xylamidine tosylate, was without effect. Furthermore, these agents at the doses employed did not effect the discriminability of saline. Depletion of 5-HT with PCPA potentiated the effects of a sub-threshold dose of mescaline and slightly reduced the discriminability of saline. The results indicate that mescaline produces its discriminative stimulus properties by directly stimulating central serotonergic receptors.

Using a food-reinforced two-lever operant method, rats (n = 9) were trained to discriminate 0.16 mg/kg LSD from saline. Tests for stimulus generalization in rats so trained indicated that the purported 5-HT antagonists cyproheptadine (1.25 and 10 mg/kg), methysergide (0.16 to 10 mg/kg) and mianserin (2.5 to 40 mg/kg) produced partial generalization with LSD. The hallucinogens mescaline (5 to 40 mg/kg) and quipazine (1.25 to 5 mg/kg) were also generalized with LSD. The data suggest that cyproheptadine, methysergide and mianserin may produce partial agonist effects in addition to their antagonist action at central 5-HT receptor sites.