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In superfusion experiments with a crude synaptosomal fraction from the nucleus accumbens of rats, lysergic acid diethylamide, mescaline and N,N-dimethyltryptamine (representing different chemical classes of psychotomimetics) produced a concentration-related inhibition of K+-evoked [3H]dopamine release whereas spontaneous release remained unchanged. The nonpsychotomimetic ergoline lisuride tested at the same concentration range did not modulate spontaneous or K+-evoked [3H]dopamine release. The inhibitory effects of the psychotomimetics tested were antagonized by equal concentrations of haloperidol or methiothepine. It is postulated that the effects of psychotomimetics on DA release were triggered via simultaneous action at presynaptic dopamine and 5-hydroxytryptamine receptors which are located at dopamine nerve endings in the nucleus accumbens.

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.

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.

Microinjections of LSD (0.05 microgram), mescaline (0.5 microgram) and serotonin (10 microgram) into the medial raphe nucleus of rats resulted in a strong potentiation of apomorphine (1 mg/kg i.p.)-induced hypermotility. The potentiating effect of LSD or serotonin was suppressed by simultaneous injections of methysergide (0.05 microgram) or cyproheptadine (0.05 microgram) into the medial raphe nucleus. The same doses of LSD injected into the dorsal raphe nucleus and of LSD and mescaline injected into the nucleus accumbens failed to influence locomotor activity, whereas injections of higher doses of LSD and mescaline into the nucleus accumbens inhibited spontaneous and apomorphine-stimulated locomotor activity. It is concluded that the potentiating effect of systemically administered low doses of hallucinogens was triggered by preferential actions on the serotonergic system in the medial raphe nucleus.

The amine releasing action of mescaline was investigated in rat isolated hypothalamus labeled with 3H-metaraminol. Mescaline had no effect on the uptake of 3H-metaraminol but produced its release in a concentration-related manner. 4 x 10(-4) M mescaline, which produced submaximal effects was used for subsequent experiments. 3 x 10(-5) M cocaine had no effect on the 3H-metaraminol releasing action of mescaline. Mescaline was fully effective in Ca2+-free medium while 6 x 10(-2) M KCl was ineffective. 3 x 10(-7) M tetrodotoxin or 6 x 10(-5) M lidocaine partially blocked mescaline-induced release but substantially or completely blocked 3 x 10(-2) M KCl-induced release. Prior exposure of hypothalamus to 3 x 10(-4) M tyramine reduced the releasing action of mescaline. Thus, mescaline appears to release 3H-metaraminol both by Ca2+-independent (tyramine-like) and Ca2+-dependent (lidocaine-sensitive) mechanisms. 3 x 10(-4) M tyramine and 6 x 10(-2) M KCl released 14C from control hypothalamus labelled with 14C-mescaline, but not from reserpinized hypothalamus. The amounts of 14C recovered in 14C-mescaline labeled control and reserpinized hypothalamus at the end of 50 min of efflux were similar suggesting a poor retention of 14C-mescaline by storage particles.

The characteristic behavioral effects of mescaline in cats were nearly completely blocked by pretreatment with low doses of either a specific serotonin antagonist (methysergide) or a dopamine specific antagonist (haloperidol). These blocking effects were not due to non-specific actions, since methysergide did not block the behavioral effects of apomorphine, and haloperidol did not block the behavioral effects of 5-methoxy-N,N-dimethyltryptamine. Thus, it appears that the behavioral effects of mescaline are dependent upon the simultaneous action of the drug at both serotonin and dopamine receptors.

We compared the effects of the hallucinogens 2,5-dimethoxy-4-methylamphetamine (DOM), mescaline and the simulant D-amphetamine, applied by microiontophoresis to rat dorsal raphe (DR) units. DR neuron firing rate was relatively insensitive to DOM and unaffected by mescaline, but was clearly inhibited by D-amphetamine. Intravenous DOM usually inhibited, but this effect was correlated with blood pressure changes; i.v. D-amphetamine produced inconsistent responses. These results suggest that most of the effects seen on i.v. administration of phenethylamines are not mediated directly on the serotonergic cell.

In order to further evaluate the extent to which particular 5-HT receptor subtypes (5-HT1, 5-HT2) might be involved in the behavioral effects of hallucinogenic drugs, rats were trained to discriminate mescaline (10 mg/kg i.p.) from saline and were given substitution (generalization) and combination (antagonism) tests with putatively selective serotonergic and related neuroactive compounds. The mescaline cue generalized to relatively high doses of the 5-HT2 agonists, 2,5-dimethoxy-4-methylamphetamine (DOM), LSD and psilocybin; the extent of generalization to 5-HT1 agonists (8-hydroxy-2-[diethylamino]tetralin (8-OHDPAT), RU-24969 and 8-hydroxy-2-[di-n-propylamino]tetralin (TFMPP] was unclear. Combinations of the training drug and sufficiently high doses of 5-HT2 antagonists (ketanserin, LY-53857, pirenperone) were followed by saline-lever responding; less selective central 5-HT (metergoline), and DA (SCH-23390, haloperidol) antagonists, did not block the mescaline cue. These data suggest that 5-HT2 receptors are involved in the stimulus properties of mescaline.

Metabolism of 14C-tetrahydrocannabinol (14C-THC) by rat liver microsomal preparations in vitro was studied in the absence and presence of other psychoative drugs. Disappearance of 14C-THC, and changes in metabolite patterns as shown by thin layer chromatography, were studied. SKF 525-A, pentobarbital, phenobarbital and amphetamine all produced an apparently non-competitive inhibition of THC metabolism. The inhibition produced by meprobamate was at least partly competitive. Morphine and mescaline had no evident effect. SKF 525-A and the barbiturates markedly decreased the concentrations of all the major THC metabolites found in the incubation media. In contrast, none of the drugs tested in vivo, with the exception of SKF 525-A, had any effect on the biliary 14C-excretion or metabolite pattern, or on final tissue levels of 14C, when administered in doses comparable to those used for studies of interaction with THC in vivo. SKF 525-A, however, did markedly decrease the excretion of total 14C and alter the pattern of THC metabolities in the bile, and increased the final tissue 14C levels. It is concluded that in vivo interactions between THC and other psychoactive drugs are probably not explainable primarily on the basis of altered THC metabolism.