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At least 19 recordsLinked to original sources
PubMed1984

Electroconvulsive shock treatments enhance responsiveness of forebrain neurons to serotonin.

Electroconvulsive therapy remains one of the most effective treatments of major depression. The effect of electroconvulsive shocks (ECSs) on the responsiveness of hippocampal pyramidal neurons to serotonin, norepinephrine, gamma-aminobutyric acid and 5-methoxydimethyltryptamine was studied in rats pretreated with one or six ECSs. Control rats were given subconvulsive shocks. Microiontophoretic experiments were conducted 36 hr after the last shock in urethane-anesthetized or low cerveau isolé preparations. Responsiveness of hippocampal pyramidal neurons to microiontophoretic applications of serotonin was markedly enhanced in rats pretreated with six ECSs. Responsiveness to 5-methoxydimethyltryptamine, a postsynaptic agonist which is not an adequate substrate for the high-affinity serotonin reuptake process, was also enhanced in rats pretreated with six ECSs, indicating that the increased responsiveness to serotonin was due to a postsynaptic modification. The effects of norepinephrine and of gamma-aminobutyric acid applied on the same neurons were not modified by repeated ECS pretreatment. A single ECS failed to modify responsiveness to either serotonin or 5-methoxydimethyltryptamine. Inasmuch as long-term tricyclic antidepressant drug administration has been shown to produce a similar sensitization to serotonin, the present results suggest that enhancement of serotonergic neurotransmission might mediate the therapeutic effect of both types of treatment in major depression.

Animals↗
PubMed1983

Serotonergic-catecholaminergic interactions and foot shock-induced jumping behavior in rats.

The role of serotonergic neurons in foot shock-induced jumping behavior was evaluated by studying the effects of serotonin agonists and depletors under conditions of increasing activity of catecholaminergic neurons by combining different shock intensities with methamphetamine or clonidine pretreatment. Low shock (40 V) jumping was suppressed by three different kinds of serotonergic agonists: 5-hydroxytryptophan (50 and 100 mg/kg), 5-methoxydimethyltryptamine (1 and 5 mg/kg) and clomipramine (5 mg/kg) but these drugs did not suppress high shock (60 V) jumping. A depletor of brain serotonin, p-chlorophenylalanine (200 mg/kg), failed to affect the jumping induced by both shock intensities. The inhibitory effect of serotonergic agonists on low shock jumping was abolished by pretreatment with methamphetamine (1 mg/kg) or clonidine (100 micrograms/kg). Furthermore, 5-methoxydimethyltryptamine (5 mg/kg), a serotonergic postsynaptic receptor stimulant, potentiated high shock jumping in rats pretreated with methamphetamine (3 and 5 mg/kg). The results indicated that activation of serotonergic neurons has a differential effect on jumping behavior ranging from inhibitory to facilitatory, depending upon the increasing activity of catecholaminergic neurons.

Animals↗
PubMed1982

Involvement of serotonin in the central regulation of blood pressure: evidence for a facilitating effect on sympathetic nerve activity.

The effects of serotonin (5-HT) receptor agonists and antagonists on sympathetic nervous discharge (SND) recorded from the external carotid and splanchnic nerves were studied in baroreceptor-denervated cats. Intravenous administration of the 5-HT antagonists methysergide (0.025-1.6 mg/kg), metergoline (0.01-0.32 mg/kg), cyproheptadine (0.05-1.6 mg/kg) and cinanserin (0.2-6.4 mg/Kg) was associated with a prolonged dose-related inhibition of SND. Maximum reductions in SND produced by methysergide, metergoline, cyproheptadine and cinanserin were 90, 72, 71 and 50%, respectively. In contrast, a progressive increase in SND was observed in vehicle control animals. Methysergide, metergoline and cyproheptadine failed to reduce SND in cats pretreated with the 5-HT synthesis inhibitor p-chlorophenylalanine. Clonidine (20 micrograms/kg i.v.) significantly inhibited SND (-73%) in p-chlorophenylalanine-treated cats. The selective 5-HT agonists 5-methoxydimethyltryptamine and lisuride also reduced SND in a dose-dependent manner. The time course of the depressor effects of 5-methoxydimethyltryptamine and lisuride correlate well to their ability to inhibit 5-HT cell firing. These data indicate that 5-HT agonists which act presynaptically to inhibit 5-HT cell firing and antagonists which act postsynaptically to block the effect of synaptically released 5-HT both mediate a central reduction in SND. It is concluded that central 5-HT neurons facilitate transmission in central sympathetic pathways.

Animals↗
PubMed1987

Differential effects of substance P on serotonin-modulated spinal nociceptive reflexes.

Recent immunohistochemical studies indicate the presence of a bulbospinal substance P (SP) system, as well as a bulbospinal serotonin (5-HT) system, involved in spinal pain transmission. Although electrophysiological studies indicate that SP may modulate the effects of 5-HT on postsynaptic spinal nociceptive neurons, the functional relationship between SP and 5-HT on "pain behavior" remains obscure. To bridge this gap between mechanism and behavior, the purpose of the present study was to determine specific postsynaptic behavioral effects of SP and 5-HT on local spinal nociceptive reflexes in spinally transected animals. Administration of the 5-HT agonists 5-methoxydimethyltryptamine (5-MeODMT) (0, 0.5, 1.5, 2.0 mg/kg) and quipazine (0, 5, 10, 20 mg/kg) 2 days after transection significantly expanded the receptive field (RF) areas of three spinal reflexes, as previously reported. Intrathecal administration of SP alone (0, 0.25, 2.5, 7.5 ng) also resulted in hyperalgesia, indicated by a significant expansion of the RF areas of all three nociceptive reflexes. However, administration of SP, in animals pretreated with 5-HT agonists, decreased the 5-HT-induced expansion of RF size. Therefore, SP had opposite effects on spinal nociceptive reflexes depending on whether or not the animal was pretreated with 5-HT agonists, i.e., hyperalgesia in the absence of 5-HT agonists, and analgesia in the presence of 5-HT agonists. The two effects of SP on local spinal reflexes may be related to the anatomical organization of the two spinal SP systems: 1) SP released from primary afferents facilitates nociceptive reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Monoamine oxidase inhibitor poisoning resulting from Internet misinformation on illicit substances.

The Internet may represent a new mechanism by which adolescents initiate the use of illicit substances. The existence of multiple partisan websites providing misinformation regarding the safety of these substances may lead to an increase in unsafe behavior among this age group. Adverse outcomes related to Internet-based drug information are rarely identified. We report a case of an adolescent whose use of the Internet to obtain drug information led to severe poisoning from the combination of a monoamine oxidase inhibitor, harmaline, and a hallucinogenic tryptamine, 5-methoxydimethyltryptamine (5-MeO-DMT).

Adolescent↗
PubMed1992

Pharmacological characterization of lower esophageal sphincter relaxation induced by swallowing, vagal efferent nerve stimulation, and esophageal distention.

To characterize the neural pathways involved in lower esophageal sphincter relaxation, intraluminal pressures from the lower esophageal sphincter of the opossum were monitored during swallowing, vagal efferent nerve stimulation, and intraluminal balloon distention in the presence and absence of pharmacologic antagonism of putative neurotransmitters. The combination of atropine, hexamethonium, and 5-methoxydimethyltryptamine, which is known to block ganglionic transmission in the vagal inhibitory pathway to the lower esophageal sphincter, significantly antagonized LES relaxation induced by both swallowing and vagal stimulation, but did not affect the LES relaxation induced by balloon distention. Administration of the nitric oxide synthase inhibitor N omega nitro-L-arginine methyl ester, on the other hand, markedly inhibited LES relaxation induced by vagal stimulation, swallowing, and balloon distention, and this effect was reversed by administration of the nitric oxide synthase substrate L-arginine. These studies indicate that the distension-induced intramural pathway mediating LES relaxation does not involve ganglionic transmission similar to that of the vagal inhibitory pathway to the LES. However, the LES relaxation induced by all forms of stimuli appears to depend on nitric oxide as a final mediator.

Animals↗
PubMed1992

5-Hydroxytryptamine 1a receptor agonists block prepulse inhibition of acoustic startle reflex.

Presentation of a nonstartling stimulus (prepulse) 100 msec before a startle-eliciting auditory stimulus (pulse) reduces startle reflex amplitude in mammals. Prepulse inhibition of acoustic startle reflex is smaller in schizophrenics than in nonschizophrenics, a phenomenon that has been hypothesized to reflect sensorimotor gating deficits underlying schizophrenic psychosis. Five 5-hydroxytryptamine1a (5-HT1a, serotonin) receptor agonists: 8-hydroxy-2-(di-n-propylamino) tetraline (8-OHDPAT), 5-methoxydimethyltryptamine, buspirone, gepirone and ipsapirone, were tested for effects on prepulse inhibition and startle reflex amplitude in rats. All five agents reduced prepulse inhibition at doses that had no effect on startle reflex amplitude or motor activity. Reduction of prepulse inhibition by 8-OHDPAT was antagonized by (-)propranolol, a 5-HT1a receptor antagonist, and partially by haloperidol, a dopamine D2 receptor antagonist, but not by ketanserin or methysergide, 5-HT2 receptor antagonists. 8-OHDPAT did not reduce prepulse inhibition in subjects pretreated with reserpine or tetrabenazine to deplete neuronal amines, but interpretation of this result is complicated because reserpine and tetrabenazine given alone reduced prepulse inhibition. The results indicate that 5-HT1a receptor agonists block prepulse inhibition of acoustic startle reflex, possibly via dopaminergic mechanisms.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Central action of ipsapirone, a new anxiolytic drug, on serotoninergic, noradrenergic and dopaminergic functions.

Ipsapirone (TVX Q 7821, 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-1,2-benzisothiazol-3- (2H)one-1, 1-dioxidehydrochloride), a new anxiolytic drug in respect of the evaluation of its effect on central 5-hydroxytryptamine (5-HT), noradrenaline and dopamine functions was studied. It was found that ipsapirone inhibits induced by 8-OH-DPAT and 5-methoxydimethyltryptamine (agonists of 5-HT1A receptors) behavioural effects (flat body posture and forepaw treading) in normal and reserpinized rats. Ipsapirone partly inhibited in rats but not in mice the 8-OH-DPAT-induced hypothermia. Ipsapirone, administered at high doses, decreased the body temperature in rats and mice, inhibited the 5-hydroxytryptophan-induced head twitches in mice and the tryptamine-induced convulsions and tremor in rats. In the hind limb flexor reflex preparation of the spinal rat only high doses of the drug inhibited stimulation induced by quipazine, m-chlorphenylpiperazine, 8-OH-DPAT and St 587 (an agonist of alpha 1-adrenoceptors). Ipsapirone did not block the fenfluramine- and m-chlorphenylpiperazine-induced hyperthermia in rats at an ambient temperature of 28 degrees C. The drug did not affect clonidine-induced sedation and inconsiderably attenuated clonidine-induced hypothermia in mice. It attenuated the d-amphetamine-induced locomotor hyperactivity in mice and rats but, given alone, decreased the locomotor activity. The obtained results indicate that ipsapirone exhibits 5-HT1A antagonistic effect, and only at high doses it can also produce an inhibitory effect on 5-HT2 and the alpha 1-adrenergic function.

Animals↗
PubMed1979

On the action of nicotine and cotinine on central 5-hydroxytryptamine neurons.

The actions of nicotine, and its main metabolite cotinine, on 5-hydroxytryptamine (5-HT) neurons in the brain of the rat have been assessed biochemically (on turnover, uptake, release, overflow and binding of 5-HT in brain) and functionally (on extensor reflex activity, which is 5-HT dependent). Nicotine and cotinine in repeated doses of 2 mg/kg caused a reduction of brain 5-HT turnover, which was not blocked by pretreatment with mecamylamine, and nicotine sifnificantly inhibited the effects of norfenfluramine and 5-methoxydimethyltryptamine on extensor reflex activity, effects counteracted by mecamylamine. In low concentrations cotinine weakly inhibits the uptake and retention of 5-HT and also increases its spontaneous release in vitro. The biochemical findings suggest that the reduction of 5-HT and also increases its spontaneous release in vitro. The biochemical findings suggest that the reduction of 5-HT turnover caused by high doses of nicotine are mediated, at least in part, by its main metabolite cotinine. The experiments on extensor reflexes indicate that nicotine can block the functional expression of 5-HT receptor activity in the spinal cord by an action beyond the 5-HT receptor at nicotine-like cholinergic receptors whose location is also discussed.

Amides↗
PubMed1982

Neurophysiological effects of hallucinogens on serotonergic neuronal systems.

Low intravenous doses of the hallucinogen d-lysergic acid diethylamide (LSD) markedly suppress the discharge of serotonin (5-HT)-containing neurons in the dorsal raphe nucleus of the rat. Microiontophoretically applied LSD also inhibits the firing of 5-HT neurons, indicating that the inhibitory effect is mediated directing on 5-HT neurons. Forebrain neurons receiving a major serotonergic input are relatively insensitive to LSD. Other indole hallucinogens (i.e., psilocin, dimethyltryptamine, and 5-methoxydimethyltryptamine) also preferentially inhibit raphe firing as compared to postsynaptic forebrain neurons. These observations led to the hypothesis that hallucinogens produce their psychoactive effects by acting preferentially upon 5-HT autoreceptors in the dorsal raphe allowing postsynaptic neurons to escape from the tonic inhibitory action of 5-HT neurons. However, problems exist with the concept that hallucinogens produce their psychoactive effects by disinhibiting postsynaptic neurons. First, the time course of the behavioral and neuronal effects of LSD do not correlate. Second, 5-HT neurons do not become tolerant to the inhibitory actions of LSD. Third, the hallucinogen mescaline fails to directly inhibit 5-HT neurons. Finally, the nonhallucinogen lisuride markedly suppresses the discharges of 5-HT neurons. These observations suggest that postsynaptic actions of hallucinogens may be of prime importance in producing their psychedelic effects. Evidence is presented to suggest that the hallucinogens may act postsynaptically to sensitize both serotonergic and noradrenergic receptors. It is suggested that a mechanism of receptor sensitization, in distinction to disinhibition, might account for the altered perceptual reactivity produced by these drugs.

Animals↗
PubMed1981

Long-term treatment with zimelidine leads to a reduction in 5-hydroxytryptamine neurotransmission within the central nervous system of the mouse and rat.

Male rats and mice received a 14 day peroral treatment with zimelidine, a novel antidepressant drug. Zimelidine produced a 70 and 60% reduction in the number of high affinity [3H]5-hydroxytryptamine (5-HT) and [3H]D-lysergic acid diethylamide (LSD) binding sites, respectively, and induced low affinity binding sites for [3H]5-HT and for [3H]D-LSD. The head twitch behaviour induced by 5-hydroxytryptophan and 5-methoxydimethyltryptamine was attenuated and reductions of prolactin and growth hormone were observed. These findings give further evidence that long-term treatment with zimelidine can produce a reduction of 5-HT neurotransmission in several brain regions.

Animals↗
PubMed2006

Efficient and sensitive method for quantitative analysis of alkaloids in hardinggrass (Phalaris aquatica L.).

An efficient high-performance thin-layer chromatography (HPTLC) method for the analysis of alkaloids in hardinggrass (Phalaris aquatica L.) was developed. The method employed HPTLC glass plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of ethyl acetate/chloroform/7 N NH4OH in methanol (8:2:1, v/v/v). Using unidimensional double-development, bands were well separated for 10 alkaloid standards as well as alkaloids observed in hardinggrass plant extracts. Identities of compounds observed using HPTLC were validated by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Software was used to quantify individual alkaloids in plant samples based on HPTLC retention factors and intensities relative to standards of known concentration. Correlation coefficients of 0.99 were obtained between estimated and actual concentrations for four standards (methyltyramine, hordenine, gramine, and 5-methoxydimethyltryptamine), with linearity in the range of 120-3840 ng/spot. The HPTLC method is repeatable and specific for beta-carboline, tryptamine, gramine, and tyramine type alkaloids in mixed standard and plant extracts. Initial results indicate substantial variation in alkaloid composition among and within hardinggrass populations.

Alkaloids↗
PubMed1986

Pharmacological differentiation and characterization of 5-HT1A, 5-HT1B, and 5-HT1C binding sites in rat frontal cortex.

Drug interactions with 5-HT1 (5-hydroxytryptamine type 1) binding site subtypes were analyzed in rat frontal cortex. 8-Hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT) displays high affinity (Ki 3.3 +/- 1 nM) for 29 +/- 3% of total [3H]5-HT binding in rat frontal cortex and low affinity (Ki 9,300 +/- 1,000) for 71 +/- 4% of the remaining 5-HT1 sites. Therefore, non-5-HT1A binding in rat frontal cortex was defined as specific [3H]5-HT binding observed in the presence of 100 nM 8-OH-DPAT. 5-Methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl) 1 H indole (RU 24969), 1-(m-trifluoromethylphenyl)piperazine (TFMPP), mianserin, and methysergide produce shallow competition curves of [3H]5-HT binding from non-5-HT1A sites. Addition of 10(-3) M GTP does not increase the apparent Hill slopes of these competition curves. Computer-assisted iterative curve fitting suggests that these drugs can discriminate two distinct subpopulations of non-5-HT1A binding sites, each representing approximately 35% of the total [3H]5-HT binding in the rat frontal cortex. All three 5-HT1 binding site subtypes display nanomolar affinity for 5-HT and 5-methoxytryptamine. A homogeneous population of 5-HT1A sites can be directly labeled using [3H]8-OH-DPAT. These sites display nanomolar affinity for 8-OH-DPAT, WB 4101, RU 24969, 2-(4-[4-(2-pyrimidinyl)-1-piperazinyl] butyl)-1,2-benzisothiazol-3-(2H)one-1, 1-dioxidehydrochloride (TVX Q 7821), 5-methoxydimethyltryptamine, and d-lysergic acid diethylamide. The potencies of RU 24969, TFMPP, and quipazine for [3H]5-HT binding are increased by addition of 100 nM 8-OH-DPAT and 3,000 nM mianserin to the [3H]5-HT binding assay. Moreover, the drugs have apparent Hill slopes near 1 under these conditions. This subpopulation of total [3H]5-HT binding is designated 5-HT1B. By contrast, methysergide and mianserin become more potent inhibitors of residual [3H]5-HT binding to non-5-HT1A sites in the presence of 100 nM 8-OH-DPAT and 10 nM RU 24969. The drug competition curves under these conditions have apparent Hill slopes of near unity and these sites are designated 5-HT1C. Drug competition studies using a series of 24 agents reveals that each 5-HT1 subtype site has a unique pharmacological profile. These results suggest that radioligand studies can be used to differentiate three distinct subpopulations of 5-HT1 binding sites labeled by [3H]5-HT in rat frontal cortex.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Tryptamine and some related molecules block the accumulation of a light-sensitive pool of cyclic AMP in the dark-adapted, dark-incubated mouse retina.

Dark-adapted retinas of mice (C57BL/6J) incubated in the dark in media containing 1 mM 3-isobutylmethylxanthine (IBMX) or 5 mM Co2+ accumulate cyclic AMP (cAMP). A portion of this pool is light sensitive, as light can prevent or reverse its accumulation. Similarly, tryptamine, serotonin, 5-methoxytryptamine, bufotenine, and 5-methoxydimethyltryptamine can block the accumulation of the light-sensitive pool of cAMP, whereas tryptophan, melatonin, N-acetylserotonin, 5-methoxytryptophol, and tetrahydro-beta-carbolines are inactive. The phenomenon is not seen with mutant mouse retinas (rd/rd), which lack most photoreceptors, but persists in abnormal retinas containing photoreceptors but with extensive neuronal depletion in the inner retina. Tryptamine also inhibits cAMP accumulation in either dark or light-adapted retinas exposed to forskolin alone but not in media containing high levels of forskolin plus 1 mM IBMX. There is some suggestion that serotonin 5-HT-2 antagonists can partially reverse the action of the tryptamines, but hitherto undescribed receptors may be involved. Current data suggest that photoreceptors are the target for the action of the tryptamines.

1-Methyl-3-isobutylxanthine↗
PubMed1978

Evidence of 5-HT participation in vagal inhibitory pathway to opossum LES.

Studies were performed in anesthetized opossums to investigate the nature of vagal-stimulated sphincter relaxation, which is resistant to antagonism by a combination of hexamethonium and atropine. The sphincter pressures were measured with water-filled and continuously perfused catheters anchored in the lower esophageal sphincter. Neither increase in the doses of hexamethonium and atropine nor addition of diphenhydramine further modified the vagal response. However, administration of 5-methoxydimethyltryptamine in the presence of hexamethonium and atropine abolished vagally stimulated sphincter relaxation. In animals pretreated with parachlorophenylalanine, addition of atropine and hexamethonium also abolished vagally stimulated sphincter relaxation. In the experiments in which lower esophageal sphincter relaxation on vagal stimulation was abolished, the local stimulation of intramural neurons still produced normal lower esophageal sphincter relaxation. These studies suggest that 5-hydroxytryptamine may participate in the vagal inhibitory pathway to the lower esophageal sphincter.

Animals↗
PubMed1998

Characterization of enhanced behavioral responses to L-DOPA following repeated administration in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease.

Long-term treatment of Parkinson's disease with dopamine-replacing agents such as L-3,4-dihydroxyphenylalanine (L-DOPA) is compromised by many side-effects, most notably involuntary movements, L-DOPA-induced dyskinesia. Acute challenge with dopamine-replacing drugs elicits a rotational response in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease. This rotation is contraversive to the lesion and is considered to represent an antiparkinsonian effect. More recently, it has become clear that the rotational response shows plasticity and that repeated L-DOPA or apomorphine therapy is accompanied by a marked enhancement in this response. In this study, we demonstrate that the enhanced behavioral response to repeated dopamine-replacement therapy seen in the 6-OHDA-lesioned rat has pharmacological characteristics similar to L-DOPA-induced dyskinesia seen in MPTP-lesioned primates and man. Thus, the magnitude and rate of development of the enhanced response to L-DOPA treatment is related to both the number of doses and the size of the dose of L-DOPA administered. In contrast, de novo administration of dopaminergic drugs that are associated with a lower incidence of dyskinesia, e.g., bromocriptine or lisuride, does not lead to an enhanced behavioral response following repeated treatment. However, following a single "priming" administration of apomorphine, the rotational response elicited by subsequent bromocriptine administrations is enhanced with repeated treatment. Once established, the enhanced behavioral response to repeated L-DOPA-administration (6.5 mg/kg, twice daily) can, like L-DOPA-induced dyskinesia in man and MPTP-treated monkeys, be selectively reduced by coadministration of L-DOPA with the alpha2-adrenergic receptor antagonist yohimbine (10 mg/kg, -95%), the 5-HT uptake inhibitor 5-MDOT (2 mg/kg, -90%), or the beta-adrenergic receptor antagonist propranalol (10 mg/kg, -35%). While these rats do not exhibit symptoms of dyskinesia per se, this rodent model does exhibit behaviors, the underlying mechanism of which is likely to be similar to that underlying L-DOPA-induced dyskinesia and may prove useful in studying the molecular and cellular mechanisms of L-DOPA-induced dyskinesia in Parkinson's disease.

Adrenergic alpha-Agonists↗
PubMed1990

Pharmacodynamic effects of serotonin (5-HT) receptor ligands in pigs: stimulation of 5-HT2 receptors induces malignant hyperthermia.

In pigs, the serotonin-2 (5-HT2) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 0.8 mg/kg, induced "psychotic" behaviour (e.g., grimacing, backward locomotion, blank stare) and a muscular syndrome, which is known as malignant hyperthermia (MH) in pigs and humans. This syndrome is characterized by generalized skeletal muscle rigidity, leading to an increase in body temperature, marked acidosis, hyperkaliaemia, cyanosis and elevation of lactate, carbon dioxide and the muscle enzyme creatine kinase (CK) in plasma. In pigs which were selectively bred for susceptibility to MH induction by known triggering agents, such as halothane, the administration of DOI was fatal in 3 out of 5 animals. In genetically susceptible pigs, MH was also induced by 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), 0.5-1.8 mg/kg, and D-lysergic acid diethylamide (LSD), 60-110 micrograms/kg. Furthermore, 5-MeO-DMT and LSD induced head shakes in the animals, which had not been observed after DOI and could not be blocked by 5-HT2-antagonists, ketanserin (0.5-5 mg/kg) and ritanserin (1-2.5 mg/kg). The psychotomimetic effects of 5-MeO-DMT could be blocked by ketanserin or ritanserin, which, depending on the dose, also reduced or totally prevented the hyperthermia and metabolic changes induced by 5-MeO-DMT in pigs. Administration of 5-MeO-DMT, 1.8 mg/kg, was fatal in 4 of 5 MH-susceptible pigs, whereas pigs injected with this dosage after pretreatment with ketanserin (0.5-5 mg/kg) or ritanserin (1-2.5 mg/kg) did not die. In pigs from MH-resistant littermates, administration of 5-MeO-DMT was not fatal. Comparison of metabolic changes in susceptible and non-susceptible pigs suggested that the marked increase in plasma potassium, which arises principally from damaged muscle cells, is primarily responsible for the fatal effect of DOI and 5-MeO-DMT in genetically susceptible individuals. In MH-susceptible pigs, which were anesthetized, relaxed and artificially ventilated, 5-MeO-DMT did not induce hyperthermia, thus substantiating that the marked hyperthermia observed in conscious pigs was a result of muscle activation and not due to effects on thermoregulation or blood pressure. The results indicate that hallucinogenic drugs with 5-HT2 agonistic effects trigger a life-threatening syndrome, MH, in genetically susceptible pigs. 5-HT2 antagonists, such as ketanserin or ritanserin, are capable of counteracting the fatality of this syndrome.

Amphetamines↗