Pharmacodynamic effects of serotonin (5-HT) receptor ligands in pigs: stimulation of 5-HT2 receptors induces malignant hyperthermia.
W Löscher, U Witte, G Fredow, M Ganter, K Bickhardt
Naunyn-Schmiedeberg's Archives of Pharmacology June 1, 1990 DOI: 10.1007/BF00171727 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Pigs selectively bred for susceptibility or resistance to malignant hyperthermia |
| Interventions | DOI 5-MeO-DMT LSD ketanserin ritanserin |
| Dose | DOI 0.8 mg/kg; 5-MeO-DMT 0.5-1.8 mg/kg; LSD 60-110 micrograms/kg; ketanserin 0.5-5 mg/kg; ritanserin 1-2.5 mg/kg |
| Topics | Serotonin |
| Citations | 48 |
| Key findings | Hallucinogenic drugs with serotonin-2 receptor agonistic effects trigger fatal malignant hyperthermia in genetically susceptible pigs, which can be prevented by pretreatment with serotonin-2 antagonists. |
Abstract
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.
Comparable studies
Other experimental studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain | 1997 | Experimental study |
Citations in the library
Cited by 8
- A narrative synthesis of research with 5-MeO-DMT. Journal of Psychopharmacology March 1, 2022
- Effects of a single dose of psilocybin on behaviour, brain 5-HT2A receptor occupancy and gene expression in the pig European Neuropsychopharmacology December 4, 2020
- 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents - A Review. ACS Pharmacology & Translational Science June 14, 2024
- Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice Acta Pharmaceutica Sinica B August 6, 2016
- Anaesthetic implications of psilocybin and lysergic acid diethylamide: what is old is now new: A narrative review on psychedelics and anaesthesia. European journal of anaesthesiology May 1, 2025
and 3 more in the library
Cites 7
- Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences December 17, 1984
- Lysergic acid diethylamide and 2,5-dimethoxy-4-methylamphetamine are partial agonists at serotonin receptors linked to phosphoinositide hydrolysis. Journal of Pharmacology and Experimental Therapeutics September 1, 1988
- Subtypes of the 5-HT receptor mediating the behavioural responses to 5-methoxy-N,N-dimethyltryptamine in the rat European Journal of Pharmacology October 1, 1985
- Serotonin receptor subtype mediation of the interoceptive discriminative stimuli induced by 5-methoxy-N,N-dimethyltryptamine. Psychopharmacology 1987
- Hallucinogenic drug interactions with neurotransmitter receptor binding sites in human cortex. Psychopharmacology 1989
and 2 more in the library