An animal model of schizophrenia based on chronic LSD administration: old idea, new results.
Danuta Marona‐lewicka, Charles D. Nichols, David E Nichols
Neuropharmacology February 23, 2011 DOI: 10.1016/j.neuropharm.2011.02.006 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Rats (including Sprague-Dawley), young and older animals |
| Interventions | LSD haloperidol olanzapine MDL-100907 non-competitive NMDA antagonists |
| Dose | 0.16 mg/kg every other day |
| Duration | Chronic administration >3 months, with effects persisting at least three months after cessation |
| Topics | LSD |
| Keywords | Animals Rats, sprague-dawley Akathisia, drug-induced Disease models, animal Dna-binding proteins Receptors, dopamine d2 Receptor, serotonin, 5-ht2a Receptor, serotonin, 5-ht2c Receptors, n-methyl-d-aspartate Receptors, thyroid hormone Nerve tissue proteins Receptors, steroid Rna, messenger Dopamine agonists Antipsychotic agents Random allocation Behavior, animal Motor activity Psychotic disorders Schizophrenia Gene expression regulation Male |
| Key findings | Chronic low-dose LSD in rats produced persistent psychosis-like behaviors (hyperactivity, hyperirritability, anhedonia, social impairment) lasting at least three months after cessation, transiently reversed by haloperidol and olanzapine but not MDL-100907. Non-competitive NMDA antagonists fully substituted for LSD only in the later temporal phase (LSD90) and only in older animals. The authors propose this as a new animal model that may mimic the development and progression of schizophrenia better than acute amphetamine or NMDA antagonist models. |
Abstract
Many people who take LSD experience a second temporal phase of LSD intoxication that is qualitatively different, and was described by Daniel Freedman as "clearly a paranoid state." We have previously shown that the discriminative stimulus effects of LSD in rats also occur in two temporal phases, with initial effects mediated by activation of 5-HT(2A) receptors (LSD30), and the later temporal phase mediated by dopamine D2-like receptors (LSD90). Surprisingly, we have now found that non-competitive NMDA antagonists produced full substitution in LSD90 rats, but only in older animals, whereas in LSD30, or in younger animals, these drugs did not mimic LSD. Chronic administration of low doses of LSD (>3 months, 0.16 mg/kg every other day) induces a behavioral state characterized by hyperactivity and hyperirritability, increased locomotor activity, anhedonia, and impairment in social interaction that persists at the same magnitude for at least three months after cessation of LSD treatment. These behaviors, which closely resemble those associated with psychosis in humans, are not induced by withdrawal from LSD; rather, they are the result of neuroadaptive changes occurring in the brain during the chronic administration of LSD. These persistent behaviors are transiently reversed by haloperidol and olanzapine, but are insensitive to MDL-100907. Gene expression analysis data show that chronic LSD treatment produced significant changes in multiple neurotransmitter system-related genes, including those for serotonin and dopamine. Thus, we propose that chronic treatment of rats with low doses of LSD can serve as a new animal model of psychosis that may mimic the development and progression of schizophrenia, as well as model the established disease better than current acute drug administration models utilizing amphetamine or NMDA antagonists such as PCP.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
Citations in the library
Cited by 34
- Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology May 1, 2020
- Psilocybin – Summary of knowledge and new perspectives European Neuropsychopharmacology December 17, 2013
- Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine Journal of Neuroscience November 30, 2020
- Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms Pharmacological Reviews December 16, 2020
- Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans European Neuropsychopharmacology January 16, 2015
and 29 more in the library
Cites 15
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- A Single Dose of Lysergic Acid Diethylamide Influences Gene Expression Patterns within the Mammalian Brain Neuropsychopharmacology May 1, 2002
- Lysergic acid diethylamide and [−]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex Brain Research August 27, 2004
- How LSD Originated Journal of Psychedelic Drugs 1979
- Molecular genetic responses to lysergic acid diethylamide include transcriptional activation of MAP kinase phosphatase‐1, C/EBP‐β and ILAD‐1, a novel gene with homology to arrestins Journal of Neurochemistry June 18, 2004
and 10 more in the library