An animal model of schizophrenia based on chronic LSD administration: Old idea, new results

Autor: Danuta Marona-Lewicka, David E. Nichols, Charles D. Nichols
Rok vydání: 2011
Předmět:
Male
Receptors
Steroid
Psychosis
medicine.medical_specialty
Nerve Tissue Proteins
Motor Activity
Pharmacology
Receptors
N-Methyl-D-Aspartate
Article
Rats
Sprague-Dawley
Random Allocation
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Dopamine
Internal medicine
Receptor
Serotonin
5-HT2C
medicine
Haloperidol
Animals
Receptor
Serotonin
5-HT2A
RNA
Messenger
Amphetamine
Neurotransmitter
Lysergic acid diethylamide
Receptors
Thyroid Hormone
Behavior
Animal
Receptors
Dopamine D2
Anhedonia
medicine.disease
Rats
DNA-Binding Proteins
Disease Models
Animal
Lysergic Acid Diethylamide
Endocrinology
Gene Expression Regulation
Psychotic Disorders
chemistry
Dopamine Agonists
Schizophrenia
Serotonin
medicine.symptom
Psychology
Serotonin 5-HT2 Receptor Agonists
Akathisia
Drug-Induced
Antipsychotic Agents
medicine.drug
Zdroj: Neuropharmacology. 61:503-512
ISSN: 0028-3908
DOI: 10.1016/j.neuropharm.2011.02.006
Popis: 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.
Databáze: OpenAIRE
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