title: An animal model of schizophrenia based on chronic LSD administration: old idea, new results.
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.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, 575 Stadium Mall Dr., Purdue University, West Lafayette, IN 47906-2091, USA.
authors.forename: Danuta
authors.initials: D
authors.lastname: Marona-Lewicka
authors.forename: Charles D
authors.initials: CD
authors.lastname: Nichols
authors.forename: David E
authors.initials: DE
authors.lastname: Nichols
mesh_terms: D017109:Akathisia, Drug-Induced / Q000209:etiology; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D008238:Lysergic Acid Diethylamide / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011618:Psychotic Disorders / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry*; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D014150:Antipsychotic Agents; D004268:DNA-Binding Proteins; D018491:Dopamine Agonists; D009419:Nerve Tissue Proteins; C490411:Nr4a3 protein, mouse; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D058826:Serotonin 5-HT2 Receptor Agonists; D008238:Lysergic Acid Diethylamide