Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice
J. Moreno, Terrell Holloway, Adrienne Umali, Vinayak Rayannavar, Stuart C. Sealfon, Javier González-Maeso
Psychopharmacology July 28, 2012 DOI: 10.1007/s00213-012-2809-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical mouse study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Clozapine Lysergic acid diethylamide (LSD) Haloperidol |
| Dose | 25 mg/kg/day clozapine; 1 mg/kg/day haloperidol |
| Duration | 21-day chronic treatment; experiments at 1, 7, 14, and 21 days after last dose |
| Measures | [3H]Ketanserin binding, 5-HT2A mRNA expression, Head-twitch behavior, c-fos expression, egr-1 expression, egr-2 expression |
| Topics | LSD |
| Key points | Chronic clozapine (21 days) in mice reduced LSD-induced head-twitch behavior and downregulated 5-HT2A receptor binding for up to 14 days after treatment, with partial recovery of c-fos induction at 7 days. The authors suggest 5-HT2A receptor downregulation may contribute to persistent therapeutic-like effects of atypical antipsychotics, effects not seen with short clozapine or chronic haloperidol. |
Abstract
In schizophrenia patients, optimal treatment with antipsychotics requires weeks to months of sustained drug therapy. However, single administration of antipsychotic drugs can reverse schizophrenia-like behavioral alterations in rodent models of psychosis. This raises questions about the physiological relevance of such antipsychotic-like activity. This study evaluates the effects of chronic treatment with clozapine on the cellular and behavioral responses induced by the hallucinogenic serotonin 5-HT2A receptor agonist lysergic acid diethylamide (LSD) as a mouse model of psychosis. Mice were treated chronically (21 days) with 25 mg/kg/day clozapine. Experiments were conducted 1, 7, 14, and 21 days after the last clozapine administration. [3H]Ketanserin binding and 5-HT2A mRNA expression were determined in mouse somatosensory cortex. Head-twitch behavior, expression of c-fos, which is induced by all 5-HT2A agonists, and expression of egr-1 and egr-2, which are LSD-like specific, were assayed. Head-twitch response was decreased and [3H]ketanserin binding was downregulated in 1, 7, and 14 days after chronic clozapine. 5-HT2A mRNA was reduced 1 day after chronic clozapine. Induction of c-fos, but not egr-1 and egr-2, was rescued 7 days after chronic clozapine. These effects were not observed after short treatment (2 days) with clozapine or chronic haloperidol (1 mg/kg/day). Our findings provide a murine model of chronic atypical antipsychotic drug action and suggest downregulation of the 5-HT2A receptor as a potential mechanism involved in these persistent therapeutic-like effects.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
Citations in the library
Cited by 6
- d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology International Journal of Molecular Sciences November 23, 2016
- Differences across sexes on head-twitch behavior and 5-HT2A receptor signaling in C57BL/6J mice. Neuroscience Letters September 25, 2022
- Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics. Molecular Psychiatry September 1, 2023
- Preclinical models of antipsychotic drug action The International Journal of Neuropsychopharmacology June 10, 2013
- Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT2A Receptor Agonists in Mice. ACS Chemical Neuroscience July 28, 2022
and 1 more in the library
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