Clozapine Reverses Phencyclidine-Induced Desynchronization of Prefrontal Cortex through a 5-HT(1A) Receptor-Dependent Mechanism.
Lucila Kargieman, Maurizio S Riga, Francesc Artigas, Pau Celada
Neuropsychopharmacology February 2012 DOI: 10.1038/npp.2011.249 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study (genetic knockout and pharmacological antagonist design) Peer reviewed |
|---|---|
| Population | Wild-type C57BL/6 mice and 5-HT1A and 5-HT2A receptor knockout mice on the same background |
| Interventions | Phencyclidine (PCP) Clozapine WAY-100635 |
| Dose | PCP 10 mg/kg intraperitoneally; clozapine 0.5 mg/kg intraperitoneally |
| Measures | Local field potentials (LFPs) in the prefrontal cortex; slow cortical oscillations (SCO; 0.15-4 Hz) |
| Topics | Serotonin |
| Key findings | PCP (10 mg/kg) reduced prefrontal slow cortical oscillations equally in wild-type, 5-HT2A knockout, and 5-HT1A knockout mice (to 58±4%, 42±7%, and 63±7% of pre-drug values; n=23, 13, 11). Clozapine (0.5 mg/kg) reversed the PCP effect in wild-type and 5-HT2A knockout mice but not in 5-HT1A knockout mice or in wild-type mice pretreated with the 5-HT1A antagonist WAY-100635, suggesting clozapine's action involves 5-HT1A receptor activation without requiring 5-HT2A blockade. |
Abstract
The non-competitive NMDA receptor (NMDA-R) antagonist phencyclidine (PCP)-used as a pharmacological model of schizophrenia-disrupts prefrontal cortex (PFC) activity. PCP markedly increased the discharge rate of pyramidal neurons and reduced slow cortical oscillations (SCO; 0.15-4 Hz) in rat PFC. Both effects were reversed by classical (haloperidol) and atypical (clozapine) antipsychotic drugs. Here we extended these observations to mice brain and examined the potential involvement of 5-HT(2A) and 5-HT(1A) receptors (5-HT(2A)R and 5-HT(1A)R, respectively) in the reversal by clozapine of PCP actions. Clozapine shows high in vitro affinity for 5-HT(2A)R and behaves as partial agonist in vivo at 5-HT(1A)R. We used wild-type (WT) mice and 5-HT(1A)R and 5-HT(2A)R knockout mice of the same background (C57BL/6) (KO-1A and KO-2A, respectively). Local field potentials (LFPs) were recorded in the PFC of WT, KO-1A, and KO-2A mice. PCP (10 mg/kg, intraperitoneally) reduced SCO equally in WT, KO-2A, and KO-1A mice (58±4%, 42±7%, and 63±7% of pre-drug values, n=23, 13, 11, respectively; p<0.0003). Clozapine (0.5 mg/kg, intraperitoneally) significantly reversed PCP effect in WT and KO-2A mice, but not in KO-1A mice nor in WT mice pretreated with the selective 5-HT(1A)R antagonist WAY-100635.The PCP-induced disorganization of PFC activity does not appear to depend on serotonergic function. However, the lack of effect of clozapine in KO-1A mice and the prevention by WAY-100635 indicates that its therapeutic action involves 5-HT(1A)R activation without the need to block 5-HT(2A)R, as observed with clozapine-induced cortical dopamine release.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 7
- The natural hallucinogen 5-MeO-DMT, component of Ayahuasca, disrupts cortical function in rats: reversal by antipsychotic drugs. The International Journal of Neuropsychopharmacology August 1, 2014
- The serotonin hallucinogen 5-MeO-DMT alters cortico-thalamic activity in freely moving mice: Regionally-selective involvement of 5-HT1A and 5-HT2A receptors. Neuropharmacology November 1, 2018
- The serotonergic hallucinogen 5-methoxy-N,N-dimethyltryptamine disrupts cortical activity in a regionally-selective manner via 5-HT(1A) and 5-HT(2A) receptors. Neuropharmacology February 1, 2016
- Effects of Hallucinogens on Neuronal Activity. Current Topics in Behavioral Neurosciences 2018
- Lu AF35700 reverses the phencyclidine-induced disruption of thalamo-cortical activity by blocking dopamine D1 and D2 receptors. European Journal of Pharmacology August 15, 2023
and 2 more in the library
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- Activation of thalamocortical networks by the N-methyl-D-aspartate receptor antagonist phencyclidine: reversal by clozapine. Biological Psychiatry May 15, 2011
and 3 more in the library