Related Experiment Video
Updated: Dec 9, 2025
A Multiple Integrated Social Stress Model for Psychiatric Disorders in Female C57BL/6J Mice
Published on: July 15, 2025
Effects of Doxycycline in Swiss Mice Predictive Models of Schizophrenia
Ana Carolina Issy1,2,3, João Francisco C Pedrazzi1,2,3, Anna Beatriz Saito van Oosten1
1Dental School of Ribeirão Preto, Department of Basic and Oral Biology, University of São Paulo (USP), Ribeirão Preto, SP, Brazil.
Abstract:
Schizophrenia patients show very complex symptoms in several psychopathological domains. Some of these symptoms remain poorly treated. Therefore, continued effort is needed to find novel pharmacological strategies for improving schizophrenia symptoms. Recently, minocycline, a second-generation tetracycline, has been suggested as an adjunctive treatment for schizophrenia. The antipsychotic-like effect of doxycycline, a minocycline analog, was investigated here. We found that both minocycline and doxycycline prevented amphetamine-induced prepulse inhibition (PPI) disruption. However, neither of them blocked MK801-induced effects, albeit doxycycline had a modest impact against ketamine-induced effects. Neither c-Fos nor nNOS expression, which was evaluated in limbic regions, were modified after acute or sub-chronic treatment with doxycycline. Therefore, apomorphine inducing either PPI disruption and climbing behavior was not prevented by doxycycline. This result discards a direct blockade of D2-like receptors, also suggested by the lack of doxycycline cataleptic-induced effect. Contrasting, doxycycline prevented SKF 38393-induced effects, suggesting a preferential doxycycline action at D1-like rather than D2-like receptors. However, doxycycline did not bind to the orthosteric sites of D1, D2, D3, D4, 5-HT2A, 5-HT1A, and A2A receptors suggesting no direct modulation of these receptors. Our data corroborate the antipsychotic-like effect of doxycycline. However, these effects are probably not mediated by doxycycline direct interaction with classical receptors enrolled in the antipsychotic effect.
Insights
Doxycycline exhibits antipsychotic-like effects in preclinical models, potentially offering new therapeutic avenues for schizophrenia. Its mechanism appears to involve D1-like receptors rather than direct classical receptor interactions.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Schizophrenia presents complex symptoms, with many remaining poorly treated, necessitating novel pharmacological strategies.
- Minocycline, a tetracycline antibiotic, has shown promise as an adjunctive schizophrenia treatment.
Purpose of the Study:
- To investigate the antipsychotic-like effects of doxycycline, a minocycline analog.
- To explore the potential mechanisms underlying doxycycline's effects on schizophrenia-related behaviors.
Main Methods:
- Evaluated doxycycline's effects on amphetamine-, MK801-, and ketamine-induced prepulse inhibition (PPI) disruption in animal models.
- Assessed c-Fos and nNOS expression in limbic regions following doxycycline treatment.
- Investigated doxycycline's interaction with dopamine (D1, D2, D3, D4), serotonin (5-HT2A, 5-HT1A), and adenosine (A2A) receptors.
Main Results:
- Doxycycline, like minocycline, prevented amphetamine-induced PPI disruption.
- Doxycycline showed a modest effect against ketamine-induced PPI disruption but not MK801-induced effects.
- Doxycycline did not alter c-Fos or nNOS expression and did not induce catalepsy, suggesting no direct D2-like receptor blockade.
- Doxycycline prevented SKF 38393-induced effects, indicating a potential action at D1-like receptors.
- Doxycycline did not bind to the tested classical antipsychotic receptors.
Conclusions:
- Doxycycline demonstrates antipsychotic-like properties in preclinical models.
- The mechanism of action for doxycycline's antipsychotic effects may involve D1-like receptors, distinct from direct classical receptor antagonism.
