Effects of Doxycycline in Swiss Mice Predictive Models of Schizophrenia.

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.