Acute anxiogenic-like effects of selective serotonin reuptake inhibitors are attenuated by the benzodiazepine diazepam in BALB/c mice

Selective serotonin re-uptake inhibitors (SSRIs), which are used commonly to treat anxiety disorders, have characteristic anxiogenic effects following acute administration. Treatment with anxiolytic benzodiazepines (BZs) may reduce these effects, although little is known about potential drug interactions. Our study evaluated acute anxiogenic-like effects of SSRIs, alone and combined with a BZ. Adult male BALB/c mice received fluoxetine (3.0–30.0 mg/kg, i.p.) or citalopram (3.0–30.0 mg/kg, i.p.) alone or in combination with diazepam (0.3–10.0 mg/kg, i.p.), after which they were evaluated with the light/dark and open-field tests for anxiogenesis/anxiolysis. In addition, release of the stress hormone corticosterone was assessed following combined SSRI/BZ administration. In the light/dark and open-field tests, acute SSRIs produced a behavioral profile consistent with anxiogenesis, while diazepam produced an anxiolytic-like profile. Pre-treatment with diazepam (0.3–10 mg/kg) reversed the effects of an anxiogenic-like dose of an SSRI (18 mg/kg fluoxetine, 30 mg/kg citalopram) in both light/dark and open-field tests. Diazepam, fluoxetine or citalopram, and their combination all significantly increased plasma corticosterone levels to the same degree. These findings suggest that a BZ-type drug can attenuate acute anxiogenic-like effects of an SSRI via a mechanism independent of corticosterone regulation.

Research highlights
► Selective serotonin re-uptake inhibitors (SSRIs) have acute anxiogenic effects.
► Anxiolytic benzodiazepines (BZs) may reduce these effects.
► The BZ diazepam reduced measures of anxiogenic effects by two SSRIs in mice.
► Unexpected locomotor activity changes occurred with diazepam/SSRI combinations.
► BZs may alleviate acute SSRI anxiogenesis, but unwanted side effects are possible.