The International Journal of Neuropsychopharmacology

Research Article

Enhancement of cortical extracellular 5-HT by 5-HT1A and 5-HT2C receptor blockade restores the antidepressant-like effect of citalopram in non-responder mice

Eleonora Calcagnoa1, Sara Guzzettia2, Alessandro Canettaa2, Claudia Fracassoa3, Silvio Cacciaa3, Luigi Cervoa2 and Roberto W. Invernizzia1 c1

a1 Laboratory of Neurochemistry and Behaviour, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via La Masa 19, 20156 Milan, Italy

a2 Laboratory of Experimental Psychopharmacology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via La Masa 19, 20156 Milan, Italy

a3 Laboratory of Drug Metabolism, Department of Neuroscience, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via La Masa 19, 20156 Milan, Italy

Abstract

We recently found that the response of DBA/2 mice to SSRIs in the forced swim test (FST) was impaired and they also had a smaller basal and citalopram-stimulated increase in brain extracellular serotonin (5-HT) than ‘responder’ strains. We employed intracerebral microdialysis, FST and selective antagonists of 5-HT1A and 5-HT2C receptors to investigate whether enhancing the increase in extracellular 5-HT reinstated the anti-immobility effect of citalopram in the FST. WAY 100635 (0.3 mg/kg s.c.) or SB 242084 (1 mg/kg s.c.), respectively a selective 5-HT1A and 5-HT2C receptor antagonist, raised the effect of citalopram (5 mg/kg) on extracellular 5-HT in the medial prefrontal cortex of DBA/2N mice (citalopram alone 5.2±0.3 fmol/20 μl, WAY 100635+citalopram 9.9±2.1 fmol/20 μl, SB 242084+ citalopram 7.6±1.0 fmol/20 μl) to the level reached in ‘responder’ mice given citalopram alone. The 5-HT receptor antagonists had no effect on the citalopram-induced increase in extracellular 5-HT in the dorsal hippocampus. The combination of citalopram with WAY 100635 or SB 242084 significantly reduced immobility time in DBA/2N mice that otherwise did not respond to either drug singly. Brain levels of citalopram in mice given citalopram alone or with 5-HT antagonists did not significantly differ. The results confirm that impaired 5-HT transmission accounts for the lack of effect of citalopram in the FST and suggest that enhancing the effect of SSRIs on extracellular 5-HT, through selective blockade of 5-HT1A and 5-HT2C receptors, could be a useful strategy to restore the response in treatment-resistant depression.

(Received September 09 2008)

(Reviewed October 11 2008)

(Revised November 11 2008)

(Accepted November 17 2008)

(Online publication January 06 2009)

Correspondence:

c1 Address for correspondence: Dr R. W. Invernizzi, Laboratory of Neurochemistry, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via La Masa 19, 20156 Milan, Italy. Tel.: +39 02 39014556 Fax: +39 02 3546277 Email: rinvernizzi@marionegri.it