Abstract

(1) Brains-on-Line, Antonius Deusinglaan 1, Groningen, The Netherlands;

(2) Department of Biomonitoring and Sensoring, University Centre forPharmacy, Antonius Deusinglaan 1, Groningen, The Netherlands;

(3) H Lundbeck A/S, Ottiliavej 9, Copenhagen, Denmark;

(4) Department ofMedicinal Chemistry, Rijksuniversiteit Groningen, Antonius Deusinglaan 1, Groningen, The Netherlands;

(5) Department of Psychiatry, UniversityMedical Centre of Groningen, Hanzeplein 1, Groningen, The Netherlands.

The treatment of depression may be improved by using an augmentation approach involving selective serotonin reuptake inhibitors (SSRIs) in combination with compounds that focus on antagonism of inhibitory serotonin receptors. Using microdialysis coupled to HPLC, it has recently been shown that the systemic co-administration of 5-HT 2C antagonists with SSRIs augmented the acute effect ofSSRIs on extracellular 5-HT. In this paper, we have investigated the mechanism through which this augmentation occurs. The increase in extracellular 5-HT was not observed when both compounds were locally infused. However, varying the route of administration for both compounds differentially revealed that an augmentation took place when the 5-HT 2C antagonist was locally infused into ventralhippocampus and the SSRI given systemically, but not when systemic 5-HT 2C antagonist was co-administered with the local infusion ofcitalopram. This suggests that the release of extracellular serotonin in ventral hippocampus may be controlled by (an)other brain area(s). As 5-HT 2C receptors are not considered to be autoreceptors, this would implicate that other neurotransmitter systems are involved inthis process. To investigate which neurotransmitter systems were involved in the interaction, systemic citalopram was challenged with several glutamatergic, GABA-ergic, noradrenergic, and dopaminergic compounds to determine their effects on serotonin release in ventral hippocampus. It was determined that the involvement of glutamate, norepinephrine, and dopamine in the augmentation did not seem likely, whereas evidence implicated a role for the GABA-ergic system in the augmentation.

Neuropsychopharmacology (2007) 32, 1550–1557; doi:10.1038/sj.npp.1301287; published online 3 January 2007.

Keywords: microdialysis; citalopram; 5-HT2C receptor; SB242084; GABA; augmentation.