1. ¹Brains-on-Line, Antonius Deusinglaan 1, Groningen, The Netherlands
2. ²Department of Biomonitoring and Sensoring, University Centre for Pharmacy, Antonius Deusinglaan 1, Groningen, The Netherlands
3. ³H Lundbeck A/S, Ottiliavej 9, Copenhagen, Denmark
4. ⁴Department of Medicinal Chemistry, Rijksuniversiteit Groningen, Antonius Deusinglaan 1, Groningen, The Netherlands
5. ⁵Department of Psychiatry, University Medical Centre of Groningen, Hanzeplein 1, Groningen, The Netherlands

Correspondence: Dr TIFH Cremers, Department of Biomonitoring and Sensoring, University Centre for Pharmacy, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands. Tel: +31 621506340; Fax: +31 503636908; E-mail: t.i.f.h.cremers@rug.nl

Received 17 February 2006; Revised 21 September 2006; Accepted 25 September 2006; Published online 3 January 2007.

Abstract

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 of SSRIs 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 ventral hippocampus and the SSRI given systemically, but not when systemic 5-HT_2C antagonist was co-administered with the local infusion of citalopram. 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 in this 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.