Elsevier

Neuropharmacology

Volume 36, Issues 4–5, April–May 1997, Pages 467-473
Neuropharmacology

Effect of 5-HT1A Receptor Antagonists on Citalopram-induced Increase in Extracellular Serotonin in the Frontal Cortex, Striatum and Dorsal Hippocampus

https://doi.org/10.1016/S0028-3908(97)00060-9Get rights and content

Abstract

The aim of the present study was to compare the effects of citalopram, either alone or combined with 5-HT1A receptor antagonists, on extracellular serotonin levels in brain regions innervated by the dorsal or median raphe nuclei. Using intracerebral microdialysis in awake rats with separate probes in the frontal cortex or dorsal hippocampus, we studied the ability of 8 mg/kg s.c. (—)penbutolol, a β-adrenoceptor antagonist with antagonist action at 5-HT1A and 5-HT1B receptors, and 0.3 mg/kg s.c. WAY-100635, a selective 5-HT1A receptor blocker, to modify the effect of 1 and 10 mg/kg i.p. citalopram on extracellular serotonin. Both doses of citalopram had more effect on extracellular serotonin levels in the dorsal hippocampus than in the frontal cortex. The effect of 1 mg/kg citalopram was significantly potentiated by (—)penbutolol in the frontal cortex only, but a clear-cut potentiation of the effect of citalopram was seen in both regions at a dose of 10 mg/kg. The effect of 10 mg/kg citalopram was potentiated by WAY-100635 in the frontal cortex but not in the dorsal hippocampus.

In a second set of experiments, the combined effect of WAY-100635 and citalopram was studied in the same rat implanted with vertical probes in the striatum and dorsal hippocampus. Citalopram (1 and 10 mg/kg i.p.) raised extracellular serotonin to a similar extent in both regions. However, 0.3 mg/kg s.c. WAY-100635 potentiated the effect of 10 mg/kg citalopram in the striatum but not in the dorsal hippocampus. The results suggest that only a combined blockade of 5-HT1A and 5-HT1B receptors potentiates the effect of citalopram on extracellular concentrations of serotonin in the dorsal hippocampus. The findings may be relevant in designing clinical trials aimed at enhancing the antidepressant action of selective serotonin re-uptake inhibitors by combining them with serotonin receptor antagonists. © 1997 Elsevier Science Ltd.

Section snippets

Animals

Male Sprague Dawley rats (CD-COBS, Charles River, Italy) weighing 300–350 g were housed four to a cage under standard laboratory conditions with food and water freely available.

Procedures involving animals and their care were conducted in conformity with the institutional guidelines that are in compliance with national and international laws and policies (EEC Council Directive 86/609, OJ L 358,1, 12/12/1987; NIH Guide for the Care and Use of Laboratory Animals, NIH Publication No. 85-23, 1985).

Dialysis procedure

Effect of citalopram on extracellular 5-HT in the frontal cortex, dorsal hippocampus and striatum

Citalopram (1 and 10 mg/kg i.p.) significantly increased extracellular 5-HT by 143% and 255% of baseline levels in the frontal cortex and by 236% and 435% in the dorsal hippocampus (Fig. 2Fig. 3). Statistical analysis of the overall effect of citalopram, calculated from 20 to 180 min after injection, revealed a significant effect of treatment (Ftreat1,16 = 13.0, P < 0.002) and area (Farea1,16 = 11.8, P < 0.003), but not of treatment by area (Ftreat × area1,16 = 1.2, n.s.), indicating that the

DISCUSSION

The main aim of the study was to compare the effect of 5-HT1A receptor antagonists on the ability of citalopram to modify extracellular 5-HT in three brain regions that are differently innervated by the dorsal and median raphe nuclei (Azmitia and Segal, 1978).

In agreement with previous results from separate experiments (Invernizzi et al. (1992), Invernizzi et al. (1995)), 1 and 10 mg/kg citalopram had a greater effect on extracellular 5-HT levels in the dorsal hippocampus than frontal cortex,

Acknowledgements

The generous gifts of WAY-100635 (Pharmacia, Nerviano, Italy), (−)penbutolol (Dr Luca, Hoechst Italia S.p.A., Milan, Italy) and citalopram (Dr Hyttel, Lundbeck, Denmark) are gratefully acknowledged. A.L. and C.V. are recipient of fellowships from Fondazione Angelo e Angela Valenti, Italy and Zambon group, Spain. This work was partially supported by the CNR (National Research Council, Rome, Italy) Contract No. 95.01078.CT04.

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