Findings from preclinical studies have suggested that supplementing selective serotinin reuptake inhibitor (SSRI) treatment with a 5-HT1A antagonist may produce a reduction in the delay between initiation of treatment and anti-depressant response in patients. In the present study we have assessed the activity of pindolol on 5-hydroxytryptamine (5-HT) cells in the dorsal raphe nucleus (DRN) and in addition performed combination experiments with fluoxetine.
Experiments were carried out in accordance with the Animal (Scientific Procedures) Act, 1986. Male Sprague-Dawley rats (250-350 g, Harlan, UK) were anaesthetised with chloral hydrate (400 mg kg-1 I.P.; maintained with I.V. supplements via the lateral tail vein). Body temperature was maintained at 35-37 °C throughout the experiment using a heating pad. Animals were placed in a stereotaxic frame, the scalp incised and a burr hole made in the skull above the DRN (-7.8 mm AP from bregma, 0.0 mm lateral). Extracellular recordings were made using 2 M NaCl-filled single-barrelled electrodes with in vitro impedances of 1.6-3.0 M¢. The electrode was lowered through five tracks (separated by 0.2 mm) in the DRN and the number of spontaneously active serotonergic cells and their firing rates were examined. DRN cells were identified according to previously established criteria (Aghajanian et al. 1978). Rats received either vehicle or fluoxetine (10 mg kg-1 I.P.), followed 30 min later by treatment with either pindolol (1, 5 or 20 mg kg-1) or vehicle (S.C.). Recordings commenced 30 min following the administration of pindolol or its vehicle. Animals were humanely killed at the end of the experiment. Data were analysed using ANOVA with post-hoc t test for comparison of means, the experimentwise error rate was set at P < 0.05.
Administration of pindolol (1, 5 and 20 mg kg-1 S.C.; 2.0 ± 0.2, 1.0 ± 0.2, 1.7 ± 0.4, means ± S.E.M., n = 5, 7, 5, respectively) significantly decreased the number of spontaneously active 5-HT cells/track (2.8 ± 0.5; n = 9 vehicle/vehicle control) as did fluoxetine alone (10 mg kg-1 I.P.; 1.2 ± 0.2; n = 5). The fluoxetine-induced decrease in the number of cells/track was reversed by the addition of 5 and 20 mg kg-1, but not 1 mg kg-1, pindolol (2.0 ± 0.4, 1.8 ± 0.3, 0.8 ± 0.2, respectively, n = 4 all groups). In contrast, pindolol had no effect on firing rate when given alone and did not attenuate the decrease in firing rate observed with fluoxetine (10 mg kg-1 I.P.).
This study illustrates the agonist and antagonist properties of pindolol at the 5-HT1A receptor and may help to explain the variable results obtained with pindolol in SSRI augmentation clinical trials.
- Aghajanian, G.K., Wang, R.Y. & Baraban, J. (1978). Brain Res. 153, 169-175.