Trevor Sharp⁽¹⁾, Elena Castro^(2)
(1)Department of Clinical Pharmacology. University of Oxford - Oxford. United Kingdom
⁽²⁾ Clinical Pharmacology. University of Oxford - Oxford. United Kingdom

	[Pharmacology]	[Psychiatry]

INTRODUCTION

It is well established that selective serotonin reuptake inhibitors (SSRI) are effective in the treatment of major depression, however, as with other antidepressants, several weeks of treatment are necessary before their full therapeutic effect becomes apparent. SSRIs may not be clinically effective at the start of treatment because the drugs cause indirect activation of presynaptic (somatodendritic) 5-HT1A autoreceptors within the midbrain raphe nuclei. This reduces 5-HT neuronal firing and decreases 5-HT release in the terminal regions ^(1,8).

Animal data show that selective antagonists of the 5-HT1A receptor potentiate the effects of the SSRIs on presynaptic 5-HT function by preventing 5-HT1A autoreceptor activation ⁽⁷⁾. On this basis clinical trials have tested the utility of the b-adrenoceptor/5-HT1A ligand pindolol (specifically, (±)-pindolol) in SSRI augmentation. Significantly, pindolol/SSRI combinations have been found to produce a more rapid onset of antidepressant action in some although not all studies ⁽¹¹⁾.

A factor complicating the use of 5-HT1A antagonists in depression is that in addition to blocking the presynaptic 5-HT1A receptor, these drugs will also block the postsynaptic 5-HT1A receptor, an effect which could interfere with the antidepressant effect. In the case of pindolol (specifically, (-)-pindolol), however, there is animal data indicating that it is presynaptic selective ⁽¹⁵⁾ but this is not confirmed in other studies ⁽⁶⁾. Pindolol is known to have high affinity for 5-HT1A sites in membrane preparations of rat and human brain as well as cells transfected with the human 5-HT1A receptor ^(9,12) but information on the affinity of pindolol at presynaptic and postsynaptic 5-HT1A receptors is needed.

Here we have determined the affinity of (±)-pindolol for different populations of native 5-HT1A receptors in postmortem human and rat brain using receptor autoradiography and the selective 5-HT1A radioligand [3H]WAY-100635.

Discussion Board

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[ABSTRACT] [INTRODUCTION] [MATERIAL & METHODS] [RESULTS] [FIGURES] [DISCUSSION] [CONCLUSIONS] [ACKNOWLEDGEMENTS] [REFERENCES] [Discussion Board]

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	[Pharmacology]	[Psychiatry]

Trevor Sharp, Elena Castro
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Last update: 26/01/00