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]

DISCUSSION

Drugs which block presynaptic (somatodendritic) 5-HT1A receptors are candidates for testing as adjuncts to SSRIs to improve the treatment of severe depressive illness. The purpose of this receptor autoradiographic study was to determine the affinity of the b-adrenoceptor/5-HT1A ligand (±)-pindolol for pre- and postsynaptic 5-HT1A receptors in rat and human brain. Using the selective antagonist radioligand [3H]WAY-100635, our results show that (±)-pindolol has high affinity for presynaptic (DRN) and postsynaptic (CA3, CA1 and dentate gyrus in rat and CA1 in human) 5-HT1A receptors in both species. In the rat (±)-pindolol did not show preference for the presynaptic receptor although in the human the drug showed a significant though modestly higher affinity for the 5-HT1A site in the DRN versus CA1.

A cross species (rat, human, guinea pig, primate) study of the affinity of (-)-pindolol at pre- and postsynaptic 5-HT1A receptor was recently reported by Raurich et al., ⁽¹⁴⁾. The latter study found that (-)-pindolol did not discriminate between 5-HT1A sites in the DRN and hippocampus which is in broad keeping with the present data. Our finding of a slightly higher affinity of (±)-pindolol for the human DRN could therefore be a chance finding. However, the fact that we made within subject measurements of drug affinity at pre- and postsynaptic sites adds to the power of our experimental design and would increase the probability of detecting small changes. Clearly, the issue will only be resolved definitively by the study of a larger number of postmortem human brains.

The finding that (±)-pindolol has equal affinity at the rat pre- and postsynaptic 5-HT1A receptor agrees with the results of a recent electrophysiological study which found that (-)-pindolol blocked 5-HT1A agonist-induced electrophysiological responses in the rat DRN and hippocampus with equal potency ⁽⁶⁾. These question the original idea that pindolol is ineffective at blocking postsynaptic 5-HT1A receptors in hippocampus ⁽¹⁵⁾. The latter conclusion was derived from experiments in which systemically administered pindolol did not block the inhibition of hippocampal neurones by microiontophoretically applied 5-HT1A agonist. In the light of the newer findings, it may be the 5-HT1A antagonist property of pindolol was not adequately assessed in the study of Romero et al., possibly because agonists were applied locally in too high concentrations.

Interestingly, despite the evidence that the affinity of pindolol for pre- and postsynaptic 5-HT1A receptors is similar if not the same, recent PET imaging studies using the ligand [11C]WAY-100635 report that (±)-pindolol displays a slight but consistent preferential occupancy for the pre- versus postsynaptic 5-HT1A receptor in both human and rat brain in vivo ^(10,13). Rather than being explained by affinity differences, these PET data might be explained by evidence that in vivo (±)-pindolol causes a fall in endogenous 5-HT in the terminal areas ⁽⁵⁾. Thus, as a consequence of decreased extracellular 5-HT a greater number of PET ligand molecules would occupy the postsynaptic 5-HT1A receptors and a higher dose of pindolol would be needed to displace them ⁽¹⁰⁾. Whatever the explanation, the PET studies indicate that the preferential occupancy of presynaptic 5-HT1A receptors by (±)-pindolol covers a narrow dose range that may be difficult to achieve in routine clinical practice ⁽¹³⁾.

The augmentation of SSRIs by drugs blocking the presynaptic 5-HT1A receptor could be compromised by simultaneous blockade of the postsynaptic 5-HT1A receptor, if it is assumed that activation of the latter receptor mediates the antidepressant effect. However, the latter assumption is based largely on indirect evidence: e.g. that antidepressant drugs and ECS cause an adaptive increase in postsynaptic 5-HT1A receptor function ⁽²⁾. Recent immediate early gene experiments from this laboratory certainly indicate that SSRI/5-HT1A antagonists in combination increase postsynaptic 5-HT receptor function ⁽⁴⁾, but through 5-HT receptors that are not of the 5-HT1A subtype. Increased transmission through non-5-HT1A receptors could therefore contribute to an antidepressant effect.

Discussion Board

Any Comment to this presentation?

[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