Future Perspectives

Given the current lack of selective 5-HT1A-receptor antagonists available for human use, it seems that the final testing of the above hypothesis will have to wait until such compounds have been developed. The current lack of selectivity and limited number of 5-HT1A receptor antagonists leaves open several important questions. Furthermore, it is unknown whether other mixed P-adrenoceptor/5-HT1A receptor ligands, such as penbutolol or tertatolol would be effective when used in combination with SSRIs. Also, it has not been established whether the action of pindolol is exerted exclusively via 5-HT1A receptors. Indeed,

Fig. 9.6. Autoradiographic images showing the labelling of 5-HTia receptors with [3H]8-OH-DPAT in rat (A1-B2) and human (C1-D2) brain sections through the hippocampus and dorsal raphé. (A1-D1) Total binding of [3H]8-OH-DPAT (0.49 nM). (A2-D2) The addition of (-)pindolol (10-7 M) to the incubation medium strongly inhibits binding of the radioligand to 5-HT1A receptors. The effects of (-)pindolol are comparable among regions and across species. Abbreviations: CA1, CA1 hippocampal field; CA3, CA3 hippocampal field; DG, dentate gyrus; DR, dorsal raphé nucleus; Ent, entorhinal cortex; IP, interpeducular nucleus; MnR, median raphé nuclus. Bars: 3 mm (A=B, C=D).

Fig. 9.6. Autoradiographic images showing the labelling of 5-HTia receptors with [3H]8-OH-DPAT in rat (A1-B2) and human (C1-D2) brain sections through the hippocampus and dorsal raphé. (A1-D1) Total binding of [3H]8-OH-DPAT (0.49 nM). (A2-D2) The addition of (-)pindolol (10-7 M) to the incubation medium strongly inhibits binding of the radioligand to 5-HT1A receptors. The effects of (-)pindolol are comparable among regions and across species. Abbreviations: CA1, CA1 hippocampal field; CA3, CA3 hippocampal field; DG, dentate gyrus; DR, dorsal raphé nucleus; Ent, entorhinal cortex; IP, interpeducular nucleus; MnR, median raphé nuclus. Bars: 3 mm (A=B, C=D).

this issue has important consequences in terms of drug development. Finally, it is uncertain whether a putative blockade of postsynaptic 5-HT1A receptors would diminish the benefits of enhancing the presynaptic serotonergic function. It has been suggested that an enhanced transmission through hippocampal 5-HT1A receptors could be the common pathway by which a variety of antidepressant drugs, including SSRIs, monoamine oxidase inhibitors, tricyclic drugs and even drugs with a primary noradrenergic action, exert their antidepressant effects.13,59 This hypothesis could be easily tested by the administration of a selective 5-HT1A receptor antagonist able to block pre-and postsynaptic receptors. This should provoke a rapid relapse of recovered patients treated with different antidepressant drugs. However, it seems likely that other 5-HT receptors and brain areas are involved in the action of antidepressants, given the large number of 5-HT receptors and the anatomical evidence that cortical areas are involved in the pathophysiology of depression.103,104 Research of the mode of action of SSRIs should establish the 5-HT receptor subtypes and brain areas involved in their action using complementary experimental models in animals and humans. Non-invasive imaging techniques, such as PET scanning, are likely to provide a more complete view of the actions of SSRIs than any other methodology used so far. More specifically, this technique will undoubtedly help to establish the relationship between 5-HT1A receptor occupancy and therapeutic action of SSRIs which appears to be crucial for the development of new and more effective antidepressant drugs.

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