Miller, Jacqueline Kay; (1995) Autoradiographic study of the distribution of 5-ht re-uptake sites in rat and human brain. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The selective serotonin re-uptake inhibitors (SSRI's) are a novel group of antidepressants which are rapidly becoming a popular choice of drug for the successful treatment of depression. The hypothesis of their mode of action, however, in conjunction with the cause of depression, remains subject to many inconsistencies. By using autoradiography to determine the distribution of the recognition sites of these drugs in the rat brain, it may be possible to detect discrete alterations in the serotonin re-uptake site which are not revealed in membrane binding studies. In the human brain, isolated areas of tissue have been used to provide some details of the sites of recognition of the SSRI's, however these studies have been limited by technical problems. Experimental protocols were established for the use of the SSRI 3H-paroxetine with autoradiography. The distribution of 3H-paroxetine binding sites in the rat brain revealed a heterogeneity of binding site densities, with the highest binding levels observed in the raphe nuclei in the brainstem. Direct injection of 5,7-dihydroxytryptamine (a selective serotonergic neurotoxin) into the dorsal raphe produced a reduction in 3H-paroxetine binding levels throughout the brain, thereby confirming the selectivity of 3H-paroxetine for the serotonin nerve terminal transporter site. A novel method of performing autoradiography in human whole brain sections was developed. By modifying a technique originally used for cutting whole body animal sections, it was possible to cryosection whole brain coronal slices (40μm) for use in autoradiography, whilst preserving the integrity of the brain tissue. The distribution of 3H-paroxetine binding sites within the human brain was determined and the symmetry of these binding sites established. A species difference in the localisation of the serotonin re-uptake site in rat and human brain was detected in a comparative study using 3H-paroxetine.

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