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Localisation and modulation of gabab and 5-ht3 receptors in rodent brain: an autoradiographic study

Pratt, Gerard David; (1991) Localisation and modulation of gabab and 5-ht3 receptors in rodent brain: an autoradiographic study. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Autoradiographical visualisation of GABAB binding sites in sections of rat brain has extended the findings of previous reports in that within the frontal cortex, the distribution of such sites is clearly laminated into four distinct regions. Furthermore, GABAB binding sites have also been identified in the dorsal vagal complex of the brainstem, especially within the nucleus tractus solitarius (NTS). In parallel with these GABAergic medullary receptors, detailed analysis of the autoradiography of the 5-HT3 receptor radioligand, [3H]BRL43694 (as well as [3H]zacopride, [3H]GR65630 and [3H]quipazine) has also been investigated within this region. Using histological markers in conjunction with autoradiography, 5-HT3 binding sites were localised in the area postrema, dorsal motor vagal nucleus and the nucleus of the spinal tract of the trigeminal nerve. However, by far the highest concentration of sites was observed in the NTS. As the NTS/dorsal vagal complex provides the site of termination for the majority of vagal afferent fibres, S-HTj, GABAg and GABA Receptor autoradiography was examined 10 days after vagal lesioning achieved via chronic unilateral nodose ganglionectomy. Since all three binding site categories were reduced ipsilaterally in the dorsal vagal complex, this suggested that such sites are likely to be located presynaptically on vagal afferent fibres that terminate in this region. Conflicting and inconsistent reports regarding GABAB receptor modulation by chronic antidepressant treatment prompted the use of receptor autoradiography (restricted to the sub-laminal regions of the frontal cortex) in an attempt to resolve this issue. Administration of imipramine (14 days) either orally or via subcutaneously implanted osmotic minipumps failed to increase GABAB receptor numbers in this region. In contrast, chronic oral and i.p. administration (21 days) of desipramine significantly up-regulated GABAB receptors in lamina I of the frontal cortex with a concomitant beta-adrenoceptor down-regulation. Repeated administration of amitriptyline, paroxetine or the centrally-active GABAB receptor antagonist, CGP 35348 was ineffective at modulating GABAB receptors. Conversely, another putative GABAB receptor antagonist, designated as Compound X, like desipramine, also increased GABAB receptor densities in the frontal cortex, but again only in lamina I. Despite the increase in GABAB receptor numbers produced by despramine, this drug, like the majority of the above treatment regimes, failed to increase the sensitivities of the GABAB receptor-modulation of forskolin- and noradrenaline-stimulated adenylyl cyclase activity. However, treatment with Compound X produced an apparent enhancement of the GABAB receptor-mediated inhibition of forskolin-stimulated adenylyl cyclase. The phosphonic acid derivative of GABA, 3-aminopropylphosphinic acid (3-APA), has been characterised as a GABAB receptor agonist. Whilst it is 10 times more potent than (-)-baclofen at displacing [3H]GABA from GABAB binding sites, it is equipotent with (-)-baclofen at inhibiting forskolin-stimulated adenylyl cyclase. Conversely, whilst (-)-baclofen is a full agonist with respect to the noradrenaline-stimulated system, 3-APA appeared to act as a partial agonist in this response. These contrasting findings may be indices of the possible existence of GABAB receptor subtypes.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Localisation and modulation of gabab and 5-ht3 receptors in rodent brain: an autoradiographic study
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest
Keywords: Pure sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10111963
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