O'Connell, Mark Thomas; (1997) Activation of 5-HT1A receptors: Behavioural and neurochemical studies. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In rat brain the serotonin (5-hydroxytryptamine, 5-HT) receptor subtype, 5-HT1A receptor, is present at greatest density in the raphe nuclei on 5-HT cell bodies as a presynaptic autoreceptor, where its activation can decrease neuronal firing, reduce 5-HT synthesis, and decrease the release of 5-HT at terminal sites. The 5-HT1A receptor is also located postsynaptically where its activation produces behavioural responses such as components of the serotonergic syndrome. In this thesis the effects of 5-HT1A receptor activation by single and repeated administration of the selective agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH- DPAT) and by administration of the antagonist / partial agonist, 8-[2-[4-(2- methoxyphenyl)-1 -piperazinyl]ethyl]-8-azaspiro1[4,5]-decane-7,9-dione dihydrochloride (BMY 7378) were studied. Using a standardised experimental design, in which the effects of pretreatment with a 1 mg/kg s.c. dose of 8-OH-DPAT for 1,3 or 14 days on responses to a challenge dose of 0.5 mg/kg s.c. 8-OH-DPAT, the following results were obtained. Different behavioural responses to activation of 5-HT1A receptors by 8-OH-DPAT had strikingly different vulnerabilities to attenuation by 8-OH-DPAT pretreatment. Components of the 5-HT syndrome previously demonstrated to be mediated by postsynaptic 5-HT1A receptors were substantially attenuated after a single 8-OH-DPAT pretreatment. However another postsynaptic 5-HT1A receptor mediated response, tail-flick, and hyperphagia, a response to activation of presynaptic 5-HT1A receptors were both unaffected by 1,3 or 14 days pretreatment. The hypothermic effect of 8-OH-DPAT which, m the rat (as supported by evidence in this thesis), was shown to be a postsynaptically mediated 5-HT1A receptor response, was progressively attenuated over fourteen pretreatments. These results indicate that the process of desensitisation of responses to activation of the 5-HT1A receptor is complex and may be due to the presence of spare receptors (receptor reserve) or changes in secondary messenger interactions or by modulation of other downstream neurotransmitters. Evidence for a postsynaptic location for the 5-HT1A receptors mediating hypothermia was derived from results demonstrating that gross 5-HT depletion by the 5-HT synthesis inhibitor, p-chlorophenylalanine (pCPA) failed to attenuate the hypothermic effects of 8-OH-DPAT or BMY 7378. More convincing still was the finding that 8-OH-DPAT, a strong agonist at both presynaptic and postsynaptic 5-HT1A sites has comparable ED50 values for both hypothermia and hyperphagia, while BMY 7378, which is an agonist at presynaptic 5-HT1A receptors but mainly an antagonist at postsynaptic sites has an ED50 value for hypothermia which is two orders of magnitude greater than that for hyperphagia. In addition, infusion of BMY 7378 into the dorsal raphe was without clear hypothermic effect. The consequences of partial 5-HT depletion (circa 50%) following a single pCPA administration, on extracellular 5-HT in the frontal cortex, was investigated to assess the availability of 5-HT for release when the tissue content is lowered. Results indicate that the availability of 5-HT for release falls in proportion to the depletion of 5- HT stores. However, the resulting tissue 5-HT / 5-HIAA ratio would suggest that increased conservation of the partially depleted 5-HT stores may occur. In conclusion, the neurochemical and behavioural effects of activation of 5- HT1A receptors as indicated in this thesis are complex. Effects of this type as well as desensitisation of the 5-HT1A autoreceptor could play some part in antidepressant action.

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