PubMed · 9415187
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P M Rowe. 1995. How do antidepressants work?. https://doi.org/10.1016/s1357-4310(95)90551-0
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Little experimental evidence has been reported for diverse signaling via 5-hydroxytryptamine (5-HT)1A receptors despite the fact that agonists seem to be more efficacious at dorsal raphe somatodendritic 5-HT1A autoreceptors than at postsynaptic 5-HT1A receptors. The present study investigated Ca2+ responses in Chinese hamster ovary (CHO)-K1 cells expressing a human 5-HT1A receptor by 5-HT, prototypical 5-HT1A agonists, N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methyl-6-; methylaminopyridin-2-yl)-methylaminomethyl]-piperidine (F 14679), and especially N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methylpyridin-2-yl)-; methylaminomethyl]piperidine (F 13640) as representative ligands of a new chemical class (methylamino-pyridine) that combines both high efficacy and selectivity for 5-HT1A receptors. 5-HT (pEC50 = 6.70 +/- 0.02) induced a pertussis toxin-sensitive, transient high-magnitude Ca2+ response. High-magnitude Ca2+ responses (Emax, percentage versus 5-HT) were also found with F 13640 (107 +/- 4), 5-carboxamidotryptamine (100 +/- 3), and F 14679 (87 +/- 3). In contrast, the prototypical 5-HT1A receptor agonists buspirone, ipsapirone, and 8-(hydroxy-2-(di-n-propylamino)tetralin, and also flesinoxan and eptapirone, were virtually inactive (< or =5). This atypical pattern of 5-HT1A receptor activation contrasts with the broad spectrum of the ligands' partial agonist properties as observed by measuring guanosine 5'-O-(3-[35 S]thio)triphosphate ([35S]GTPgammaS) binding responses with membranes of either CHO-K1 or C6-glial cells stably expressing a human 5-HT1A receptor. Remarkably, differences between ligands that seem small in the [35S]GTPgammaS binding assay translate into huge differences in the magnitude of Ca2+ responses. Therefore, some of these 5-HT1A ligands (i.e., F 13640) may in a selective way induce responses that may be not at all be achieved with other ligands (i.e., buspirone). In conclusion, the pharmacology of 5-HT1A receptor ligands seems to be codetermined by the effector pathway.
RATIONALE: Exposure to a single session of uncontrollable inescapable shock (IS), but not to identical controllable escapable shock, produces a potentiation of morphine's rewarding properties that is unusual in that the stressor can be given a number of days before the drug administration in an environment quite different from the drug context. Many other behavioral outcomes of stressors that depend on the uncontrollability of the stressor are mediated by alterations in serotonergic (5-HT) neurons within the dorsal raphe nucleus (DRN). OBJECTIVES: The present experiments examined the role of the DRN and 5-HT in mediating the effect of IS on the rewarding properties of morphine as assessed by conditioned place preference (CPP). METHODS: In experiment 1, subjects received small electrolytic lesions of the DRN and were tested for morphine (3.0 mg/kg, SC) CPP after IS or control treatment. In experiment 2, subjects received an intra-DRN microinjection of the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1.0 microg/0.5 microl) either before IS or before morphine (3.0 mg/kg, SC) injections during CPP testing. RESULTS: IS potentiated morphine CPP in controls, but both DRN lesion and intra-DRN 8-OH-DPAT, either before IS or before morphine administration, completely blocked this effect. CONCLUSIONS: These data implicate alterations in DRN 5-HT neurons in the potentiation of morphine reward produced by uncontrollable stress.
The ex vivo effect of tribomechanically micronized zeolite (MZ) on the binding of 3H-8-OH-DPAT to 5-HT(1A) and 3H-5-HT to 5-HT(1B) receptors was investigated in the brain of nontumorous (control) and mammary carcinoma bearing female mice. During 14 and 28 days mice were fed with standard food, standard food supplemented with 25% of MZ, or standard food supplemented with 25% of non tribomechanically micronized zeolite (non-MZ). A reduced binding of 3H-8-OH-DPAT to 5-HT(1A) receptors in mammary carcinoma bearing mice was found when compared to control mice fed with standard food for 28 days, suggesting a time dependent alteration of 5-HT(1A) receptors in mammary carcinoma. The addition of MZ for 28 days in these mice abolished the decrease in 5-HT(1A) receptors binding, indicating a possible beneficial effect of MZ, at least on 5-HT(1A) receptors in mammary carcinoma bearing mice. The preliminary data show that MZ administered as a food supplement (25%) for 14 days induced a transient decrease in the binding of 3H-5-HT to brain 5-HT(1B) receptors only in control, but not in tumor-bearing mice, that disappeared after 28 days of MZ-supplemented food administration. The mechanism of the indirect action of MZ on the brain serotonergic receptors might be achieved by the alterations in the electrolytes balance, and/or by the regulation of the immune system.