Raul Manhães de Castro

Effects of stress on the functional properties of pre- and postsynaptic 5-HT1B receptors in the rat brain

Numerous studies have clearly shown that the turnover and release of serotonin (5-hydroxytryptamine, 5-HT) are increased under acute stressful conditions. Inasmuch as this latter process is under the control of a feedback mechanism involving the stimulation of presynaptic 5-HT1B autoreceptors, we have investigated the possible effects of acute restraint (40 min) on the functional properties of 5-HT1B receptors. The efficacy of the selective 5-HT1B receptor agonist 3-[1,2,5,6-tetrahydropyrid-4-yl]pyrrolo-[3,2-b]pyrid-5-one (CP-93,129) in inhibiting in vitro the K+-evoked release of [3H]5-HT, was significantly reduced in stressed rats as compared to naive animals. Similarly, the responsiveness of 5-HT1B receptors inhibiting the release of [3H]acetylcholine (presynaptic 5-HT1B heteroreceptors), was reduced by restraint. These effects were observed in the hippocampus, but using the inhibitory effect of CP-93,129 on forskolin-stimulated adenylyl cyclase activity as an index of 5-HT1B receptor function, it could be shown that the 5-HT1B receptors located in the substantia nigra are also desensitized by stress. The number as well as the apparent affinity constant of 5-HT1B binding sites labelled by [125I]iodocyanopindolol, as measured by quantitative autoradiography and membrane binding, were similar in naive and restraint-stressed rats suggesting that the stress-induced desensitization of 5-HT1B receptors is not due to a reduced number of 5-HT1B binding sites. As stress is thought to be a causal factor for the etiology of anxiety and depression, these results support the potential involvement of 5-HT1B receptor dysfunction in the development of these neurological disorders.

Antagonism by citalopram and tianeptine of presynaptic 5-HT1B heteroreceptors inhibiting acetylcholine release

The interactions of citalopram and tianeptine, two antidepressants having opposite effects on serotonin (5-HT) uptake, with 5-HT1B presynaptic heteroreceptors located on cholinergic terminals were investigated. In rat hippocampal synaptosomes, citalopram (0.01 or 0.1 microM) or tianeptine (0.01-10 microM) did not modify the basal or the K(+)-evoked release of [3H]acetylcholine. Only at the concentration of 100 microM did tianeptine significantly decrease (-18%) the K(+)-evoked release of [3H]acetylcholine without affecting the spontaneous outflow of radioactivity. The inhibitory effect of 7-trifluoromethyl-4-(4-1-piperazinyl)-pyrrolo[1,2-a]quinoxaline (CGS 12066B), a 5-HT1B receptor agonist, on the stimulation-induced release of [3H]acetylcholine was reduced in a concentration-dependent manner by citalopram and tianeptine. Both drugs completely reversed the inhibitory effects of CGS 12066B at concentrations that did not modify by themselves the release of [3H]acetylcholine. In contrast, tianeptine, up to a concentration of 1 microM, failed to antagonise the inhibitory effect of the muscarinic receptor agonist carbachol on K(+)-evoked [3H]acetylcholine release. Finally, the administration of tianeptine ex vivo (10 or 20 mg/kg) modified neither the depolarisation-induced release of [3H]acetylcholine nor the inhibitory effect of CGS 12066B on this presynaptic process. These findings further confirm that antidepressants interact in vitro with presynaptic 5-HT1B heteroreceptors.

Sub-chronic cold stress reduces 5-HT1A receptor responsiveness in the old but not in the young rat

The inhibitory effect of the prototypical 5-hydroxytryptamine (5-HT)1A receptor agonist 8-hydroxy-2-(di-n-propyl amino)tetraline (8-OH-DPAT) on forskolin-stimulated adenylyl cyclase activity, has been examined as an index of the functional activity of 5-HT1A receptors in the hippocampus of young (3 months) and old (18 months) rats exposed during 24 h or 5 days to cold. In both young and old rats exposed to cold stress during 24 h, there was a reduction in the potency (EC50) and/or the maximal inhibitory effect (Emax) of 8-OH-DPAT in reducing forskolin-induced cAMP accumulation. The properties of the hippocampal 5-HT1A sites labelled by [3H]8-OH-DPAT were not affected by these stressful conditions. Moreover, while the sensitivity of 5-HT1A receptors to 8-OH-DPAT in young rats returned to control values after 5 days of cold exposure, old rats still exhibited a significant desensitization of 5-HT1A receptors as compared to naive animals. These results point out the capacity of young but not of old rats to adapt to the aversive effects of a subchronic stressor.

L-tryptophan administration and increase in cerebral serotonin levels: Systematic review

Abstract The amino acid tryptophan (2‐Amino‐3‐(lH‐indol‐3‐yl)‐propanoic acid; Trp) is a precursor of the neurotransmitter serotonin (5‐hydroxytryptamine; 5‐HT) that performs various brain functions. The administration of Trp is used in experimental studies to manipulate the serotonergic system, however the dose of Trp required to raise brain 5‐HT levels is controversial. The aim of this study was to systemically review the effect of the administration of different doses of Trp on cerebral 5‐HT levels. Two independent authors conducted a systematic review in the electronic databases. Twenty‐five studies were included in the present review. Trp was administered orally, intraperitoneally or subcutaneous in adult animals. The brain 5‐HT levels elevated after Trp administration in different intensities, dependent of the brain region evaluated and the time of administration. Further studies are needed to assess the dose‐response of Trp administration to brain 5‐HT levels.

102Rhm: Could it be a cosmic-ray chronometer?

Looking for a possible cosmic-ray chronometer, we have studied the decay modes of 102Rhm,g. Its ground state has a half-life of 207 days, and decays to 102Ru and 102Pd via β++e (80%) and β− (20%) respectively. The meta-stable state has a 2.9-year half-life, and decays to 102Ru and 102Rhg via e decay (≈100%) and a highly converted isomeric transition (0.23%) respectively, with no indication of β+ or β− decays. In the absence of the atomic electrons, the isomeric state will only decay either via β+ or an M4 γ decay of 90 keV, both not observed. Measurements of the most probable β+ branch were performed with a germanium multi-detector system, through sum coincidence method, and allow setting an upper limit of 2.5×10−6 per decay, with 95% confidence level. From this upper limit, a partial half-life greater than 1.2×106 years is inferred. Investigation of the isomeric transition is under way.