Synthesis, binding affinities for alpha-adrenoceptor and eudismic analysis of chiral benzodioxane derivatives and their chiral opened analogues.
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Animals↗
Biomedical subjects
N Brunello
Publications and source records attributed to N Brunello.
Absence of [3H]SCH 23390 specific binding sites in anterior pituitary: dissociation from effects on prolactin secretion.
We extended a previous study that had shown the selective D1 receptor antagonist SCH 23390, at relatively high doses, to stimulate prolactin (PRL) secretion in the rat and weakly inhibit [3H]spiperone binding to striatum and anterior pituitary (AP) membranes. No specific [3H]SCH 23390 binding sites, up to the micromolar range, were detected in rat AP while specific, saturable [3H]SCH 23390 binding sites (low nanomolar range) were observed in the striatum. In vivo SCH 23390 (1 mg/kg s.c.) induced higher plasma PRL levels, not reversible by the D1 agonist SKF 38393. Similarly the postsynaptic serotonin (5-HT) antagonists metergoline and cyproheptadine did not influence the SCH 23390 effect on PRL. SCH 23390 was also unable to antagonize the decrease of PRL secretion induced by the selective D2 agonist LY 171555. However this latter compound prevented SCH 23390 as well as sulpiride from increasing the PRL concentrations above the control values. These data rule out the possibility that D1 or 5-HT receptors mediate the stimulation of PRL release by SCH 23390. This effect is more likely to be due to a weak indirect interaction with AP-D2 receptors, as indicated by the non-competitive inhibition of [3H]spiperone binding to AP exerted by SCH 23390. Alternatively, non-specific mechanisms triggered by the multiple behavioral changes elicited by such high doses of SCH 23390 may be involved.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Endocrine effects of 5-methoxytryptoline, 5-hydroxytryptoline and tryptoline, putative modulators of rat serotonergic system.
The effects of tryptolines (TH beta Cs), putative endogenous compounds acting on the serotonergic function, have been studied on endocrine parameters in rats. In particular, graded doses of 5-methoxytryptoline (5-MeOT), 5-hydroxytryptoline (5-OHT) and tryptoline (Tp) were ip or iv administered to the animals and the circulating titers of prolactin (PRL), growth hormone (GH) and luteinizing hormone (LH) were assayed either at 20 min or at various times after the injection of the compounds. The data herein reported show that TH beta Cs exert endocrine effects, at least in a pharmacological condition. However, the three compounds unequally affect anterior pituitary function. In fact, while 5-MeOT, 5-OHT and Tp all enhance plasma PRL concentrations in a quick, short lasting and dose-related manner, 5-MeOT and Tp induce also decreases of serum LH levels in ovariectomized rats, and 5-MeOT only is able to diminish plasma GH titers. These findings underline an endocrine effect for TH beta Cs in pharmacological conditions and may suggest a functional role for these compounds in the control of anterior pituitary function.
Animals↗
Effect of some tricyclic and nontricyclic antidepressants on [3H]imipramine binding and serotonin uptake in rat cerebral cortex after prolonged treatment.
Chronic administration of different antidepressant drugs reduced the number of [3H]imipramine [( 3H]IMI) binding sites in rat cerebral cortex. In the same experimental conditions, fluvoxamine and dothiepin, as well as desmethylimipramine, induced an increase in the maximal velocity of high affinity serotonin (5HT) uptake in cortical slices, whereas citalopram and viloxazine were ineffective in this regard. Our results indicate that even if 5HT uptake and [3H]IMI binding sites are located on the same nerve terminals, they are differently modulated. Increased Vmax of the 5HT uptake process could be due to a rebound phenomenon after withdrawal from drugs that acutely inhibit 5HT uptake. The effect on [3H]IMI sites might be explained through either the agonist properties of the drugs towards these sites or the involvement of mechanisms still unknown.
Animals↗
[Neuromediator changes during cerebral aging. The effect of Ginkgo biloba extract].
Ginkgo biloba extract exerts a specific effect on the noradrenergic system and on beta-receptors. No variation was found in alpha 2-receptors and serotonin uptake. These findings provide the first evidence of central effects of a drug acting on cerebral ageing, connected specifically to reactivation of the noradrenergic system in the cerebral cortex.
Aging↗
Ontogenetic studies on mu, delta and kappa opioid receptors in rat brain.
The ontogenetic pattern of multiple opioid binding sites in rat brain from birth until weaning has been investigated. [3H]-dihydromorphine ([3H]-DHM)3 [3H]-D-Ala2-D-Leu5-enkephalin ([3H]-DADLE) and [3H]-dynorphin A (1-8) ([3H]-DYN) as markers of mu (mu), delta (delta) and Kappa (kappa) sites were utilized respectively. The analysis of the kinetic parameters of [3H]-DHM binding shows that, at birth, mu sites possess an affinity similar to that of adult animals, and a density of 50%, which reaches 80% of the adult value at day 4. On the contrary, [3H]-DADLE binding in the first post-natal days shows low affinity and low density and delta-sites do not reach values comparable to the adult ones until the second week of life. The kinetic parameters of [3H]-DYN binding are almost undetectable during the preweanling period, due to the very low density of kappa sites at this stage of life. Displacement studies with mu-, delta- and kappa-selective ligands show that the Ki values on [3H]-DHM binding sites were similar in 4 day old and adult animals for all the tested compounds, whereas Ki values on [3H]-DADLE and [3H]-DYN binding sites reflected an immaturity of delta and kappa receptors. In conclusion, our data suggest that multiple opioid receptors follow different ontogenetic patterns. In the first stages of life only mu receptors are almost mature and possibly mediate endogenous opioid actions and exogenous opiate pharmaco-toxicological effects.
Aging↗
Interaction of beta-casomorphins with multiple opioid receptors: in vitro and in vivo studies in the newborn rat brain.
beta-Casomorphins (beta-CMs) are peptidic fragments of bovine beta-casein with potent opioid activity. In view of a possible physiological meaning of these milk-derived compounds, we have studied the affinity of some natural beta-CMs and some semisynthetic analogues for mu-, delta- and kappa-brain opioid receptors in newborn and adult rat. Moreover we have investigated whether a chronic treatment with the potent analogue D-Ala2-beta-CM-4-NH2 during the suckling period could affect mu and delta opioid receptor function. Our findings demonstrate that beta-CMs are mu-oriented compounds both in adult and in newborn rat brain. They display the same mu-affinity in newborn as well as in adult animals, however delta and kappa-affinities appear different, probably due to the lower degree of maturation of these two receptors in the first days of life. A prolonged treatment with D-Ala2-beta-CM-4-NH2 during the preweanling period is able to induce a delay in the ontogenetic increase of delta-receptor affinity, whereas it affects neither the affinity nor the density of mu-receptors. This effect could be related to a general action of opioids on cerebral maturative processes; moreover we point out that a beta-CMs analogue, given orally to newborn animals, can induce modifications at central level, suggesting thus the hypothesis that beta-CMs could be a biologically active peptide in the first stages of life.
Animals↗
Interaction of putative endogenous tryptolines with the hypothalamic serotonergic system and prolactin secretion in adult male rats.
The effect of 5-methoxytryptoline (5-MeOT), 5-hydroxytryptoline (5-OHT) and tryptoline (Tp), putative endogenous derivatives of the tryptamines, on plasma prolactin (PRL) concentrations has been investigated in the adult male rat. The possible involvement of the hypothalamic serotonergic system has been considered in the mediation of the hormonal effect of the tryptolines. Therefore, plasma PRL levels have been evaluated in rats receiving tryptolines after different pharmacological manipulations of central serotonergic function. Although the three compounds increased the plasma titers of PRL in a dose-dependent manner and enhanced the hypothalamic content of serotonin (5HT), they appear to affect the serotonergic system through different mechanisms. In particular, 5-OHT might act at a presynaptic level, since its hyperprolactinemic effect was antagonized both by the depletion of central 5HT content after p-chlorophenylalanine and by the degeneration of serotonergic terminals after 5,7-dihydroxytryptamine. In contrast, 5-MeOT behaved as if it had a postsynaptic site of action, being counteracted by the serotonergic postsynaptic antagonists metergoline and cyproheptadine. The unsubstituted tetrahydro-beta-carboline, Tp, is probably active at both pre- and postsynaptic sites. The enhancing effect of Tp on PRL secretion was antagonized by chronic treatment with p-chlorophenylalanine, while it was also maintained in 5,7-dihydroxytryptamine-lesioned rats. These findings suggest that tryptolines may play a functional role in PRL secretion by interacting with central serotonergic systems through different biochemical mechanisms.
5-Hydroxytryptophan↗
Lack of serotonergic modulation on 3H-imipramine binding sites in basal conditions and during prolonged treatment with desmethylimipramine.
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Animals↗
Age-related changes in 5HT uptake and [3H]imipramine binding sites in rat cerebral cortex.
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Aging↗
Biochemical and behavioral changes in rats after prolonged treatment with desipramine: interaction with p-chlorophenylalanine.
The decrease in the Bmax value of 3H-dihydroalprenolol (3H-DHA) binding to cortical membranes of rat brain induced by long-term administration of desipramine (DMI) was prevented by concomitant treatment with parachlorophenylalanine (pCPA). Acute administration of DMI significantly decreased locomotor activity in saline- and (pCPA)-pretreated rats. DMI-induced inhibition of locomotor activity was abolished in (pCPA)-pretreated rats chronically treated with DMI. Conversely, in pCPA-pretreated animals, acute DMI could still significantly decrease the locomotion of chronically DMI-treated rats. The data presented indicate that an intact serotoninergic system is required to enable antidepressant drugs to induce biochemical and behavioral changes following their chronic administration.
Animals↗
Effects of an extract of Ginkgo biloba on noradrenergic systems of rat cerebral cortex.
Oral treatment of rats with Ginkgo biloba extract (Gb) elicited a biphasic effect on normetanephrine (NMN) content of cerebral cortex; an initial decrease was evident after 45 minutes, followed by a marked increase that was evident after 14 days. Chronic treatment with Gb led to decreases in the density of 3H-dihydroalprenolol binding (after 27 days or 2 months) and in isoproterenol-stimulated adenylate cyclase activity (after 2 months) of the cerebral cortex. Taken together, these results indicate that the effects of Gb on the central beta-adrenergic system might be involved in its therapeutic actions.
Adenylyl Cyclases↗
Presynaptic and transynaptic mechanisms involved in the subsensitivity of rat cortical noradrenergic system after long-term antidepressant treatment.
Chronic treatment with antidepressants has been shown to produce a subsensitivity of noradrenergic neurons, both at presynaptic and postsynaptic sites. Important mechanisms, whereby the activity of noradrenergic neurons is regulated, could be the sensitivity of presynaptic alpha 2-adrenoceptors and the participation of transynaptic mechanisms involving other neurons. In this report we demonstrate that transynaptic factors involving the serotonergic system may be relevant to the regulation of the function of alpha 2-receptors in antidepressant chronically treated animals. In fact, we provide evidence of a markedly deminished responsiveness of noradrenergic neurons to an alpha 2-agonist (clonidine) or antagonist (mianserin) in biochemical and behavioral studies following serotonergic denervation with 5,7-dihydroxytryptamine. These results indicate that a functional interrelationship between serotonergic and noradrenergic systems might play an important role in the adaptive changes which bring the noradrenergic neurons to a lower level of activity after chronic antidepressant administration.
5,7-Dihydroxytryptamine↗
Serotonergic modulation of cortical rat noradrenergic system in the mechanism of action of antidepressant drugs.
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5,7-Dihydroxytryptamine↗
Modulation of opioid system in C57 mice after repeated treatment with morphine and naloxone: biochemical and behavioral correlates.
C57 BL/6J (C57) mice display a particular pattern of responses following morphine administration, such as a rapid development of tolerance to the pharmacological action of the opiate and an increase in locomotor activity after a single injection of the drug. We have measured met-enkephalin content and the responsiveness of different opiate receptors after repeated administration of morphine and naloxone. Prolonged morphine administration changes neither met-enkephalin levels, nor the density of the opiate receptors in mice brain. In contrast repeated administration of the opiate antagonist naloxone, produced a marked increase in the number of 3H- DHM and 3H- DADLE binding sites in striatum and brainstem without modifying met-enkephalin concentrations. Behavioral studies have indicated that the morphine-induced increase in locomotor activity is enhanced in naloxone pretreated mice, thus suggesting a possible correlation between the behavioral response to morphine in C57 mice and the higher number of opiate receptors in the striatum.
Animals↗
Behavioural and biochemical effects in C57BL/6J mice after a prolonged treatment with the delta-opiate antagonist ICI 154129.
A long term treatment with the delta-selective opiate antagonist NN-bisallyl-Tyr-Gly-Gly-psi-(CH2S)-Phe-Leu-OH (ICI 154129) produces an increase in the number of delta-opiate binding sites, whereas the same treatment with the non selective opiate antagonist naloxone results in an enhancement of both mu- and delta-binding sites. This biochemical effect in naloxone-pretreated mice is paralleled by a more pronounced increase in locomotor activity induced by a challenge dose of morphine. In contrast, no difference in the effect of morphine was seen in ICI 154129-pretreated mice with respect to control. These data suggest that the locomotor response to morphine in C57 mice is not mediated through delta-opiate receptors.
Adrenergic alpha-Antagonists↗
Behavioural changes after acute and chronic administration of typical and atypical antidepressants in rats: interactions with reserpine.
Acute administration of desipramine, mianserin and viloxazine produces a significant decrease of locomotor activity in rats. Conversely, the locomotion of rats receiving the antidepressants for a prolonged period of time is not modified with respect to control animals. Moreover, the reserpine-induced decrement of locomotion is not influenced by chronic treatment with any of the antidepressants used in the present study. Since tolerance develops rapidly to these behavioural effects they may be indicative of compensatory changes in neuronal systems which may occur during prolonged antidepressant treatment.
Animals↗
On the mode of action of imipramine: relationship between serotonergic axon terminal function and down-regulation of beta-adrenergic receptors.
Recognition sites for [3H]imipramine and [3H]mianserin are located in different structures and regulate different neuronal functions. Recognition sites for [3H]imipramine are located on serotonergic terminals, are part of the supramolecular organization of the uptake mechanisms and can be down-regulated by prolonged administration of the drug. When the number of recognition sites for imipramine is down-regulated, uptake of 5-hydroxytryptamine (5HT) in rat brain hippocampal slices is increased. The presence of the binding sites for imipramine in 5HT terminals is essential to mediate the down-regulation of recognition sites for norepinephrine (NE) and NE-mediated stimulation of adenylate cyclase. Mianserin binds on a site that is modulated by 5HT, the number of its binding sites is not down-regulated by repeated treatment and, like imipramine, decreases the NE-dependent cyclase but not the number of beta-adrenergic receptor recognition sites. Repeated treatment with imipramine and mianserin down-regulated the number of 5HT2 recognition sites. Several lines of evidence indicate that binding site for mianserin is related but not identical to the 5HT2 receptor binding site.
Animals↗