Showing papers on "Serotonin published in 1987"

Electrophysiological responses of serotoninergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists.

Abstract: A direct comparison was made of the effects of serotonin 5-HT1A and 5-HT1B selective compounds on the spontaneous firing rate of dorsal raphe serotoninergic neurons in chloral-hydrate-anesthetized rats. Following intravenous administration, the 5-HT1A selective compounds ipsapirone (TVX Q 7821) and LY 165163 potently inhibited single-unit activity in a dose-dependent manner whereas the 5-HT1B selective compounds, m-chlorophenylpiperazine (mCPP) and trifluoromethylphenylpiperazine (TFMPP), displayed only weak or irregular actions. Low microiontophoretic currents of ipsapirone and LY 165163 were also effective in suppressing spontaneous firing; dose-response relationships for the 5-HT1A compounds were indistinguishable from that of 5-HT itself. In contrast, dorsal raphe neurons were only weakly responsive to microiontophoretic application of mCPP and TFMPP; dose-response relationships for the 5-HT1B compounds were significantly displaced from that of 5-HT. In intracellular studies, ipsapirone and LY 165163, when added to the media bathing brain slices, mimicked the actions of 5-HT in hyperpolarizing dorsal raphe cell membranes and decreasing input resistance; however, the maximal effects of the 5-HT1A compounds on these membrane properties exceeded those of 5-HT. In summary, dorsal raphe 5-HT neurons appear highly responsive to 5-HT1A, but not to 5-HT1B compounds; these findings are discussed with regard to the 5-HT receptor subtypes as candidates for the somatodendritic autoreceptor of dorsal raphe neurons.

Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding.

Abstract: Functional serotonin (5-hydroxytryptamine, 5-HT) receptors have been divided into three subtypes: 5-HT1,-like, 5-HT2 and 5-HT3, (ref. 1). Brain binding sites have been identified for both the 5-HT1, and 5-HT2 subtypes. Receptors of the 5-HT3 type have been characterized on isolated peripheral tissue models such as the rat vagus nerve2, guinea-pig ileum3 and isolated rabbit heart4. Using these models, selective 5-HT3 receptor antagonists such as MDL 72222 (ref. 5), ICS 205-930 (ref. 6), GR38032F (ref. 7) and BRL 43694 (ref. 8) have been developed. Recently, GR38032F, MDL 72222 and ICS 205-930 have been shown to have behavioural effects in rodents and primates that undoubtedly reflect an action in the central nervous system (refs 9–11 and unpublished observations), suggesting the existence of 5-HT3 receptors in the brain. Here we report direct evidence for the existence of 5-HT3 receptors in rat brain tissue and their distribution, based on high affinity binding of the potent 5-HT3 receptor antagonist 3H-GR65630 to homogenates of rat entorhinal cortex. Selective 5-HT3 receptor antagonists and agonists inhibited binding of 3H-GR65630 with high affinities which correlated well with their actions on the rat isolated vagus nerve2. Binding was differentially distributed throughout the brain with high concentrations in cortical and limbic areas.

Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine.

Abstract: The neurochemical effects of the unique psychedelic agent, methylenedioxymethamphetamine (MDMA), indicate it may be a serotonergic neurotoxin related to agents such as p-chloroamphetamine. MDMA had a biphasic effect on cortical serotonin concentrations beginning with an acute depletion of the transmitter which reached a maximum between 3 and 6 hr after drug administration. This early phase of depletion was reversible because cortical serotonin concentrations had recovered to control levels by 24 hr. However, transmitter concentrations were reduced significantly 1 week later, indicating a second phase of depletion. The latter phase of depletion was associated with a decrease in synaptosomal [3H]serotonin uptake due to a loss in the number of uptake sites with no change in the affinity of the carrier for serotonin. This neurotoxic effect of MDMA was found to be a property of the (+)-stereoisomer of the drug as only this enantiomer produced the depletion of cortical serotonin and the decrease in synaptosomal serotonin uptake at 1 week. In contrast to this, both stereoisomers of the drug could produce the acute depletion of cortical serotonin measured 3 hr after drug administration. Coadministration of the selective serotonin uptake inhibitor, fluoxetine, completely blocked the reduction in cortical serotonin concentrations 1 week after MDMA. Administration of fluoxetine at various times after MDMA revealed that the long-term effects of the drug developed independently of the acute depletion of serotonin and could be partially blocked by the uptake inhibitor as long as 6 hr after drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential modulation of three separate K-conductances in hippocampal CA1 neurons by serotonin

Abstract: The hippocampus receives a dense serotonin-containing innervation from the divisions of the raphe nucleus1,2. Serotonin applied to hippocampal neurons to mimic the action of endogenous transmitter often produces complex and variable responses (see for example ref. 3). Using voltage-clamp methods and new ligands that are selective for subtypes of serotonin receptors4,5, we have been able to clarify the mechanism of serotonin action on CA1 cells in rat hippocampal slices. We describe three distinct actions of serotonin (or 5-HT) on identified K-conductances in these cells. First, it activates a Ca-independent K-current which is responsible for neuronal hyperpolarization and is inhibitory. Second, it simultaneously suppresses the slow Ca-dependent K-conductance that is largely responsible for the accommodation of cell firing in CA1 neurons6–8: this produces a paradoxical increase in neuronal dis-charge in response to a depolarizing input. Third, serotonin produces a more slowly developing and long-lasting suppression of an intrinsic voltage-dependent K-conductance, Im (ref. 9), leading to neuronal depolarization and excitation. The hyperpolarizing response is mediated by class 1A serotonin receptors, whereas the other responses are not. Modulation of these different conductances by endogenously released serotonin could therefore change the probability or the duration (or both) of neuronal firing in the mammalian brain in different ways to give inhibitory, excitatory or mixed effects.

3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites.

Abstract: This study examines the effects of repeated systemic administration (20 mg/kg s.c., twice daily for 4 days) of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on levels of brain monoamines, their metabolites and on the density of monoamine uptake sites in various regions of rat brain. Marked reductions (30-60%) in the concentration of 5-hydroxyindoleacetic acid were observed in cerebral cortex, hippocampus, striatum, hypothalamus and midbrain at 2 weeks after a 4-day treatment regimen of MDMA or MDA; less consistent reductions in serotonin (5-HT) content were observed in these brain regions. In addition, both MDMA and MDA caused comparable and substantial reductions (50-75%) in the density of [3H]paroxetine-labeled 5-HT uptake sites in all brain regions examined. In contrast, neither MDMA nor MDA caused any widespread or long-term changes in the content of the catecholaminergic markers (i.e., norepinephrine, dopamine, 3,4 dihydroxyphenylacetic acid and homovanillic acid) or in the number of [3H]mazindol-labeled norepinephrine or dopamine uptake sites in the brain regions examined. These data demonstrate that MDMA and MDA cause long-lasting neurotoxic effects with respect to both the functional and structural integrity of serotonergic neurons in brain. Furthermore, our measurement of reductions in the density of 5-HT uptake sites provides a means for quantification of the neurodegenerative effects of MDMA and MDA on presynaptic 5-HT terminals.

Modifications of the serotonin system by antidepressant treatments: implications for the therapeutic response in major depression.

Abstract: Results of electrophysiological single-cell recording studies suggest that most, if not all, types of antidepressant treatments increase 5-hydroxytryptamine (5-HT) neurotransmission. Tricyclic antidepressants, electroconvulsive shock treatment, mianserin, adinazolam, and possibly sleep deprivation may exert their therapeutic effect through sensitization of postsynaptic neurons to 5-HT. Serotonin reuptake blockers may relieve depression through an increased efficacy of the presynaptic element resulting from a desensitization of somatodendritic and terminal 5-HT autoreceptors. Similarly, monoamine oxidase inhibitors may act by increasing the efficacy of 5-HT neurons. Intensification of 5-HT function appears to be a common denominator to antidepressant treatments; however, evidence suggests that this modification may only be a link in a chain of events leading to an antidepressant response.

Porcine coronary arteries with regenerated endothelium have a reduced endothelium-dependent responsiveness to aggregating platelets and serotonin.

Abstract: To test the ability of regenerated endothelium to evoke endothelium-dependent relaxations, male Yorkshire pigs underwent balloon endothelial denudation of the proximal left anterior descending coronary artery. Endothelium-dependent responses were examined in vitro, in rings of coronary segments taken from the denuded area or from the proximal left circumflex coronary artery. The experiments were performed 8 days or 4 weeks after the denudation. Endothelial regrowth was confirmed by histologic examination 8 days after the denudation and by demonstrating the presence of endothelium-dependent relaxations to bradykinin; at that time aggregating platelets evoked normal endothelium-dependent responses. However, 4 weeks after the denudation, the relaxations to aggregating platelets were markedly depressed although continuous endothelial lining was present, and the endothelium-dependent responses to bradykinin, adenosine diphosphate, the Ca2+-ionophore A23187, platelet activating factor, and thrombin were unaltered. Four weeks after denudation, endothelium-dependent relaxations to serotonin were depressed. Higher concentration of serotonin induced endothelium-dependent contractions in quiescent rings with regenerated endothelium, suggesting that regenerated endothelial cells may produce endothelium-derived constricting factor(s) and release less endothelium-derived relaxing factor(s) when exposed to the monoamine. The endothelium-dependent relaxation to serotonin was not reduced by the S2-serotonergic antagonist ketanserin but prevented by the combined S1- and S2-serotonergic blocker methiothepin. The platelet-induced relaxation was due to released serotonin and adenine nucleotides in control left circumflex coronary arteries, but in left anterior descending coronary artery with regenerated endothelium, it was due solely to the latter. The platelet-induced contractions were due to activation of receptors on the smooth muscle cells. Four weeks after denudation, regenerated endothelial cells were morphologically different from native cells; they were elongated and cuboidal, and the number of the cells had increased twofold. At this state, eccentric myointimal thickening was present in the previously denuded portion. These experiments indicate that the protective role of endothelial cells against the vasoconstriction induced by aggregating platelets is depressed in the chronic regenerated state. A lack of responsiveness to serotonin appears to be the cause for the endothelial dysfunction.

Relative efficacies of piperazines at the phosphoinositide hydrolysis-linked serotonergic (5-HT-2 and 5-HT-1c) receptors.

Abstract: Serotonin (5-HT)-stimulated phosphoinositide hydrolysis is mediated by the 5-HT-2 receptor in rat cerebral cortex and by the 5-HT-1c receptor in rat choroid plexus. These systems were used to determine relative efficacies of piperazine derivatives at the 5-HT-2 and 5-HT-1c receptors. Both quipazine and 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) stimulated phosphoinositide hydrolysis in cerebral cortex, and these effects were blocked by ketanserin. The maximum responses to these agonists were 80% of the maximum response to 5-HT. m-Trifluoromethylphenylpiperazine (TFMPP), m-chlorophenylpiperazine (MCPP) and 1-(1-naphthyl)-piperazine (1-NP) did not stimulate phosphoinositide hydrolysis in cerebral cortex at concentrations that blocked the effect of 5-HT. In the choroid plexus, TFMPP and MCPP, as well as MK-212 and quipazine, increased phosphoinositide hydrolysis and mianserin blocked these effects. MK-212 had an efficacy which was equal to that of 5-HT, whereas quipazine, MCPP and TFMPP were partial agonists in the choroid plexus. 1-NP did not stimulate phosphoinositide hydrolysis in choroid plexus but completely blocked the effect 5-HT. On the basis of these data, we conclude that quipazine and MK-212 are partial agonists at 5-HT-2 receptors in cerebral cortex, whereas 1-NP, TFMPP and MCPP are pure antagonists of the cortical 5-HT-2 receptor. However, TFMPP and MCPP as well as quipazine and MK-212 are agonists at the 5-HT-1c receptor, while 1-NP is a pure antagonist of the 5-HT-1c receptor in choroid plexus.

Presynaptic serotonergic dysfunction in patients with Alzheimer's disease.

Abstract: Indices of presynaptic serotonergic nerve endings were assayed in neocortical biopsy samples from patients with histologically verified Alzheimer's disease. The concentrations of 5-hydroxytryptamine (serotonin) and 5-hydroxyindoleacetic acid, serotonin uptake, and K+-stimulated release of endogenous serotonin were all found to be reduced below control values. Changes occurred in samples from both the frontal and temporal lobes, but they were most severe (at least a 55% reduction) in the temporal lobe. This is indicative of substantial serotonergic denervation. Values for serotonergic markers in Alzheimer's disease samples did not show correlations with rating of the severity of dementia, indices of cholinergic innervation, or senile plaque and cortical pyramidal neurone loss. However, neuronbrillary tangle count and an index of glucose oxidation (both probably reflecting pyramidal cells) correlated with the concentration of 5-hydroxyindoleacetic acid.

Tianeptine, a selective enhancer of serotonin uptake in rat brain.

Abstract: Tianeptine is a tricyclic agent provided with antidepressant activity in experimental models and in clinical trials. In vitro tianeptine and its two principal metabolites have no effects on monoamine uptake, release or neurotransmitter receptor binding. The biochemical effect of tianeptine in vivo after acute or repeated treatment indicates an enhanced serotonin uptake in cortex and hippocampus but not in mesencephalon, with no effect on noradrenaline or dopamine uptake. This enhanced serotonin uptake is not due to decrease in serotonin release, but is related to increase in the Vmax of the uptake carrier for serotonin. The fact that enhancers as well as inhibitors of serotonin uptake are provided with antidepressant activity challenge simple conclusion as to their mechanism of action. The possibility that increased serotonin uptake after repeated treatment may be related to the antidepressant activity exerted by these drugs, and drugs enhancing serotonin uptake might have antidepressant activity, with an earlier onset, is proposed.

Corticotropin-releasing factor administration elicits a stress-like activation of cerebral catecholaminergic systems

Abstract: The cerebral content of the biogenic amines, dopamine (DA), norepinephrine (NE), and serotonin (5-HT) and their catabolites 30 min after CRF or saline injections was determined using HPLC with electrochemical detection. Injection of CRF (1.0 μg) into the lateral ventricles (ICV) of mice produced a behavioral activation in which their motor movements appeared as bursts of activity followed by periods of immobility. CRF administration (ICV or SC) did not alter the concentrations of DA, NE, tryptophan, 5-HT, or 5-hydroxyindoleacetic acid (5-HIAA) in any brain region measured. ICV CRF increased the concentrations of dihydroxyphenylacetic acid (DOPAC), the major catabolite of DA, and of 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG), the major catabolite of NE, in several brain regions. DOPAC:DA ratios were consistently increased in prefrontal cortex, septum, hypothalamus, and brain stem relative to animals injected with saline. MHPG:NE ratios were also increased in the prefrontal cortex and hypothalamus, with a marginal effect (p=0.06) in brain stem. SC CRF significantly increased DOPAC:DA in prefrontal cortex, and MHPG:NE in prefrontal cortex, hypothalamus and brain stem. Pretreatment with naloxone did not prevent any of the neurochemical responses to ICV CRF, but naloxone alone increased DOPAC:DA in medial profrontal cortex, and decreased MHPG:NE in nucleus accumbens in CRF-injected mice. These results suggest that administration of CRF either centrally or peripherally induces an activation of both dopaminergic and noradrenergic systems in several regions of mouse brain. The pattern resembles that we observe in mice following stressful treatments such as footshock or restraint, but the effect of CRF on noradrenergic systems is less pronounced. Also, brain free tryptophan which is consistently increased in all brain regions by footshock or restraint was not altered by CRF. Thus CRF triggers a response in CNS catecholamine systems that resembles, but does not precisely mimic, that observed following commonly used stressors. This activation of CNS catecholamine metabolism may be related to some of the behavioral effects of CRF, but not all of them because naloxone, which prevents the effects of CRF on exploratory behavior, did not alter the catecholamine responses to CRF.

Biochemical Changes During Clomipramine Treatment of Childhood Obsessive-Compulsive Disorder

Abstract: • Peripheral measures of serotonergic and noradrenergic function were obtained in 29 obsessive-compulsive adolescents and 31 age- and sex-matched controls, as well as in a subsample of 22 patients after five weeks of treatment with clomipramine hydrochloride (134 ± 33 mg/d) (mean ± SD) given in a double-blind placebo-controlled trial. Drug-free obsessive-compulsive subjects did not differ from controls on measures of platelet serotonin and monoamine oxidase (MAO) activity, nor on plasma epinephrine or norepinephrine concentrations at rest and after a standard orthostatic challenge procedure. Compared with placebo, treatment with clomipramine was clinically effective and produced a marked decrease in platelet serotonin concentration, a trend toward a reduction in platelet MAO activity, and a rise in standing plasma norepinephrine. Clinical improvement during drug therapy was closely correlated with pretreatment platelet serotonin concentration and MAO activity, as well as with the decrease in both measures during clomipramine administration. This suggests that the effects of clomipramine on serotonin uptake may be essential to the antiobsessional action observed.

Dopamine and serotonin systems in human and rodent brain: effects of age and neurodegenerative disease

Abstract: The nonpathological age-related changes in the dopamine- and serotonin-containing neurotransmitter systems in human and rodent brain are reviewed. The dopamine system exhibits age-related declines both presynaptically and postsynaptically. Presynaptically, both the levels of dopamine and the number of midbrain dopamine-containing neurons decline by up to 50% at advanced ages in the absence of neurological disease. Postsynaptically, the density of D-2 dopamine receptors decreases by 40%, while D-1 dopamine receptors either increase (man) or remain stable (rodents). Additional reductions of dopamine levels and D-2 receptors have been reported in Alzheimer's disease (AD), but these changes are relatively small, and not consistently observed. The levels of serotonin appear stable during normal aging, and presynaptic markers such as (3H)imipramine binding may actually increase. In human brain, the two major classes of serotonin receptor (S-1 and S-2) decrease by 30 to 50% over the lifespan. In AD, both presynaptic and postsynaptic markers of the serotonin system are reduced, including a loss of the serotonin-containing raphe neurons. The additional loss of serotonin receptors in AD approaches 80% when compared with young normals. A hypothesis is presented to explain the typically young age at onset of schizophrenia (usually before 30 years of age) and the older age at onset of parkinsonism (rarely before 50 years of age) within the context of normal age-related declines in the dopamine system occurring in the absence of neurological disorders. The possibility that chronic cocaine abuse might accelerate the development of parkinsonism is discussed.

Rat brain serotonin receptors in Xenopus oocytes are coupled by intracellular calcium to endogenous channels.

Abstract: Serotonin activates chloride currents in Xenopus oocytes injected with a subfraction of rat brain poly(A)+ mRNA. Patch-clamp recordings from cell-attached patches showed that serotonin, applied locally outside the patch, caused the opening of channels of approximately equal to 3 pS conductance and an average lifetime of approximately equal to 100 msec. The extrapolated reversal potential indicated that the channels are chloride-selective. Single-channel currents with similar characteristics were observed in inside-out patches from native oocytes in response to elevated calcium concentrations on the cytoplasmic side. Measurements of intracellular calcium concentration ([Ca2+]i) by fura-2 fluorescence showed approximately equal to 10-fold increases in [Ca2+]i in response to serotonin application in both normal and calcium-free Ringer solution in mRNA-injected oocytes. Little or no response to serotonin was observed in native oocytes. These results suggest that serotonin activation of receptors that are inserted into the oocyte membrane following injection of rat brain poly(A)+ mRNA can induce calcium release from intracellular stores. The increase in [Ca2+]i subsequently activates calcium-dependent chloride channels. Because calcium-dependent chloride channels and a receptor-controlled mechanism of internal calcium release have been shown to exist in native oocytes, we conclude that the newly inserted serotonin receptors utilized the endogenous second-messenger-mediated calcium release to activate endogenous calcium-dependent chloride channels.

Piperazine derivatives including the putative anxiolytic drugs, buspirone and ipsapirone, are agonists at 5-HT1A receptors negatively coupled with adenylate cyclase in hippocampal neurons.

Abstract: Two putative anxiolytic drugs [ipsapirone (TVXQ 7821) and buspirone], structurally unrelated to benzodiazepines, have negligible ataxic and sedative side effects. These drugs are piperazine analogs which interact at 5-HT1 binding sites. It is demonstrated here that these drugs and two other piperazine derivatives, trifluoromethylphenylpiperazine (TFMPP) and m-chlorophenylpiperazine (mCPP), are agonists at 5-HT1A receptors, a subclass of the 5-HT1 receptor, mediating inhibition of forskolin (100 μM) stimulated adenylate cyclase in particulate fractions of guinea pig hippocampus as well as inhibition of the formation of cyclic AMP promoted by vasoactive intestinal polypeptide (0.1 μM) plus forskolin (1 μM) in mouse hippocampal neurons in primary culture. This study demonstrates that these piperazine based drugs act in both brain homogenate preparations and in intact neurons in a similar manner. The biochemical models described here may aid in the development of even more active drugs in this class.

Autoradiographic localization of 3H-paroxetine-labeled serotonin uptake sites in rat brain.

Abstract: Paroxetine is a potent and selective inhibitor of serotonin uptake into neurons. Serotonin uptake sites have been identified, localized, and quantified in rat brain by autoradiography with 3H-paroxetine; 3H-paroxetine binding in slide-mounted sections of rat forebrain was of high affinity (KD = 10 pM) and the inhibition affinity constant (Ki) values of various drugs in competing 3H-paroxetine binding significantly correlated with their reported potencies in inhibiting synaptosomal serotonin uptake. Serotonin uptake sites labeled by 3H-paroxetine were highly concentrated in the dorsal and median raphe nuclei, central gray, superficial layer of the superior colliculus, lateral septal nucleus, paraventricular nucleus of the thalamus, and the islands of Calleja. High concentrations of 3H-paroxetine binding sites were found in brainstem areas containing dopamine (substantia nigra and ventral tegmental area) and norepinephrine (locus coeruleus) cell bodies. Moderate concentrations of 3H-paroxetine binding sites were present in laminae I and IV of the frontal parietal cortex, primary olfactory cortex, olfactory tubercle, regions of the basal ganglia, septum, amygdala, thalamus, hypothalamus, hippocampus, and some brainstem areas including the interpeduncular, trigeminal, and parabrachial nuclei. Lower densities of 3H-paroxetine binding sites were found in other regions of the neocortex and very low to nonsignificant levels of binding were present in white matter tracts and in the cerebellum. Lesioning of serotonin neurons with 3,4-methylenedioxyamphetamine caused large decreases in 3H-paroxetine binding. The autoradiographic distribution of 3H-paroxetine binding sites in rat brain corresponds extremely well to the distribution of serotonin terminals and cell bodies as well as with the pharmacological sites of action of serotonin.