Serotonin Receptors In Rat Brain Research Articles

Differential effects of amyloid-beta 1–40 and 1–42 fibrils on 5-HT1A serotonin receptors in rat brain

Evidence accumulates suggesting a complex interplay between neurodegenerative processes and serotonergic neurotransmission. We have previously reported an overexpression of serotonin 5-HT1A receptors (5-HT1AR) after intrahippocampal injections of amyloid-beta 1–40 (Aβ40) fibrils in rats. This serotonergic reactivity paralleled results from clinical positron emission tomography studies with [18F]MPPF revealing an overexpression of 5-HT1AR in the hippocampus of patients with mild cognitive impairment. Because Aβ40 and Aβ42 isoforms are found in amyloid plaques, we tested in this study the hypothesis of a peptide- and region-specific 5-HT1AR reactivity by injecting them, separately, into the hippocampus or striatum of rats. [18F]MPPF in vitro autoradiography revealed that Aβ40 fibrils, but not Aβ42, were triggering an overexpression of 5-HT1AR in the hippocampus and striatum of rat brains after 7 days. Immunohistochemical approaches targeting neuronal precursor cells, mature neurons, and astrocytes showed that Aβ42 fibrils caused more pathophysiological damages than Aβ40 fibrils. The mechanisms of Aβ40 fibrils–induced 5-HT1AR expression remains unknown, but hypotheses including neurogenesis, glial expression, and axonal sprouting are discussed.

Electrophysiological examination of the effects of sustained flibanserin administration on serotonin receptors in rat brain

5-HT1A receptor agonists have proven to be effective antidepressant medications, however they suffer from a significant therapeutic lag before depressive symptoms abate. Flibanserin is a 5-HT1A receptor agonist and 5-HT2A receptor antagonist developed to possibly induce a more rapid onset of antidepressant action through its preferential postsynaptic 5-HT1A receptor agonism. Flibanserin antagonized the effect of microiontophoretically-applied DOI in the medial prefrontal cortex (mPFC) following 2 days of administration, indicating antagonism of postsynaptic 5-HT2A receptors. This reduction in the effect of locally-applied DOI was no longer present following 7-day flibanserin administration. Two-day flibanserin administration only marginally reduced the firing activity of dorsal raphe (DRN) 5-HT neurons. Following 7 days of administration, 5-HT neuronal firing activity had returned to normal and the somatodendritic 5-HT1A autoreceptors were desensitized. The responsiveness of postsynaptic 5-HT1A receptors located on CA3 hippocampus pyramidal neurons and mPFC neurons, examined using microiontophoretically-applied 5-HT and gepirone, was unchanged following a 7-day flibanserin treatment. As demonstrated by the ability of the 5-HT1A receptor antagonist WAY 100635 to selectively increase the firing of hippocampal neurons in 2- and 7-day treated rats, flibanserin enhanced the tonic activation of postsynaptic 5-HT1A receptors in this brain region. The results suggest that flibanserin could be a therapeutically useful compound putatively endowed with a more rapid onset of antidepressant action.

Changes in Dopamine 2 and Serotonin Receptors in Rat Brain after Long-Term Verapamil Treatment: Comparison of Verapamil and Lithium

Rat brain 5-HT2 and dopamine2 receptors were assessed following a chronic (3 weeks) administration of verapamil, lithium, and a combination of these two drugs. A significant increase in the number of 5-HT2 receptors was observed in the frontal cortex after the verapamil treatment, but the lithium and combined treatment had no effect on the densities of either binding sites. These data suggest that one or more of the mechanisms of the antimanic effect of verapamil may be involved in the change in 5-HT2 binding sites in a manner that is different from that of lithium.

Chronic treatment with clozapine or haloperidol differentially regulates dopamine and serotonin receptors in rat brain

Long-term administration of the atypical neuroleptic clozapine (CLZ) poses a much lower risk of extrapyramidal side effects (EPS) than does the use of typical neuroleptics such as haloperidol (HAL). To investigate the neural mechanisms of the differing CNS activities of these two drugs, we used quantitative autoradiography to measure changes in dopamine and serotonin receptors in rats after injection with CLZ or HAL for 21 days at clinically relevant dose ratios. Levels of D1, D2, and 5-HT2 receptors were determined in frontal cortex, caudate-putamen, and nucleus accumbens. Rats that received CLZ chronically showed CNS receptor changes markedly different from those in chronic HAL-treated animals. Whereas rats treated chronically with HAL showed enhanced striatal D2 binding (average increase of 42%), those treated with CLZ did not. In contrast, chronic CLZ, but not chronic HAL, induced enhanced striatal D1 binding (average increase of 43%). Finally, CLZ treatment decreased 5-HT2 receptor binding by an average of 37%, while HAL had no significant effect. The effects of chronic HAL or CLZ treatment on receptors were similar in all forebrain areas examined. However, since D1 and 5-HT2 receptors are more abundant than D2 sites in limbic and neocortical areas, the preferential modulation of D1 and 5-HT2 receptors by CLZ suggests a greater impact of this atypical neuroleptic on activity of the limbic system than that achieved by the typical neuroleptic, HAL. These findings suggest that the clinical profile of atypical neuroleptics such as CLZ may be attributed to their effects on a receptor profile differing in pharmacological characteristics and anatomical distribution from that affected by typical neuroleptics.

Interaction of SM-3997 with serotonin receptors in rat brain.

The propensity of SM-3997 to displace 3H-ligands was tested in vitro in a number of receptor-binding assays. SM-3997 possessed a high affinity towards 5-HT1A receptors, low affinity towards dopamine (D2) and 5-HT2 receptors, and no affinity towards benzodiazepine (BZ), GABA, 5-HT1B and adrenergic receptors. Moreover, SM-3997 facilitated neither 3H-flunitrazepam binding nor 3H-muscimol binding. These results suggest that the action of SM-3997 may be mediated via central 5-HT1A receptors but not the BZ-GABA receptor complex.

Interaction of SM-3997 with Serotonin Receptors in Rat Brain

The propensity of SM-3997 to displace 3H-ligands was tested in vitro in a number of receptor-binding assays. SM-3997 possessed a high affinity towards 5-HT1A receptors, low affinity towards dopamine (D2) and 5-HT2 receptors, and no affinity towards benzodiazepine (BZ), GABA, 5-HT1B and adrenergic receptors. Moreover, SM-3997 facilitated neither 3H-flunitrazepam binding nor 3H-muscimol binding. These results suggest that the action of SM-3997 may be mediated via central 5-HT1A receptors but not the BZ-GABA receptor complex.

Beta-Adrenoceptor blocking agents recognize a subpopulation of serotonin receptors in brain.

The interaction of beta-adrenoceptor blocking agents with serotonin receptors in rat brain was analyzed by quantitative light microscopic autoradiography using (-) [125I]cyanopindolol (ICYP) as a ligand. In some brain areas such as the globus pallidus and dorsal subiculum, binding of ICYP was blocked with high affinity by some serotoninergic ligands, RU-24969 and serotonin, but not by lysergic acid diethylamide and 8-hydroxy-2-(N,N-di-n-propylamino)tetralin. Some beta-blockers also showed high affinity for these sites. These results supply direct evidence for the labeling of a subclass of serotonin receptors, the 5-HT-1B class, providing anatomical and pharmacological basis for some known serotonin-related effects of beta-adrenoceptor drugs.

Acute and chronic phencyclidine administration changes serotonin receptors in rat brain

Acute and chronic phencyclidine administration changes serotonin receptors in rat brain

Inhibitory effect of lithium on neuroleptic and serotonin receptors in rat brain

We investigated the effect of acute and chronic administration of lithium on neuroleptic receptors ([ 3H]spiroperidol binding sites) and serotonin receptors ([ 3H]serotonin binding sites) in rat brain. In the limbic-forebrain, both acute and chronic lithium treatment significantly reduced the density (B max) of neuroleptic receptors, without affecting the affinity ( K d ) of those receptors. However, lithium treatment had no apparent effect on neuroleptic receptors in the caudate-putamen and frontal cortex in either acute or chronic administrations. On the other hand, acute lithium administration markedly decreased the K d and B max of serotonin receptors in the hippocampus, but not in the cerebral cortez; this distinct observation was also found in animals chronically treated with lithium. These results indicate that lithium has an inhibitory effect on neuroleptic receptors in the limbic-forebrain and on serotonin receptors in the hippocampus. Therefore, it is possible to postulate that these effects of lithium in specific brain regions may be related to the therapeutic mechanism of this drug in affective disorders.

Dopamine, serotonin and alpha-adrenergic receptor blocking activities in serum and their relationships to prolactin level in schizophrenic patients receiving long-term chlorpromazine treatment.

The clinical application of a dopamine radioreceptor assay for neuroleptics has been proposed. Simultaneous monitoring of serum antidopaminergic (anti-DA), antiserotonergic (anti-5HT) antiadrenergic (anti-NA) activities may provide a better understanding of clinical effects of neuroleptics. Serum anti-DA and anti-5HT activities were estimated by competition for 3H-spiperone binding to dopamine and serotonin receptors in rat brain, respectively, and anti-NA activity by competition for 3H-WB-4101 binding to alpha-receptors. Thirty-one patients receiving maintenance doses of chlorpromazine (CPZ) chronically were studied. Serum activities varied among patients receiving the same dose, but correlated significantly with dose. Anti-DA activity also correlated with both anti-5HT anti-NA activities, and the average ratio of anti-5HT or anti-NA to anti-DA activity was slightly reduced by metabolism of CPZ. However, some patients had a different spectrum of serum activities from that of in vitro activities. Serum prolactin (PRL) correlated weakly with all the serum activities. The serum PRL anti-DA activity ratio appeared to be independent of anti-5HT or anti-NA activity, suggesting the predominant involvement of anti-DA activity in the stimulation of PRL release.

Pharmacological evidence for the existence of two distinct serotonin receptors in rat brain

The effect of a series of indoleamines on the potassium-evoked release of previously accumulated [ 3H]serotonin from slices of rat raphe nuclei has been studied. Indoleamine agonists produced a dose-related inhibition of potassium-evoked tritium release which was reversed by methiothepin, metergoline minaserin and methysergide but not cyproheptadine or cinanserin. The relative order of antagonist potency for this effect was different from that obtained for the antagonism of indoleamine-induced inhibition of potassium-evoked tritium release from rat striatal slices previously loaded with [ 3H]-dopamine. The results show that the serotonin-autoreceptor located on cell bodies and dendrites in the raphe nucleus is different from the postsynaptic serotonin receptor located on dopamine nerve terminals in the striatum.

Lithium: Effects on serotonin receptors in rat brain

The effects of lithium on serotonin receptors in rat brain were investigated. Chronic administration of lithium resulted in reduced density of serotonin receptors in the hippocampus but no apparent effects in the cortex. Lithium in vitro had no effect on serotonin receptors in the cortex or hippocampus.