Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many studies of schizophrenic brains indicate the dysfunction of dopamine and glutamate systems in the prefrontal and frontal cortex. It seems that better understanding of mechanisms regulating functions of these neuronal cortical systems could contribute to creation of new drugs acting in the cortex selectively. This might be profitable in cognition of dysfunction and negative symptoms in schizophrenia. This article presents preclinical data concerning the role of 5-HT1A serotonin receptors in the modulation of cortical dopamine system and in psychotomimetic effects of non-competitive NMDA receptor antagonists. Neurochemical studies have shown that 5-HT1A receptor agonists increase dopamine release in the rat prefrontal cortex on the one hand, and they inhibit the augmentation of dopamine release induced by stress or amphetamine, on the other. However, the increase of dopamine release induced by non-competitive NMDA receptor antagonists is blocked by 5-HT1A receptor antagonists. Blockade of 5-HT1A receptors seems to be important also in reduction of most psychotomimetic effects induced by non-competitive NMDA antagonists both involving (locomotor hyperactivity, working memory impair) and not involving (sensorimotor gating deficits) dopamine mechanism. Thus, binding with 5-HT1A receptors can be an important site for the regulation of cortical dopamine system, both in physiological conditions and in disregulation of the system induced by stress, psychostimulants or psychotomimetics. On the other hand, 5-HT1A receptors modulate most of psychotomimetic effects of non-competitive NMDA receptor antagonists. The above results of preclinical investigations indicate that 5-HT1A receptor can be involved in the pathology of schizophrenia, what is partly confirmed by clinical postmortem studies of schizophrenic brains. These studies showed the increase of 5-HT1A receptor density in prefrontal and frontal cortex in schizophrenic brains. It also seems that 5-HT1A receptors might be a good target for the antipsychotic drugs. Although the clinical studies have demonstrated controversial data, maybe further studies using substances with selectivity to 5-HT1A receptors would help to determine more precisely the role of these receptors in pathology and pharmacotherapy of schizophrenia.
 ...
PMID:[The involvement of 5-HT1a serotonin receptors in the pathophysiology and pharmacotherapy of schizophrenia]. 1105 60

As a testable heuristic, the concept of stress response and adaptation is highly appealing, and the support for the concept is strong. This explanatory model of depression may account for hitherto apparently discordant facts--contradictory symptoms, antidepressant drugs that act on differing systems, facilitation of antidepressant response by augmentation, and response to psychotherapy and pharmacotherapy. This article has focused narrowly on specific cellular elements of the stress-adaptational mechanisms, including the AC-PKA and PLC-PKC transductional cascades, together with specific response elements, such as the HPA axis, BDNF, and NMDA receptors; however, other important mechanisms, including specific receptor subtypes (e.g., 5-HT1A and NE alpha 2), transmitter systems (e.g., acetylcholine and depamine), and hormones (e.g., thyroid and growth hormones and prolactin), which may be important, have not been discussed. As the complex interactions of these systems gradually yield to investigation, not only will new treatments be developed, but better matching of treatment to patient may become an achievable goal.
 ...
PMID:Cellular mechanisms in the vulnerability to depression and response to antidepressants. 1114 43

Prolactin secretion is controlled by the hypothalamus through different neurotransmitters which interact with multiple receptor subtypes. The discovery of different families of receptors for serotonin (5-HT1-5-HT7) and excitatory aminoacids (NMDA, KA, AMPA and metabotropic receptors) ilustrates the complexity of this regulation. Moreover, in the rat the role of different neurotransmitters changes during pubertal development. Present experiments were carried out to analyse the interactions between AMPA and serotoninergic receptors in the control of prolactin secretion in prepubertal male rats. For this purpose, 16 and 23-day old male rats were treated with 5-hydroxytryptophan (5-HTP, precursor of serotonin synthesis) plus fluoxetine (blocker of serotonin reuptake), 8-OH-DPAT (agonist of 5-HT1A receptors), DOI and alpha-Me-5-HT (agonists of 5-HT2 receptors), 1-phenylbiguanide (agonist of 5-HT3 receptors) alone or in combination with AMPA (agonist of AMPA receptors). The results obtained indicate that: (a) activation of 5-HT1A receptors stimulated PRL secretion on day 16 and inhibited it on day 23; activation of 5-HT2 receptors stimulated PRL secretion on days 16 and 23, whereas activation of 5-HT3 receptors inhibited PRL release only on day 23; (b) activation of AMPA receptors inhibited PRL secretion on day 23, but not on day 16 and (c) a cross-talk is apparent between 5-HT2 and AMPA receptors in the regulation of PRL secretion, the stimulatory effect of DOI being blocked by AMPA.
 ...
PMID:Interactions between serotoninergic and aminoacidergic pathways in the control of PRL secretion in prepubertal male rats. 1180 Feb 86

Neuropathological studies in autistic brains have shown small neuronal size and increased cell packing density in a variety of limbic system structures including the hippocampus, a change consistent with curtailment of normal development. Based on these observations in the hippocampus, a series of quantitative receptor autoradiographic studies were undertaken to determine the density and distribution of eight types of neurotransmitter receptors from four neurotransmitter systems (GABAergic, serotoninergic [5-HT], cholinergic, and glutamatergic). Data from these single concentration ligand binding studies indicate that the GABAergic receptor system (3[H]-flunitrazepam labeled benzodiazepine binding sites and 3[H]-muscimol labeled GABA(A) receptors) is significantly reduced in high binding regions, marking for the first time an abnormality in the GABA system in autism. In contrast, the density and distribution of the other six receptors studied (3[H]-80H-DPAT labeled 5-HT1A receptors, 3[H]-ketanserin labeled 5-HT2 receptors, 3[H]-pirenzepine labled M1 receptors, 3[H]-hemicholinium labeled high affinity choline uptake sites, 3[H]-MK801 labeled NMDA receptors, and 3[H]-kainate labeled kainate receptors) in the hippocampus did not demonstrate any statistically significant differences in binding.
 ...
PMID:Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. 1181 63

It has been well-known that abuse of psychostimulants such as amphetamine and methamphetamine (MAP) induces behavioral sensitization (reverse tolerance) to MAP, resulting in psychotic effects such as hallucinatory-delusional state. Animals treated with MAP repeatedly also show the behavioral sensitization to MAP. This paper focuses on the pathogenesis and mechanism underlying sensitization to MAP after repeated treatment with MAP. MAP is known to release dopamine (DA), noradrenalin (NA) and serotonin (5-HT), and bind with the same sites on DA-, NA- and 5-HT-transporters as do these monoamines, thereby inhibiting re-uptake of these substances. As a result, these monoamines accumulate in the synaptic areas unnerved by the monoamine systems. An increase in the monoamines also occurs in the dendritic areas of DA, NA and 5-HT cells probably by a mechanism similar to those in the presynaptic terminals of monoamines. Releases and syntheses of DA, NA and 5-HT are inhibited by the monoamine per se via their autoreceptors such as D2, alpha 2 and 5-HT1A receptors, respectively. It is noteworthy that repeated MAP treatment results in the reduction of DA transporters, and such a decrease in transporters has been also found in MAP abusers by PET studies, suggesting a decrease in DA transporters is related with the appearance of reverse tolerance. Repeated MAP administration induces immediate early gene such as c-fos, c-jun and arc, and the increase in arc is inhibited by D1 and NMDA antagonists, suggesting an important role of such genes in inducing reverse tolerance. In electrophysiological studies using anesthetized rats treated with MAP repeatedly, hyposensitivities and hypersensitivities to DA and MAP have been found in nucleus accumbens receiving dopaminergic input from ventral tegmental area, 24-30 h and 5 days after the final administration of MAP, respectively, although the sensitivities recovered to the normal level 10 days after the treatment. The hypersensitivities were probably mediated via D1/D2 receptors. Thus, the hypersensitivities of nucleus accumbens neurons to DA and MAP are actually completed after repeated treatment of MAP. Therefore, it is of great interest to elucidate the molecular mechanism responsible for the DA receptor hypersensitivity.
 ...
PMID:[Alteration of neuronal activities following repeated administration of stimulants]. 1191 3

Recent evidence indicates that serotonin (5-HT)1A receptor agonists may abrogate excitotoxic brain damage. We investigated whether a single i.p. injection of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), at a dose of 2.5 mg/kg, protects cholinergic neurons of the rat magnocellular nucleus basalis (MBN) against NMDA excitotoxicity when administered at post-injury intervals ranging from 6 to 96 h. Drug effects on passive avoidance learning and on the density of cortical cholinergic innervation, a measure of neuronal survival in the damaged MBN, were analyzed. Our results demonstrate that 8-OH-DPAT, when administered up to 24 h post-lesion, significantly attenuates both behavioral and neuroanatomical consequences of NMDA excitotoxicity on cholinergic MBN neurons; and support the hypothesis that 5-HT1A receptor agonists may interfere with delayed neuronal death in vivo that is of significance in the pharmacological treatment of neurological disorders associated with excitotoxic neuronal damage.
 ...
PMID:Post-lesion administration of 5-HT1A receptor agonist 8-OH-DPAT protects cholinergic nucleus basalis neurons against NMDA excitotoxicity. 1254 31

Pyramidal neurons of the medial prefrontal cortex (mPFC) project to midbrain serotonergic neurons and control their activity. The stimulation of prefrontal 5-HT2A and AMPA receptors increases pyramidal and serotonergic cell firing, and 5-hydroxytryptamine (5-HT) release in mPFC. As the mPFC contains abundant alpha1-adrenoceptors whose activation increases the excitability of pyramidal neurons, we examined the effects of their stimulation on local 5-HT release, using microdialysis. The application of the alpha1-adrenoceptor agonist cirazoline by reverse dialysis increased the prefrontal 5-HT release in a concentration-dependent manner, an effect antagonized by coperfusion of TTX, prazosin (alpha1-adrenoceptor antagonist), BAY x 3702 (5-HT1A agonist), NBQX (AMPA/KA antagonist) and 1S,3S-ACPD (mGluR II/III agonist), but not by MK-801 (NMDA antagonist). Cirazoline also enhanced the increase in 5-HT release induced by DOI (5-HT2A/2C agonist) and AMPA. In addition, M100907 (5-HT2A antagonist) but not SB-242084 (5-HT2C antagonist) reversed the cirazoline- and AMPA-induced 5-HT release. These results suggest that the stimulation of prefrontal alpha1-adrenoceptors activates pyramidal afferents to ascending serotonergic neurons. The effect of cirazoline was also reversed by coperfusion of classical (chlorpromazine, haloperidol) and atypical (clozapine, olanzapine) antipsychotics, which suggests that a functional antagonism of the alpha1-adrenoceptor-mediated activation of prefrontal neurons may partly underlie their therapeutic action.
 ...
PMID:Stimulation of alpha1-adrenoceptors in the rat medial prefrontal cortex increases the local in vivo 5-hydroxytryptamine release: reversal by antipsychotic drugs. 1462 14

The confirmed pharmacological treatment of cerebellar ataxia is still lacking. In a recent preliminary trial, we showed that D-cycloserine, a partial NMDA allosteric agonist, may relieve the symptoms. In this paper, major clinical trials to relieve ataxic symptoms are reviewed. Previous studies showed some efficacy of physostigmine in ataxic patients. However, physostigmine did not improve the ataxia in a recent double-blind crossover study. The replacement therapy of the deficient cholinergic system with choline or choline derivatives was tried in patients with Friedreich's ataxia and other ataxic patients, but the result was not definitive. A levorotatory form of hydroxytryptophan (a serotonin precursor), a serotoninergic 5-HT1A agonist, a serotoninergic 5-HT3 antagonist, and a serotonin reuptake inhibitor were also used for the therapy for ataxia. In a double-blind randomized study, buspirone, a 5-HT1A agonist was active in cerebellar ataxia, but the effect is partial and not major. The effects of the studies with the other serotoninergic drugs were not consistent. The effect of sulfamethoxazole-trimethoprim therapy in spinocerebellar ataxia type3/Machado-Joseph disease (MJD) was reported, although the therapy improved spasticity or rigidity, rather than ataxia. In contrast to previous studies, sulfamethoxazole-trimethoprim therapy in MJD had no effect in a 2001 double-blind crossover study. The thyrotropin-releasing hormone, D-cycloserine, and acetazolamide for SCA6 may have some efficacy. However, a well-designed double-blind crossover trial is needed to confirm the effect.
 ...
PMID:Pharmacological treatments of cerebellar ataxia. 1523 78

Brodmann's area (BA) 5 of the human superior parietal cortex occupies a central anatomical position between the primary motor (BA 4), somatosensory (area 3b and BA 2), cingulate (area 23c), and superior parietal association cortex (BA 7). We studied the regional and laminar distributions of the binding sites of 12 different neurotransmitter receptors (glutamatergic: AMPA, kainate, NMDA; GABAergic: GABAA, GABAB; cholinergic: muscarinic M2, nicotinic; adrenergic: alpha1, alpha2; serotoninergic: 5-HT1A, 5-HT2; dopaminergic: D1) in human postmortem brains by means of quantitative receptor autoradiography, since the structural and functional aspects of human BA 5 are widely unknown, and previous observations have demonstrated characteristic differences in receptor distribution between motor and somatosensory areas. Binding site densities were measured in the cytoarchitectonically defined BA 5 and surrounding regions. Similarities and differences of receptor distribution between cortical areas were studied by cluster analysis of mean binding site densities averaged over all cortical layers, univariate and multivariate statistics, and by density profiles representing laminar receptor distribution patterns. Based on regional heterogeneities of binding site densities and of the cytoarchitecture within BA 5, we suggest a subdivision into three subareas: medial area 5M, lateral area 5L, and area 5Ci in the region around the cingulate sulcus. BA 5 is therefore a heterogeneous cortical region, comprising three subareas showing receptor expression patterns similar to the adjoining higher order somatosensory, multimodal parietal, or cingulate regions. These findings suggest that human BA 5 constitutes a higher order cortical area, clearly distinct from the primary somatosensory and motor cortex.
 ...
PMID:Subdivisions of human parietal area 5 revealed by quantitative receptor autoradiography: a parietal region between motor, somatosensory, and cingulate cortical areas. 1580 98

Dizocilpine (MK-801; 0.3 mg/kg i.p.)-induced disruption in prepulse inhibition of the acoustic startle response (PPI) can be preferentially restored by "atypical" antipsychotics. In contrast, some findings indicate that not all of the "atypical" antipsychotics, such as clozapine and risperidone, are effective in restoring the NMDA antagonist-induced deficits in PPI. In our study, we evaluated the effect of four different "atypical" antipsychotic drugs on deficits in PPI induced by MK-801. Zotepine and risperidone have high affinities to D2-like and 5-HT2A receptors, while clozapine and olanzapine have multipharmacological profiles with the highest affinities to serotonin 5-HT1A,2A/2C receptors and muscarinic receptors. Results have shown that MK-801 disrupted PPI and increased the ASR in rats. Our results showed no effect of zotepine (1 and 2 mg/kg) and risperidone (0.1 and 1 mg/kg) on disrupted PPI by MK-801. Administration of clozapine (5 and 10 mg/kg) and olanzapine (2.5 and 5 mg/kg) restored the deficits in PPI induced by MK-801. Additionally, we found a decrease of approximately 46% in PPI after administration of clozapine (5 mg/kg) and olanzapine (2.5 and 5 mg/kg) without MK-801 treatment. In summary, the four "atypical" antipsychotics had different efficacies to restore the disrupted PPI by MK-801. Only clozapine and olanzapin restored the MK-801-induced deficits in PPI.
 ...
PMID:The effect of zotepine, risperidone, clozapine and olanzapine on MK-801-disrupted sensorimotor gating. 1582 May 28


<< Previous 1 2 3 4 5 6 7 Next >>