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

Irreversible inactivation of striatal D2 dopamine (DA) autoreceptors with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) or inactivation of striatal guanine nucleotide binding proteins (G proteins) with pertussis toxin (PT) shifted the dose-response curve for N-n-propylnorapomorphine (NPA)-mediated inhibition of gamma-butyrolactone (GBL)-induced elevation of L-3,4-dihydroxyphenylalanine (L-DOPA) to the right, with a decrease in the maximum response. For the partial agonist (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(+)-3-PPP], in contrast, there was little shift in the ED50, after inactivation of either D2 receptors or G proteins. Completely analogous effects were found at the somatodendritic 5-HT1A autoreceptor in the raphe nuclei, mediating inhibition of the synthesis of serotonin (5-HT); the full agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the partial agonist, buspirone were utilized to inhibit the synthesis of 5-HT, as measured by changes in levels of L-5-hydroxytryptophan (5-HTP). Additionally, in both systems, combined treatment with pertussis toxin, followed by EEDQ, reduced the maximum effect, when compared to either agent alone but had little further effect on the ED50. In systems exhibiting a large receptor reserve for agonists, such as those described above, the same pattern of response seen after inactivation of receptors or G proteins may reflect the operation of a common mechanism underlying the phenomenon of receptor reserve.
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PMID:The effects of pertussis toxin on dopamine D2 and serotonin 5-HT1A autoreceptor-mediated inhibition of neurotransmitter synthesis: relationship to receptor reserve. 135 48

A new potential antihypertensive drug, EMD 45609 (carmoxirole), has been characterized in various in vivo and in vitro models. EMD 45609 displayed high affinity for dopamine D2-receptors combined with negligible binding to D1-receptors in binding assays in vitro. However, in tests in vivo for central D2-receptor activity, EMD 45609 exhibited only weak activity. Thus, after p.o. administration, striatal L-DOPA accumulation in intact rats was unchanged up to 100 mg/kg p.o., i.e. doses 100 times higher than those reported to induce depressor activity. Central dopamine agonistic activity could only be verified in the more sensitive model of the reserpinized rat. EMD 45609 was more than 30 times less potent, however, than LY 141865 in reserpinized rats after s.c. administration. Similarly, in rats with 6-hydroxydopamine induced unilateral lesions of the substantia nigra, EMD 45609 was only marginally active. The shallow dose response curves and the submaximal effects obtained for central dopaminergic activity, as reflected in the inhibition of striatal L-DOPA accumulation, suggest that EMD 45609 is a partial dopamine D2-receptor agonist and in addition, owing to its ionizable structure, passes less readily into the brain than several reference compounds. A marked affinity was found towards 5-HT1A-receptors in vitro, whereas affinity for alpha 1- and alpha 2-adrenoceptors was low; accordingly, central alpha 2-adrenoceptor activity was not detected as EMD 45609 failed to affect hypothalamic L-DOPA accumulation even at 100 mg/kg s.c. In accordance with its high affinity for D2-receptors in vitro, EMD 45609 inhibited field stimulated noradrenaline release from rabbit ear arteries in nanomolar threshold concentrations at 0.5 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neurochemical profile of EMD 45609 (carmoxirole), a dopamine DA2-receptor agonist. 168 17

The partial dopamine receptor agonists SDZ 208-911 (N-[(8-alpha)-2,6-dimethylergoline-8-yl]-2,2-dimethylpropanamid e), SDZ 208-912 (N-[8-alpha)-2-chloro-6-methylergoline-8-yl]-2,2- dimethylpropanamide) and terguride (transdihydrolisuride; TDHL) were tested in biochemical, behavioral (locomotor activity) and electrophysiological assays in male rats. In reserpine-pretreated rats, SDZ 208-911 and terguride dose-dependently reduced striatal DOPA formation (NSD 1015 treatment) with similar efficacy (-80%) and potency as the selective D2 receptor agonist quinpirole (LY 171555). SDZ 208-912 only produced a partial reduction (-32%) at the highest dose tested. SDZ 208-911 and terguride partially reversed (by approximately 50%) the gamma-butyrolactone (GBL)-induced increase in striatal DOPA accumulation. Quinpirole produced a 100% reversal while SDZ208-912, per se, was inactive. While quinpirole decreased DOPA accumulation, all three partial agonists elevated striatal DOPA accumulation in non-pretreated rats with SDZ 208-912 being as potent and efficacious as haloperidol. The three partial agonists displayed comparatively high affinities in vitro for the dopamine D2 (3H-spiperone) receptor site and somewhat lower affinity for the 5-HT1A (3H-8-OH-DPAT) receptor site. SDZ 208-911 and SDZ 208-912 also showed high affinities for central alpha 2 (3H-idazoxane) receptors. In line with these findings, the partial ergoline agonists dose-dependently elevated the DOPA accumulation in the noradrenaline-rich cortical brain region and decreased the 5-HT synthesis rate (5-HTP accumulation) in the limbic brain region. Furthermore, high doses of SDZ 208-911 and terguride produced weak signs of the 5-HT behavioral syndrome (flat body posture) in reserpinized rats. In the locomotor activity studies in non-pretreated rats, SDZ 208-911, SDZ 208-912 and terguride reduced the activity to 10-20% of controls with SDZ 208-912 being approximately ten times less potent than the other two compounds. Weak postsynaptic dopamine receptor agonist effects of the partial agonists were demonstrated only in reserpine-pretreated rats; all three partial agonists tested produced occasional forward locomotion and the so-called "jerking" behavior. Extracellular single unit recordings were carried out in chloral hydrate-anesthetized rats to investigate the effects on firing rates of dopamine neurons located in the substantia nigra pars compacta. Intravenous administration of SDZ 208-911 and terguride depressed the firing rate by 42 and 53%, respectively, while apomorphine completely inhibited the cells. SDZ 208-912 only reduced the firing by 16% and some cells displayed a biphasic response with a weak depression at low doses that disappeared at high doses.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of the partial dopamine receptor agonists SDZ 208-911, SDZ 208-912 and terguride on central monoamine receptors. A behavioral, biochemical and electrophysiological study. 168 86

The concentrations and synthesis of monoamines in various hypothalamic nuclei and the influence of monoaminergic drugs on food intake were studied in two rat lines produced by selective outbreeding for voluntary high and low alcohol drinking. The hypothalamic nuclei of the alcohol-preferring AA rats contained slightly more serotonin than those of the alcohol-avoiding ANA rats, but the accumulation of 5-hydroxytryptophan after inhibition of aromatic amino acid decarboxylase was the same in both lines. There was no significant difference in the basal concentrations of catecholamines between the lines, but the accumulation of L-DOPA was significantly greater in the ANA than the AA rats, suggesting differences in catecholamine turnover. This difference was significant in the paraventricular nucleus, which is involved in the regulation of food intake. Clonidine (an alpha 2-agonist) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT1A agonist) induced hyperphagia and 1-(3-trifluoromethylphenyl)piperazine (TFMPP, a 5-HT1B agonist) induced hypophagia dose-dependently in both rat lines. Clonidine tended to be more potent in the ANA than the AA rats. Food intake following a 20-h fast was significantly lower in the ANA than AA rats. These results suggest that the alcohol-avoiding ANA and alcohol-preferring AA rats have different hypothalamic monoamine mechanisms controlling food intake, which could also partially account for their differential alcohol acceptance.
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PMID:Hypothalamic monoamines and food intake in alcohol-preferring AA and alcohol-avoiding ANA rats. 182 11

The 5-HT1A receptor agonists flesinoxan (0.2-3.2 mg kg-1 s.c.) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.025-0.4 mg kg-1 s.c.) produced (1) a dose-dependent facilitation of male rat ejaculatory behavior and (2) characteristic, dose-dependent effects on spontaneous motor activity. Thus, total locomotor activity and rearing activity were decreased. However, forward locomotion and peripheral locomotion were increased relative to the total horizontal activity. Furthermore, (3) 5-HTP accumulation, after inhibition of cerebral decarboxylase, was dose dependently decreased by both compounds in the ventral striatum and in the prefrontal cortex. There was a statistically significant decrease in DOPA accumulation in the ventral striatum after administration of a high dose of flesinoxan (3.2 mg kg-1), and a tendency for 8-OH-DPAT to produce the same effect. The efficacy of the compounds to affect male rat sexual behavior, spontaneous motor activity in the open-field and forebrain 5-HT synthesis was approximately the same, whereas flesinoxan was about an order of magnitude less potent than 8-OH-DPAT.
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PMID:Behavioral and biochemical effects of the 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT in the rat. 183 33

The administration of the 5-HT1A agonist 8-OH-DPAT (0.8 mumols kg-1 s.c.-40 min) produced an increase in dopamine (DA) turnover, estimated by the quotient (DOPAC + HVA) DA-1, in the ventral striatum of the rat. No statistically significant effects were obtained in the dorsal striatum. The accumulation of 3-MT in pargyline-treated animals (375 mumols kg-1 s.c.-60 min) was not affected by 8-OH-DPAT treatment (0.15-2.4 mumols kg-1 s.c.-30 min). These findings indicate that 8-OH-DPAT has weak antagonist properties at striatal DA receptors in normal rats. Both the 5-HT1A agonist flesinoxan (0.06-17.8 mumos kg-1 s.c. -50 min) and the mixed 5-HT1 and 5-HT2 agonist 5-MeODMT (1.6-26.0 mumols kg-1 s.c.-50 min) produced a decrease in forebrain 5-HTP accumulation (striatum and neocortex), following decarboxylase inhibition by means of NSD-1015 in reserpine treated rats, indicating stimulation of central 5-HT receptors by these two compounds. At the same time, the DOPA accumulation by the ventral striatum was decreased by flesinoxan and increased by 5-MeODMT treatment. These observations show that, under these conditions, the decrease in DA synthesis is not directly coupled to the decreased 5-HT synthesis produced by flesinoxan, as previously demonstrated for 8-OH-DPAT. Taken together with previous observations, the present results suggest that 8-OH-DPAT, depending on the experimental conditions, is an agonist or antagonist at striatal DA receptors, in all probability due to partial DA receptor agonist properties of the compound.
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PMID:Increased dopamine turnover in the ventral striatum by 8-OH-DPAT administration in the rat. 197

The ability of selective and nonselective 5-HT1A agonists, nondirect 5-HT agonists and 5-HT2 antagonists influence on the L-DOPA-disturbed rats behaviour were studied. The results indicate that agonists 5-HT1A like receptors largely than 5-HT2,3 agonists, 5-HT2 antagonists and nondirect 5-HT agonists promote restoration of the L-DOPA disturbed escape behaviour in acute stress situation.
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PMID:[The agonists of I-A serotoninergic receptors restore in rats behavior impaired by L-dihydroxyphenylalanine]. 208 66

Regional dopamine synthesis in the rat striatum was estimated by measuring DOPA accumulation following inhibition of cerebral aromatic L-amino acid decarboxylase by means of NSD-1015, 100 mg kg-1 intraperitoneally. In animals treated with reserpine, 5 mg kg-1 subcutaneously -18 h, there was a statistically significant increase in DOPA accumulation in the nucleus accumbens, the ventro-medial neostriatum, the dorso-lateral neostriatum and in the posterior limb of the neostriatum. This increase in DOPA accumulation was antagonized dose-dependently in the nucleus accumbens and ventro-medial neostriatum, but not in the other two regions, by treatment with the 5-HT1A receptor agonist 8-OH-DPAT, 0.15-2.4 mumol kg-1, whereas the partial dopamine D2 receptor agonist (-)3-PPP, 2.5-10.0 mumol kg-1, or the full dopamine D2 receptor agonist quinpirole, 0.05-0.8 mumol kg-1, antagonized the reserpine-induced increase in DOPA accumulation uniformly in all four regions of the striatum. The suppression of DOPA accumulation by 8-OH-DPAT in reserpine-treated animals, was completely antagonized by raclopride, 1 mumol kg-1, but not by (-)pindolol, 8 mumol kg-1. The accumulation of 5-HTP in all regions of the striatum as well as in the neocortex following decarboxylase inhibition and reserpine pretreatment, was also inhibited by 8-OH-DPAT, and this inhibition was unaffected by treatment with raclopride or (-)pindolol. It is concluded that 8-OH-DPAT, in addition to general effects on forebrain 5-hydroxytryptamine synthesis, selectively affects limbic forebrain dopamine synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for selective inhibition of limbic forebrain dopamine synthesis by 8-OH-DPAT in the rat. 257 Mar 61

The putative serotonin (5-HT)1A agonist 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluormethylphenyl) piperazine (LY165163, PAPP) induces hyperphagia and hypothermia in rats, but unlike other 5-HT agonists, does not induce 5-HT stereotypy even at high doses (10 mg/kg sc). LY165163 (1 mg/kg) increased striatal DOPA accumulation in animals treated with the aromatic amino acid decarboxylase inhibitor 3-hydroxy-benzylhydrazine (NSD 1015) (100 mg/kg ip). This increase was also found when the drug was given to animals pretreated with parachlorophenylalanine (pCPA) (150 mg/kg ip daily for 3 days). LY165163 (2 and 4 mg/kg sc) inhibited stereotyped behaviour induced by the dopamine (DA) agonist apomorphine (2 mg/kg sc). LY165163 (2, 4, 10 mg/kg sc) also inhibited stereotyped components of the 5-HT syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 5 mg/kg ip) which previous studies (e.g. Andrews et al. 1982) suggested to require DA (head weaving, reciprocal forepaw treading). Thus, while other 5-HT1A agonists such as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) cause stereotypy, this does not occur with LY165163, probably because the drug blocks DA receptors.
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PMID:Blockade of dopamine receptors explains the lack of 5-HT stereotypy on treatment with the putative 5-HT1A agonist LY165163. 295 21

The central regulation of blood pressure and other cardiovascular parameters may involve the baroreceptor reflex are, including both adrenergic and serotonergic pathways, as well as amino acids, as neurotransmitters. Both adrenergic and serotonergic pathways have been recognized as targets for clinically relevant, centrally acting antihypertensives, such as clonidine, guanfacine, and alpha-methyl-DOPA. The central components of the hybrid drugs urapidil and ketanserin also involve serotonergic pathways and receptors. For urapidil the stimulation of 5-HT1A-receptors is assumed to induce peripheral sympathoinhibition, whereas for ketanserin the central mechanism is unknown in detail. More recently central imidazoline (I1) receptors have been proposed as the major target for the newer antihypertensives rilmenidine and moxonidine. Clonidine, however, is assumed to be mixed I1- and alpha2-receptor agonist. The distinction between central I1- and alpha2-receptors may potentially offer the design of new antihypertensives, acting like clonidine but with fewer side effects. Finally, the amino acid pathways should be considered as potential targets for centrally acting antihypertensives. Experimental compounds on this basis are available but clinical implications appear to be very remote. In the present survey an outline is given of the various pathways, neurotransmitters, and receptors involved in the central regulation of blood pressure. The different types of centrally acting antihypertensives are subsequently discussed on this basis.
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PMID:Different types of centrally acting antihypertensives and their targets in the central nervous system. 774 57


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