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)

The reciprocal interactions between galanin and 5-HT1A receptors in the rat brain are presented. Galanin and its NH2-terminal fragments antagonize 5-HT1A receptor-mediated transmission at the postjunctional level, whereas galanin receptor activation mimics the inhibitory action of 5-HT1A receptor activation at the soma-dendritic level, leading to reductions of 5-HT metabolism and release. These interactions have been shown in both receptor binding studies and functional studies. In view of the present findings, galanin antagonists may represent a new type of anti-depressant drug, based on the 5-HT hypothesis of depression, by enhancing 5-HT release and postjunctional 5-HT1A-mediated transmission. Moreover, following intracerebroventricular injection galanin was found to be internalized in a population of hippocampal nerve cells mainly representing GABA, somatostatin, and/or NPY-immunoreactive nerve cells. The relevance of these findings is discussed in relation to the concept of volume transmission.
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PMID:Galanin modulates 5-hydroxytryptamine functions. Focus on galanin and galanin fragment/5-hydroxytryptamine1A receptor interactions in the brain. 992 78

This review discusses efforts to develop rodent models for the study of neurobiological mechanisms underlying chronic alcohol drinking, alcoholism, and abnormal alcohol-seeking behavior. Selective breeding has produced stable lines of rats that reliably exhibit high and (for comparison purposes) low voluntary alcohol consumption. In addition, animal models of chronic ethanol self-administration have been developed in rodents, who do not have a genetic predisposition for high alcohol-seeking behavior, to explore environmental influences in ethanol drinking and the effects of physical dependence on alcohol self-administration. The selectively bred high-preference animals reliably self-administer ethanol by free-choice drinking and operantly respond for oral ethanol in amounts that produce pharmacologically meaningful blood alcohol concentrations (50 to 200 mg% and higher). In addition, the alcohol-preferring rats will self-administer ethanol by intragastric infusion. With chronic free-choice drinking, the high alcohol-preferring rats develop tolerance to the high-dose effects of ethanol and show signs of physical dependence after the withdrawal of alcohol. Compared with nonpreferring animals, the alcohol-preferring rats are less sensitive to the sedative-hypnotic effects of ethanol and develop tolerance more quickly to high-dose ethanol. Nonselected common stock rats can be trained to chronically self-administer ethanol following its initial presentation in a palatable sucrose or saccharin solution, and the gradual replacement of the sucrose or saccharin with ethanol (the sucrose/saccharin-fade technique). Moreover, rats that are trained in this manner and then made dependent by ethanol-vapor inhalation or liquid diet increase their ethanol self-administration during the withdrawal period. Both the selectively bred rats and common-stock rats demonstrate "relapse" and an alcohol deprivation effect following 2 or more weeks of abstinence. Systemic administration of agents that (1) increase synaptic levels of serotonin (5-HT) or dopamine (DA); (2) activate 5-HT1A, 5-HT2, D2, D3, or GABA(A) receptors; or (3) block opioid and 5-HT3 receptors decrease ethanol intake in most animal models. Neurochemical, neuroanatomical, and neuropharmacological studies indicate innate differences exist between the high alcohol-consuming and low alcohol-consuming rodents in various CNS limbic structures. In addition, reduced mesolimbic DA and 5-HT function have been observed during alcohol withdrawal in common stock rats. Depending on the animal model under study, abnormalities in the mesolimbic dopamine pathway, and/or the serotonin, opioid, and GABA systems that regulate this pathway may underlie vulnerability to the abnormal alcohol-seeking behavior in the genetic animal models.
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PMID:Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in rodents. 1034 15

1. The basolateral amygdala (ABL) nuclei contribute to the process of anxiety. GABAergic transmission is critical in these nuclei and serotonergic inputs from dorsal raphe nuclei also significantly regulate GABA release. In mechanically dissociated rat ABL neurons, spontaneous miniature inhibitory postsynaptic currents (mIPSCs) arising from attached GABAergic presynaptic nerve terminals were recorded with the nystatin-perforated patch method and pharmacological isolation. 2. 5-HT reversibly reduced the GABAergic mIPSC frequency without affecting the mean amplitude. The serotonergic effect was mimicked by the 5-HT1A specific agonist 8-OH DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) and blocked by the 5-HT1A antagonist spiperone. 3. The GTP-binding protein inhibitor N-ethylmaleimide removed the serotonergic inhibition of mIPSC frequency. In either K+-free or Ca2+-free external solution, 5-HT could inhibit mIPSC frequency. 4. High K+ stimulation increased mIPSC frequency and 8-OH DPAT inhibited this increase even in the presence of Cd2+. 5. Forskolin, an activator of adenylyl cyclase (AC), significantly increased synaptic GABA release frequency. Pretreatment with forskolin prevented the serotonergic inhibition of mIPSC frequency in both the standard and high K+ external solution. 6. Ruthenium Red (RR), an agent facilitating the secretory process in a Ca2+-independent manner, increased synaptic GABA release. 5-HT also suppressed RR-facilitated mIPSC frequency. 7. We conclude that 5-HT inhibits GABAergic mIPSCs by inactivating the AC-cAMP signal transduction pathway via a G-protein-coupled 5-HT1A receptor and this intracellular pathway directly acts on the GABA-releasing process independent of K+ and Ca2+ channels in the presynaptic nerve terminals.
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PMID:Presynaptic serotonergic inhibition of GABAergic synaptic transmission in mechanically dissociated rat basolateral amygdala neurons. 1038 97

This study examined effects of various psychoactive drugs on the Vogel conflict test, where drinking behavior is punished by electric shocks, in ICR mice to clarify the pharmacological features of this method in mice. A benzodiazepine anxiolytic diazepam and a barbiturate pentobarbital produced significant anticonflict effects, which mean that these drugs increased the number of electric shocks mice received during 40-min test session. On the other hand, yohimbine (alpha2-receptor antagonist), caffeine (adenosine-receptor antagonist), scopolamine (muscarinic cholinergic antagonist), cyclazocine (sigma-receptor antagonist), cimetidine (H2-receptor antagonist), baclofen (GABA(B)-receptor agonist), MK-801 (NMDA-receptor antagonist), buspirone (5-HT1A-receptor agonist), chlorpromazine (dopamine-receptor antagonist) and haloperidol (dopamine-receptor and sigma-receptor antagonist) all did not produce anticonflict effects in this test using ICR mice. The results suggest that the Vogel conflict test is applicable to ICR mice and that this test in mice is appropriate as a screening method for drugs that have apparent anti-anxiety actions.
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PMID:Effects of psychoactive drugs in the Vogel conflict test in mice. 1044 May 29

7-Methoxy-6-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy]-3,4-dim ethyl-2H-1-benzopyran-2-one hydro-chloride (KA-672), structurally related to naturally occurring coumarins, has been described as a potential drug for enhancing cognitive functions. However, a detailed characterization of the pharmacological profile of KA-672 in vivo is still lacking. Quantitative neurotransmitter receptor autoradiography was used as a tool to screen for KA-672-induced changes in a number of transmitter receptors including cholinergic, noradrenergic, glutamatergic, GABAergic, and serotonergic subtypes throughout the brain. Two hours following treatment of mice with 1 mg/kg KA-672 per os, slight increases of nicotinic and M1-muscarinic cholinergic receptor binding, of alpha2-and beta-adrenoceptor as well as 5-HT1A receptors in various cerebral cortical regions were observed, whereas 5-HT2A binding sites were strikingly increased throughout the brain following KA-672 treatment. In contrast, (+/-)-alphaamino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor binding was significantly decreased in some cortical regions after drug treatment. No effects of KA-672 treatment on N-methyl-D-aspartate, kainate, GABA(A) and benzodiazepine receptor as well as M2-muscarinic cholinergic and high-affinity choline uptake binding were observed. As interactions between the cholinergic, noradrenergic and serotonergic neurotransmission have been stressed to play important roles in realizing learning and memory events, the cognition-enhancing effects of KA-672 may be due to this complex in vivo pharmacological profile of KA-672.
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PMID:Acute effect of KA-672, a putative cognitive enhancer, on neurotransmitter receptor binding in mouse brain. 1054 21

Cholinergic neurons in the laterodorsal (LDT) and the pedunculopontine (PPT) tegmental nuclei act to promote REM sleep (REMS). The predominantly glutamatergic neurons of the REMS-induction region of the medial pontine reticular formation are in turn activated by cholinergic cells, which results in the occurrence of tonic and phasic components of REMS. All these neurons are inhibited by serotonergic (5-HT), noradrenergic, and presumably histaminergic (H2 receptor) and dopaminergic (D2 and D3 receptor) cells. 5-Hydroxytryptamine-containing neurons in the dorsal raphe nucleus (DRN) virtually cease firing when an animal starts REMS, consequently decreasing the release of 5-HT during this state. The activation of GABA(A) receptors is apparently responsible for this phenomenon. Systemic administration of the selective 5-HT1A receptor agonist 8-OHDPAT induces dose-dependent effects; i.e. low doses increase slow wave sleep and reduce waking, whereas large doses increase waking and reduce slow wave sleep and REM sleep. Direct injection of 8-OHDPAT or flesinoxan, another 5-HT1A agonist into the DRN, or microdialysis perfusion of 8-OHDPAT into the DRN significantly increases REMS. On the other hand, infusion of 8-OHDPAT into the LDT selectively inhibits REMS, as does direct administration into the DRN of the 5-HT1A receptor antagonists pindolol or WAY 100635. Thus, presently available evidence indicates that selective activation of the somatodendritic 5-HT1A receptor in the DRN induces an increase of REMS. On the other hand, activation of the postsynaptic 5-HT1A receptor at the level of the PPT/LDT nuclei decreases REMS occurrence.
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PMID:Role of dorsal raphe nucleus serotonin 5-HT1A receptor in the regulation of REM sleep. 1082 40

Central serotonergic systems play an important role in regulating mood/emotion, cognition, sleep and wakefulness, appetite and locomotion and body temperature via multiple receptor subtypes. Among them, 5-HT1A and 5-HT2A/2C receptors have opposite effects with respect to certain functions. The aim of the present study was to compare the effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A receptor agonist, and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a selective 5-HT2A/2C receptor agonist, on the performance of middle-aged rats in a two-lever choice reaction task that assessed attention and vigilance functions. We also examined the effects of aniracetam, a cognition enhancer, and its major metabolites on the induced performance impairments. 8-OH-DPAT (0.3 mg/kg s.c.) reduced response speed and choice accuracy and increased response omission with a reduction of task-associated motor activity without inducing motor inability or motivational changes. These findings indicate a specific disturbance of attentional and vigilance processes. DOI caused similar impairments at the highest dose tested (3 mg/kg s.c.); at a lower dose (1 mg/kg s.c.), however, it selectively attenuated the response speed, suggesting a selective attention deficit. (-)-Alprenolol, a non-selective 5-HT1A receptor antagonist, and ritanserin, a preferential 5-HT2A receptor antagonist, blocked the 8-OH-DPAT- and DOI-induced performance impairments respectively. Aniracetam ameliorated all the performance deficits, and the metabolites N-anisoyl-GABA and 2-pyrrolidinone partially mimicked the aniracetam effect in the 8-OHDPAT-induced attentional and vigilance impairments. Nefiracetam, another cognition enhancer, improved only the 8-OH-DPAT-induced impairments. Each compound tested alone had no effect on task performance. These results indicate that both serotonergic regulations, possibly via presynaptic 5-HT1A receptors and more likely via postsynaptic 5-HT2A receptors, lead similarly to attention deficits.
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PMID:Serotonergic mechanisms involved in the attentional and vigilance task performance of rats and the palliative action of aniracetam. 1083 6

Nystatin-perforated patch recordings were made from mechanically dissociated neurons (in which functional native presynaptic nerve terminals are preserved), isolated from the basolateral amygdala regions to investigate the effects of tandospirone on gamma-aminobutyric acidergic (GABAergic) inhibition. Two types of neurons, ovoid-shaped and pyramidal-shaped neurons, were obtained from the basolateral amygdala nuclei and the electrophysiological characteristics of these two types of neurons supported the morphological classification of these isolated neurons. From the ovoid-shaped neurons, bicuculline-sensitive GABA(A)ergic miniature inhibitory postsynaptic currents (miniature IPSC) were recorded in the presence of tetrodotoxin, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and DL-2-amino-5-phosphovaleric acid (DL-AP5). Tandospirone (10 microM) reversibly and continuously inhibited the GABAergic miniature synaptic events to 66.3+/-2.1% of control (P<0.01, n=17) without affecting the miniature IPSC amplitude (104.0+/-3.1% of control, n=17). The similar inhibition of miniature IPSC frequency was mimicked by a specific 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 1 microM), and the effects of tandospirone were prevented in the presence of a specific 5-HT1A receptor antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine hydrobromide (NAN-190, 1 microM). Activation of 5-HT1A receptors by 8-OH-DPAT (1 microM) evoked no direct postsynaptic effects in enzyme-treated isolated basolateral amygdala neurons, suggesting that tandospirone acts at presynaptic 5-HT1A receptors. Furthermore, this presynaptic inhibition by tandospirone was prevented after treatment with a pertussis toxin-sensitive GTP-binding protein (G-protein) inhibitor, N-ethylmaleimide (at 3 microM for 5 min). In conclusion, in the basolateral amygdala nuclei, tandospirone activated presynaptic 5-HT1A receptors on the GABAergic nerve terminals projecting to ovoid-shaped neurons and inhibited synaptic GABA transmission via G-proteins.
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PMID:Presynaptic modulation of synaptic gamma-aminobutyric acid transmission by tandospirone in rat basolateral amygdala. 1106 21

Midbrain slices containing the dorsal and medial raphe nuclei were prepared from rat brain in order to study serotonergic-GABAergic interaction. The slices were loaded with either [3H] serotonin or [3H]GABA, superfused and the electrically induced efflux of radioactivity was determined. The GABA(A) receptor agonist muscimol (3 to 30 microM) and the GABA(B) receptor agonist baclofen (30 and 100 microM) inhibited [3H]serotonin and [3H]GABA release. These effects of muscimol were reversed by the GABA(A) antagonists bicuculline (100 microM). The GABA(B) antagonist phaclofen (100 microM) also antagonized the baclofen-induced inhibition of [3H]serotonin and [3H]GABA release. Phaclofen by itself increased [3H]serotonin release but it did not alter [3H]GABA overflow. Muscimol (10 microM) and baclofen (100 microM) also inhibited [3H]serotonin release after depletion of GABAergic neurons by isoniazid pretreatment. These findings indicate the presence of postsynaptic GABA(A) and GABA(B) receptors located on serotonergic neurons. The 5-HT1A receptor agonist 8-OH-DPAT (0.01 to 1 microM) and the 5-HT1B receptor agonist CGS-12066A (0.01 to 1 microM) inhibited the electrically stimulated [3H]serotonin and [3H]GABA release. The 5-HT1A antagonist WAY-100135 (1 microM) was without effect on [3H]serotonin and [3H]GABA efflux by itself but it reversed the 8-OH-DPAT-induced transmitter release inhibition. During KCl (22 mM)-induced depolarization, tetrodotoxin (1 microM) did not alter the inhibitory effect of CGS-12066A (1 microM) on [3H]GABA release, it did blocked, however, the ability of 8-OH-DPAT (1 microM) to reduce [3H]GABA efflux. After depletion of raphe serotonin neurons by p-chlorophenylalanine pretreatment, CGS-12066A (1 microM) still inhibited [3H]GABA release whereas in serotonin-depleted slices, 8-OH-DPAT (1 microM) was without effect on the release. We conclude that reciprocal influence exists between serotonergic projection neurons and the GABAergic interneurons or afferents in the raphe nuclei and these interactions may be mediated by 5-HT1A/B and GABA(A/B) receptors. Both synaptic and non-synaptic neurotransmission may be operative in the 5-HTergic-GABAergic reciprocal interaction which may serve as a local tuning in the neural connection between cerebral cortex and midbrain raphe nuclei.
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PMID:Reciprocal innervation between serotonergic and GABAergic neurons in raphe nuclei of the rat. 1107 65

Hypericum possesses a unique pharmacology in that it displays the pharmacology of many classes of antidepressants and new mechanisms not typical of standard antidepressants. The most potent of all its action is the moderate to high potency for inhibition of the reuptake of monoamines, serotonin, dopamine and noradrenaline and the amino-acid neurotransmitters GABA and glutamate. Unlike standard reuptake inhibitors, hypericum exerts this reuptake inhibition non-competitively by enhancing intracellular Na+ ion concentrations. At a receptor level, chronic treatment with hypericum downregulates beta1-adrenoceptor, upregulates post-synaptic 5-HT1A receptors and 5-HT2 receptors. Although the major constituent responsible for the antidepressant effect is thought to be hyperforin, other constituents such as hypericin, pseudohypericin, flavonoids and oligomeric procyanidines may also play a direct or indirect role. While reuptake inhibition may more than likely be responsible for most of the antidepressant effect, other mechanisms may also contribute alone or in combination to exert the overall antidepressant action.
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PMID:Hypericum perforatum (St John's Wort): a non-selective reuptake inhibitor? A review of the recent advances in its pharmacology. 1127 8


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