Inhibition of 5-hydroxytryptamine neuronal activity by the 5-HT agonist, DOI (original) (raw)
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Journal of Pharmacology and Experimental Therapeutics, 2005
The pharmacological properties of cyclohexanecarboxylic acid, {2-[4-(2-bromo-5-methoxybenzyl)piperazin-1-yl]ethyl}-(2trifluoromethoxyphenyl)amide (Rec 27/0224), and cyclohexanecarboxylic acid, (2-methoxy-phenyl)-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}amide (Rec 27/0074), were characterized using radioligand displacement and guanosine 5Ј-O-(3-[ 35 S]thiotriphosphate) ([ 35 S]GTP␥S) binding assays, as well as electrophysiological experiments, in rat hippocampal and dorsal raphe nucleus (DRN) slices. Both compounds showed a high affinity (K i , ϳ1 nM) and selectivity (Ͼ70-fold) at human 5-hydroxytryptamine (5-HT) 1A receptors versus other 5-HT receptors. In [ 35 S]GTP␥S binding assays on HeLa cells stably expressing human 5-HT 1A receptors, Rec 27/0224 and Rec 27/0074 inhibited basal [ 35 S]GTP␥S binding by 44.8 Ϯ 1.7% (pEC 50 ϭ 8.58) and 25 Ϯ 2.5% (pEC 50 ϭ 8.86), respectively. In intracellularly recorded CA1 pyramidal cells, 5-HT 1A (hetero)receptor-mediated hyperpolarization, elicited by 100 nM 5-carboxamidoytryptamine (5-CT), was partially antagonized by Rec 27/0224 (ϳ50%; IC 50 ϭ 18.0 nM) and Rec 27/0074 (74%; IC 50 ϭ 0.8 nM). In extracellularly recorded DRN serotonergic neurons, Rec 27/0224 and Rec 27/0074 fully antagonized the inhibition of firing caused by the activation of 5-HT 1A (auto)receptors by 30 nM 5-CT with an IC 50 of 34.9 nM and 16.5 nM, respectively. The antagonism had a slow time course, reaching a steady state within 60 min. Both compounds also antagonized the citalopram-elicited, endogenous 5-HT-mediated inhibition of cell firing. In conclusion, Rec 27/0224 and Rec 27/ 0074 exhibited inverse agonism in [ 35 S]GTP␥S binding assays and differential antagonistic properties on 5-HT 1A receptormediated responses in the hippocampus but not in the DRN. Whether this differential effect is causally related to inverse agonist activity is unclear. The qualitatively different nature of the antagonism in the hippocampus versus the DRN clearly distinguishes the compounds from neutral antagonists, such as N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-2-pyridinylcyclo-hexanecarboxamide (WAY-100635).
Synapse, 1990
The dorsal and median raphe 5-HT neurons give rise to projections that differ in axon morphology and in vulnerability to certain amphetamine derivatives. The present study was undertaken to determine if these two 5-HT systems possess different functional properties. To this end, we studied the effects of selective 5-HT1A or 5-HT1A/5-HT1B receptor agonists and of p-chloroamphetamine on extracellular levels of indoleamines, as measured by differential pulse voltammetry with extracellular levels of indoleamines, as measured by differential pulse voltammetry with electrochemically pretreated carbon fiber electrodes, in cell body and nerve terminal regions of these subsets of 5-HT neurons in the rat brain. The selective 5-HT1A agonist 8-OH-DPAT produced a gradual decrease in the height of the 300 mV oxidation peak in the dorsal raphe and in the frontal cortex, reaching a maximum of 60% 3 h after the i.v. injection of 30 micrograms/kg. However, the same dose of 8-OH-DPAT was ineffective in the median raphe and in the dentate gyrus that receives its 5-HT innervation exclusively from the median raphe. A higher dose of 8-OH-DPAT (150 micrograms/kg, i.v.) produced a 60% decrease in the height of the 300 mV oxidation peak in the median raphe, whereas only a 20% decrease was obtained in the dentate gyrus. In contrast, the non-selective 5-HT1 agonist RU 24,969 (10 mg/kg, i.p.) caused a 70% reduction of the 300 mV peak height in both the dorsal and median raphe and a 50% decrease in both the frontal cortex and the dentate gyrus. Moreover, although a high dose of 8-OH-DPAT (150 micrograms/kg, i.v.) given alone reduced by 20% the amplitude of the oxidative peak in the dentate gyrus, subsequent administration of RU 24,969 (10 mg/kg, i.p.) caused a further 30% diminution of the oxidative peak height. The greater responsiveness of dorsal as compared to median raphe 5-HT systems to 5-HT1A receptor agonists was confirmed in two further series of experiments. First, the microiontophoretic application of 8-OH-DPAT directly onto 5-HT neurons was three times more potent in suppressing the firing rate of dorsal raphe 5-HT neurons than that of their median raphe congeners. Second, 8-OH-DPAT and buspirone were ten and four times, respectively, more potent in decreasing 5-HT synthesis in the frontal cortex than in the hippocampus.(ABSTRACT TRUNCATED AT 400 WORDS)
European Journal of Pharmacology, 1997
. Using brain microdialysis, it was demonstrated that the release of 5-hydroxytryptamine 5-HT in the central nucleus of the amygdala is under inhibitory control of somatodendritic and postsynaptic 5-HT receptors. Systemic administration of flesinoxan, a selective 1A 5-HT receptor agonist, significantly reduced the extracellular levels of 5-HT in the central nucleus of the amygdala. This effect could 1A Ž Ž Ž . . Ž . be completely antagonized by the 5-HT receptor antagonist N-2-4-2-methoxyphenyl -1-piperazinyl -N-2-pyridyl cyclohexane 1A
The activation of 5-HT 2A receptors in prefrontal cortex enhances dopaminergic activity
Atypical antipsychotics show preferential 5-HT 2A versus dop-amine (DA) D 2 receptor affinity. At clinical doses, they fully occupy cortical 5-HT 2 receptors, which suggests a strong relationship with their therapeutic action. Half of the pyramidal neurones in the medial prefrontal cortex (mPFC) express 5-HT 2A receptors. Also, neurones excited through 5-HT 2A receptors project to the ventral tegmental area (VTA). We therefore hypothesized that prefrontal 5-HT 2A receptors can modulate DA transmission through excitatory mPFC-VTA inputs. In this study we used single unit recordings to examine the responses of DA neurones to local (in the mPFC) and systemic administration of the 5-HT 2A/2C agonist 1-[2,5-dimethoxy-4-iodophenyl-2-aminopropane] (DOI). Likewise, using microdialysis, we examined DA release in the mPFC and VTA (single/dual probe) in response to prefrontal and systemic drug administration. The local (in the mPFC) and systemic administration of DOI increased the firing rate and burst firing of DA neurones and DA release in the VTA and mPFC. The increase in VTA DA release was mimicked by the electrical stimulation of the mPFC. The effects of DOI were reversed by M100907 and ritanserin. These results indicate that the activity of VTA DA neurones is under the excitatory control of 5-HT 2A receptors in the mPFC. These observations may help in the understanding of the therapeutic action of atypical antipsychotics.
British Journal of Pharmacology, 1995
Electrically stimulated 5-hydroxytryptamine (5-HT) release was monitored in slices of rat dorsal raphe nucleus (DRN) by fast cylic voltammetry. Pseudo-single pulse stimulations (5 pulses at 100 Hz) were used to enable the effect of various receptor agonists to be seen without competition from endogenously released transmitter. The selective 5-HTIA receptor agonist, (+)-8-OH-DPAT (1.0 gM) decreased stimulated 5-HT release to 31 ± 3% of controls. This decrease was inhibited by the 5-HTIA receptor antagonists, (+)-WAY-1001 35 (1.0 gM) and WAY-100635 (0.1 gM) but not by the 5-HTlDB antagonist, GR127935 (0.05 gM). The selective 5-HTIB receptor agonist, CP-93129 (0.3 gM) decreased stimulated 5-HT release to 61 ± 4% of control. This effect was antagonized by the 5-HTIB receptor antagonist, isamoltane (0.5 gM) but not by (+)-WAY-100135. The 5-HTID agonist, sumatriptan (0.5 gM) decreased stimulated 5-HT release to 52 ± 2 % of controls. This decrease was blocked by GR-127935 but not by WAY-100635. These results suggest that 5-HT release in the rat DRN is under the control of 5-HTA, 5-HTB and 5-HTID autoreceptors.
Regulation by 5-HT1A receptors of the in vivo release of 5-HT and DA in mouse frontal cortex
Neuropharmacology, 2003
This study examines the effects of serotonin (5-HT) 1A receptor ligands on the in vivo release of 5-HT and dopamine (DA) in the prefrontal cortex of mice. Oral MKC-242 and 8-OH-DPAT, selective 5-HT 1A receptor agonists, decreased cortical 5-HT release at low and high doses, while the receptor agonists increased cortical DA release only at a high dose. Local application of the selective 5-HT 1A receptor antagonist, WAY100635, via a dialysis probe, antagonized oral MKC-242-induced increase in cortical DA release, but did not affect the decrease in cortical 5-HT release. Local application of 8-OH-DPAT at 100 and 300 nM via a dialysis probe increased cortical DA release, but did not affect cortical 5-HT release. The effects of oral MKC-242 and 8-OH-DPAT on 5-HT release were blocked by low and high doses of WAY100635, while blocking the agonist-induced increase in DA release required a high dose of WAY100635. These results suggest that 5-HT release and DA release in the frontal cortex of mice are regulated by pre-and postsynaptic 5-H 1A receptors, respectively, and that the presynaptic 5-HT 1A receptor-mediated response is more sensitive to inhibition by WAY100635 than the postsynaptic 5-HT 1A receptor-mediated response in mice.
European Journal of Neuroscience, 2003
In the rat, postsynaptic 5-hydroxytryptamine 2A receptors medial prefrontal cortex control the activity of the serotonergic system through changes in the activity of pyramidal neurons projecting to the dorsal raphe nucleus. Here we extend these observations to mouse brain. The prefrontal cortex expresses abundant 5-hydroxytryptamine 2A receptors, as assessed by immunohistochemistry, Western blots and in situ hybridization procedures. The application of the 5-hydroxytryptamine 2A/2C agonist DOI (100 mM) by reverse dialysis in the medial prefrontal cortex doubled the local release of 5-hydroxytryptamine. This effect was reversed by coperfusion of tetrodotoxin, and by the selective 5-hydroxytryptamine 2A receptor antagonist M100907, but not by the 5-hydroxytryptamine 2C antagonist SB-242084. The effect of DOI was also reversed by prazosin (a 1 -adrenoceptor antagonist), BAY Â 3702 (5-hydroxytryptamine 1A receptor agonist), NBQX (a-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate/kainic acid antagonist) and 1S,3S-ACPD (mGluR II/III agonist), but not by dizocilpine (N-methyl-D-aspartate antagonist). a-Amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate mimicked the 5-hydroxytryptamine elevation produced by DOI, an effect also reversed by BAY Â 3702. Likewise, the coperfusion of classical (chlorpromazine, haloperidol) and atypical antipsychotic drugs (clozapine, olanzapine) fully reversed the 5-hydroxytryptamine elevation induced by DOI. These observations suggest that DOI increases 5-hydroxytryptamine release in the mouse medial prefrontal cortex through the activation of local 5-hydroxytryptamine 2A receptors by an impulse-dependent mechanism that involves/requires the activation of local a-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate receptors. This effect is reversed by ligands of receptors present in the medial prefrontal cortex, possibly in pyramidal neurons, which are involved in the action of antipsychotic drugs. In particular, the reversal by classical antipsychotics may involve blockade of a 1 -adrenoceptors, whereas that of atypical antipsychotics may involve 5-hydroxytryptamine 2A receptors and a 1 -adrenoceptors. 2003) and involve a-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA)-mediated glutamatergic inputs (Martõ Ân-Ruiz et al.
Naunyn-Schmiedeberg's Archives of Pharmacology, 1993
The effects of the selective 5-HTiA receptor agonist (R)-8-hydroxy-2(di-n-propylamino)tetralin [(R)-8-OH-DPAT] and the novel 5-HTIA antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301] were studied with regard to the firing pattern of single mesencephalic dopamine (DA) neurons with extracellular recording techniques in chloral hydrate anesthetized male rats. Neuronal activity was studied with respect to firing rate, burst firing and regularity of firing. In the ventral tegmental area (VTA) low doses of (R)-8-OH-DPAT (2-32 gg/kg i.v.) caused an increase in all three parameters. The effect on firing rate of DA neurons was more pronounced in the parabrachial pigmentosus nucleus than in the paranigral nucleus, the two major subdivisions of VTA. In the substantia nigra zona compacta (SN-ZC), (R)-8-OH-DPAT (2-256 gg/kg i.v.) had no effect on firing rate and regularity of firing and only slightly increased burst firing. High doses of (R)-8-OH-DPAT (512-1024 #g/kg i.v.) decreased the activity of DA cells in both areas, an effect that was prevented by pretreatment with the selective DAD 2 receptor antagonist raclopride. (S)-UH-301 (100-800 ~tg/kg i.v.) decreased both firing rate and burst firing without affecting regularity of DA neurons in the VTA. In the SN-ZC, (S)-UH-301 decreased the firing rate but failed to affect burst firing and regularity of firing. These effects of (S)-UH-301 were blocked by raclopride pretreatment. Local application by pneumatic ejection of 8-OH-DPAT excited the DA cells in both the VTA and the SN-ZC, whereas (S)-UH-301 inhibited these cells when given locally. These results show that 5-HT1A receptor related compounds differentially affect the electrophysiological activity of central DA neurons. The DA receptor agonistic properties of these compound appear to contribute to the inhibitory effects of high doses of (R)-8-OH-DPAT and (S)-UH-301 on DA neuronal activity. Given the potential use of 5-HTtA receptor selective compounds in the treatment of anxiety and depression their effects on central Correspondence to T.H. Svensson at the above address DA systems involved in mood regulation and reward related processes are of considerable importance.