Regulation of central noradrenergic activity by 5-HT3 receptors located in the locus coeruleus of the rat (original) (raw)
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5-HT3-like receptors in the rat medial prefrontal cortex: further pharmacological characterization
Brain Research, 1996
The aim of the study was to further characterize the pharmacological properties of 5-hydroxytryptamine (5-HT)3-1ike receptors in the rat medial prefrontal cortex (mPFC) using combinations of biochemical and electrophysiological approaches. Phenylbiguanide (PBG) and three chlorinated derivatives, ortho-chloro-PBG (oCPBG), meta-chloro-PBG (mCPBG) and para-chloro-PBG (pCPBG), dose-dependently stimulated phosphoionositide (PI) turnover in fronto-cingulate cortical slices. All three chloro-isomers of PBG were equipotent in stimulating PI turnover. SR 57227A ((4-amino)-(6-chloro-2-pyridyl) L-piperidine hydrochloride, a novel compound with high affinity and selectivity for peripheral and central 5-HT 3 receptors) dose-dependently stimulated PI turnover in fronto-cingulate cortical slices. The rank order of potency of all the 5-HT 3 receptor agonists tested in the PI assay as compared to 5-HT was: 5-HT > 2-Me-5-HT > SR57227A > PBG = mCPBG = oCPBG = mCPBG. 5-HT and 5-HT receptor agonists depressed the firing rate of both spontaneously active and glutamate-activated quiescent mPFC cells in a current (dose)-dependent fashion. The rank order of effectiveness of these compounds was: 5-HT > SR57227A = 2-Me-5-HT = mCPBG = oCPBG = pCPBG = PBG. Unlike its action on the 5-HT 3 receptors in the periphery or cultured cell lines, D-tubocurarine chloride appears to be non-specific in blocking the depressant action of 2-Me-5-HT, 3,-aminobutyric acid and dopamine. Our results combined support the view that the pharmacological properties of 5-HT3-1ike receptors in the mPFC are not identical to those located in peripheral tissues and in cultured cell lines.
Naunyn-Schmiedeberg's Archives of Pharmacology, 1994
We analyzed the facilitatory effect of the 5-HT 3 receptor agonist 1-(m-chlorophenyl)-biguanide (mCPBG) on the electrically evoked noradrenaline release in superfused mouse brain tissue. In addition, we determined the affinities of mCPBG and two other 5-HT receptor ligands, namely. 2-methyl-5-hydroxytryptamine (2-methyl-5-HT; also a 5-HT 3 receptor agonist) and 5-carboxamidotryptamine (5-CT; a 5-HT 1 receptor agonist) for a 2 binding sites. The latter two 5-HT receptor agonists were included because of the claimed involvement of a2-adrenoceptors in their effects on noradrenaline release. In superfusion experiments on mouse brain cortex slices preincubated with 3H-noradrenaline, tritium overflow evoked by 2-rain periods of electrical field stimulation (3 Hz) was facilitated by mCPBG and, in addition, by rauwolscine (a2-adrenoceptor antagonist) and tetraethylammonium (K + channel blocker) (which were examined for comparison). The effect of mCPBG was not affected by the 5-HT 3 receptor antagonist tropisetron or by desipramine but was abolished by rauwolscine. In slices superfused with medium containing desipramine, the concentration-response curve of unlabelled noradrenaline for its inhibitory effect on the electrically (0.3 Hz) evoked overflow was shifted to the right by mCPBG and rauwolscine (apparent pA 2 5.35 and 7.88, respectively). In another series of superfusion experiments, 4 electrical pulses, administered at 100 Hz, were used to evoke tritium overflow. Tritium overflow evoked by this stimulation procedure (under which an endogenous tone of noradrenaline does not develop) was not affected by mCPBG and rauwolscine but still increased by tetraethylammonium. The specific binding of 3H-rauwolscine to rat brain cortex homogenates was displaced monophasically by unla
Neuropharmacology, 1997
The aim of the present study was to characterize in vivo the 5-HT receptor subtypes which mediate the effect of microiontophoretic applied 5-HT in the guinea pig head of caudate nucleus and orbitofrontal cortex. 5-HT and the preferential 5-HT2A receptor agonist DOI and the preferential 5-HT2C receptor agonist mCPP, suppressed the quisqualate (QUIS)-induced activation of neurons in both structures. The inhibitory effect of DOI and mCPP was not prevented by acute intravenous administration of the 5-HT12 receptor antagonist metergoline (2 mg/kg) and the 5-HT2A/2C receptor antagonist ritanserin (2 mg/kg) in the two regions nor by the selective 5-HT2A receptor antagonist MDL100907 (1 mg/kg) in the head of caudate nucleus. However, the inhibitory effect of DOI, but not that of mCPP, was antagonized by a 4-day treatment with metergoline and ritanserin (2 mg/kg/day; using minipumps implanted subcutaneously) in head of caudate nucleus, but not in orbitofrontal cortex. Microiontophoretic ejection of the 5-HT1A/7 receptor agonist 8-OH-DPAT and of the -HT1A receptor antagonist WAY100635 both suppressed the spontaneous and QUIS-activated firing activity of orbitofrontal cortex neurons. At currents which did not affect the basal discharge activity of the neuron recorded, microiontophoretic application of WAY100635 and BMY7378 failed to prevent the inhibitory effect of 8-OH-DPAT. The inhibitory effect of gepirone, which is a -HT1A receptor agonist but devoid of affinity for 5-HT7 receptors, was also not antagonized by WAY100635. Altogether, these results suggest the presence of atypical 5-HT1A receptors in the orbitofrontal cortex. The present results also indicate that the suppressant effect of DOI may be mediated by 5-HT2A receptors in head of caudate nucleus and atypical 5-HT2 receptors in orbitofrontal cortex. © 1997 Elsevier Science Ltd.
Brain Research, 1992
Whole-cell patch clamp recordings were made from neurons in the rat nucleus tractus solitarius (NTS) in transverse brainstem slices. 5-Hydroxytryptamine (5-HT. 100 p.M) and the selective 5-HT~ receptor agonist 2-methyl-5-HT (2-CH ~-5-HT, 100 p.M) depolarized 86% of NTS neurons at resting membrane potential (V m). This response was resistant to tetrodotoxin (TTX) and (~o-+ application. In addition, 2-CH3-5-HT (500 nM-10() p.M) increased the amplitude and frequency of both excitatory and inhibitory spontaneous synaptic potentials. This effect was also TTX-resistant. but was abolished by Co-'+. The effects of 2-CH3-5-HT on EPSPs and IPSPs evoked by electrical stimulation of the tractus solitarius (TS) were analyzed separately in the presence of bieuculline or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), respectively. Concentrations of 2-CH.r5-HT between 500 nM and l p.M decreased the amplitude of evoked EPSPs and IPSPs with similar potency. The selective 5-HT 3 receptor antagonists ICS 205-930 (10 nM) and MDL 72222 (10/zM) reversibly blocked the effects of 2-CH.r5-HT at all doses examined, it is concluded that 5-HT.x receptors can mediate both pre-and postsynaptic responses in the NTS.
British Journal of Pharmacology, 1993
The aims of the present study were to confirm the modulation by 5-HT3 receptors of the electrically evoked release of tritium from slices preloaded with [3H]-5-HT of guinea-pig frontal cortex, hippocampus and hypothalamus, and to assess their functional role in 5-HT release. 2 The selective 5-HT3 agonist, 2-methyl-5-HT, introduced 8 min before the electrical stimulation, enhanced in a concentration-dependent manner the evoked release of [3H]-5-HT in the three brain regions studied. The 5-HT3 agonists, phenylbiguanide and m-chlorophenyl-biguanide, did not enhance the release of tritium in frontal cortex and hypothalamus slices. 3 In hypothalamus slices, this response was lost when 2-methyl-5-HT was introduced 20 min before the stimulation, thus indicating that these 5-HT3 receptors desensitize rapidly. When 2-methyl-5-HT was added 20-min before the first stimulation period to desensitize the 5-HT3 receptors, removed for 24 min, and then reintroduced 8 min before the second stimulation period, the enhancing effect of 2-methyl-5-HT was restored, thus indicating that these 5-HT3 receptors can rapidly regain normal sensitivity. 4 The enhancing effect of 2-methyl-5-HT was attenuated by the 5-HT3 receptor antagonists m-chlorophenylpiperazine = quipazine = ondansetron > ICS 205-930 = BRL 24924 > MDL 72222 = zacopride. 5 The 5-HT reuptake blocker, paroxetine, enhanced the electrically evoked release of tritium when introduced 8 min before stimulation; this effect of paroxetine was blocked by ICS 205-930, thus indicating that these 5-HT3 receptors can be activated by endogenous 5-HT. 6 In the absence of electrical stimulation, 2-methyl-5-HT (10 gLM) produced a marked enhancement of the basal release of [3H]-5-HT which was calcium-dependent and blocked by S-zacopride but not by paroxetine. 7 The enhancing effect of 2-methyl-5-HT was dependent both on the frequency of stimulation, as indicated by the attenuated effect of 120 stimulations delivered at 1 Hz instead of 5 Hz, and on the duration of the stimulation, as indicated by the more pronounced effect of pulses delivered at 5 Hz for 24 s instead of 72 s or 120 s.
Brain Research, 1991
It has been claimed that the aversive behaviour induced by electrical stimulation of the midbrain tectum (MT) has validity as an animal model of panic attack. A great deal of evidence obtained from behavioural studies suggests that 5-HT 2 mechanisms phasically inhibit the substrates of aversion in the MT. In order to test this hypothesis we employed the technique of microiontophoresis of drugs onto neurones of the MT to assess the identity of the receptors mediating the effects of 5-hydroxytryptamine (5-HT). The results obtained show that the majority of 5-HT responsive cells in MT are cells excited by 5-HT (72%). These cells were silent or showed very low spontaneous firing activity, whereas cells depressed by 5-HT showed high spontaneous firing activity at baseline. The 5-HT1A receptor agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), buspirone and gepirone caused consistent reduction in the firing rate of cells depressed by 5-HT while they did not change the firing activity of cells excited by 5-HT. The excitatory effects induced by 5-HT on MT neurones were clearly attenuated by concomitant application of ketanserin, a highly specific 5-HT 2 antagonist. Excitatory responses to DL-homoeysteic acid were not affected by ketanserin. Previous administration of zimelidine, a selective 5-HT uptake inhibitor, caused a significant enhancement of the excitatory effects of 5-HT while similar application of gepirone did not affect the size of the excitatory responses to 5-HT. These results give electrophysiological support to the idea that 5-HT neurotransmission operating through 5-HT 2 receptors may exert a phasic control on functional processes in the Mr. It is possible that 5-HT 2 mechanisms in this region may mediate at least part of the therapeutic effects of 5-HT uptake inhibitors in panic disorders.
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
The present study attempted to determine whether noradrenaline (NA) release in rabbit hippocampus and human neocortex is modulated by presynaptic 5‐hydroxytryptamine (5‐HT) receptors Slices of rabbit hippocampus and human neocortex, loaded with [3H]‐noradrenaline ([3H]‐NA) were superfused and the effects of 5‐hydroxytryptamine (5‐HT) receptor ligands on electrically evoked [3H]‐NA release were investigated In rabbit hippocampus, 5‐HT, 5‐carboxamidotryptamine (5‐CT; 32 μm) and 2‐CH3‐5‐HT (32 μm) increased [3H]‐NA release elicited with 360 pulses/3 Hz. Facilitation of transmitter release was not influenced by the 5‐HT3 receptor antagonist, tropisetron but was prevented by the α2‐adrenoceptor antagonist, rauwolscine. When autoinhibition was avoided by stimulating the tissue with 4 pulses/100 Hz (pseudo‐one pulse‐(POP) stimulation), 2‐CH3‐5‐HT decreased evoked transmitter release, whereas 5‐HT and 5‐CT had no effect. Inhibition caused by 2‐CH3‐5‐HT was not affected by tropisetron but co...