Sleep-wake effects of meta-chlorophenyl piperazine and mianserin in the behaviorally depressed rat

The present study examined the effects of meta-chlorophenyl piperazine (mCPP) and mianserin on the sleep-wake cycle of the clomipramine-induced behaviorally screened depressed rats. Six-hour polygraphic recordings were made between 06:00 and 12:00 h, after a single injection of either saline or mianserin or mCPP into the lateral cerebral ventricle (i.c.v.) of both the depressed (n=12) and control rats (n=12). The injection of mCPP in the depressed rats caused a significant reduction in the total duration and number of rapid eye movement (REM) sleep episodes while it increased the REM sleep onset latency compared to the control saline injections. The injection of mianserin in the depressed rats also caused a significant reduction in the total duration and number of REM sleep episodes without changing the REM sleep latency. These results demonstrate for the first time that the central administration of mCPP and mianserin could act as an antidepressant in the clomipramine-induced rat model of depression.     

Effect of clonidine on the 5-hydroxytryptamine and 5-hydroxyindoleacetic acid brain levels

The effects of clonidine on the brain levels of 5-HT and 5-HIAA in rats and mice were studied. Clonidine did not change the levels of 5-HT and 5-HIAA in the whole brains of either animal species but the 5-HT concentrations were elevated in rat brain pons + medulla oblongata. Clonidine antagonized the increase in the brain 5-HIAA levels induced by apomorphine in rats and mice. The decrease in the 5-HT level and the increase in the 5-HIAA level observed in rats after L-dopa (given with peripheral decarboxylase inhibitor RO 4-4602) were counteracted by clonidine.     

The effect of venlafaxine treatment on the behavioural and neurochemical changes in the olfactory bulbectomised rat

In the present study, the effect of chronic treatment with venlafaxine on β₁ and 5-HT₂ receptor populations was examined in the frontal cortex of olfactory bulbectomised (OB) and sham operated (SO) animals. The effect of these drugs on the behaviour of the animals on the elevated plus maze and the “open field” was also assessed. Removal of the bulbs resulted in a characteristic increase in locomotor activity in the OB animals in the “open field” which was reversed by chronic venlafaxine treatment. Venlafaxine produced a slight reduction in the number of open arm entries made by the OB animals although this failed to reach significance. Maximum change in temperature from baseline, following a single dose of 8-OH-DPAT (1.5 mg kg⁻¹ SC), was used to assess the function of the 5-HT_1A receptors. Chronic venlafaxine treatment had no effect on the hypothermic response to 8-OH-DPAT in the present study. A decrease in the affinity of β₁-adrenoceptors was found following olfactory bulbectomy and this was normalised by treatment with venlafaxine. No bulbectomy-induced changes were evident 32 days post surgery in β₁-adrenoceptor density; however, chronic treatment with venlafaxine significantly reduced the density of these receptors in the OB animals. Olfactory bulbectomy did not produce any changes in 5-HT₂ receptor populations but venlafaxine administration significantly reduced the density of these receptors in both SO and OB animals. The findings of the present study further validate the usefulness of the OB as an animal model, for the detection of antidepressants from a wide variety of classes. Received: 22 August 1997/Final version: 11 November 1997     

Behavioral and biochemical effects of the 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT in the rat.

The 5-HT_1A 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 dependency 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.     

Pharmacology of (S)-homoquisqualic acid and (S)-2-amino-5-phosphonopentanoic acid [(S)-AP5] at cloned metabotropic glutamate receptors

1. In this study we have determined the pharmacological profile of (S)-quisqualic acid, (S)-2-amino-4-phosphonobutyric acid ((S)-AP4) and their higher homologues (S)-homoquisqualic acid, (S)-2-amino-5-phosphonopentanoic acid ((S)-AP5), respectively, and (R)-AP5 at subtypes of metabotropic (S)-glutamic acid (mGlu) receptors expressed in Chinese hamster ovary cells.
2. (S)-Quisqualic acid was a potent mGlu₁/mGlu₅ agonist (EC₅₀ values of 1.1 μM and 0.055 μM, respectively) showing no activity at mGlu₂ and weak agonism at mGlu₄ (EC₅₀∼1000 μM).
3. (S)-Homoquisqualic acid displayed competitive antagonism at mGlu₁ (K_B=184 μM) and full agonism at mGlu₅ (EC₅₀=36 μM) and mGlu₂ (EC₅₀=23 μM), but was inactive at mGlu₄.
4. (S)-AP4 was a potent and selective mGlu₄ agonist (EC₅₀=0.91 μM) being inactive at mGlu₁, mGlu₂ and mGlu₅ both as agonist and antagonist.
5. (S)-AP5 displayed very weak agonist activity at mGlu₄. At the mGlu₂ receptor subtype (S)-AP5 acted as a competitive antagonist (K_B=205 μM), whereas the compound was inactive at mGlu₁ and mGlu₅. (R)-AP5 was inactive at all mGlu receptor subtypes tested both as agonist and antagonist.
6. These studies demonstrate that incorporation of an additional carbon atom into the backbone of (S)-glutamic acid and its analogues, to give the corresponding homologues, and replacement of the terminal carboxyl groups by isosteric acidic groups have profound effects on the pharmacological profiles at mGlu receptor subtypes. Furthermore, (S)-homoquisqualic acid has been shown to be a potentially useful tool for differentiating mGlu₁ and mGlu₅.

     

Chronic treatment with citalopram facilitates the effect of a challenge dose on cortical serotonin output: role of presynaptic 5-HT1A receptors

In animals given citalopram (10 mg/kg) twice daily for 14 days a further dose of 1 mg/kg, administered 24 h after the last dose, markedly increased cortical dialysate serotonin (5-hydroxytryptamine, 5-HT), but had no effect in control animals. The effect on dialysate 5-HT in the dorsal raphe was not increased by the chronic treatment. At 25 μg/kg, 8-hydroxy-2-(di-n-propylamino) tetralin, an agonist at 5-HT_1A receptors, reduced cortical 5-HT output in controls but not in animals treated chronically with citalopram whereas 50 μg/kg reduced 5-HT output in both groups. These findings suggest that somatodendritic 5-HT_1A receptors are desentisized after chronic treatment with citalopram and this results in facilitation of its effect on cortical dialysate 5-HT. These results also agree with the concept that the effect of 5-HT re-uptake inhibitors on increasing 5-HT output in the frontal cortex is attenuated by their simultaneous ability to activate somatodendritic 5-HT_1A receptors via an increase of endogenous 5-HT in the raphe region.     

Biphasic effects of mianserin and desipramine on serotonin-evoked current and Cl- efflux in Xenopus oocytes.

Serotonin (5-HT, 1 μM) elicited two phases of Cl⁻ inward current in Xenopus oocytes injected with rat brain mRNA: a transient current (T-current), which was generated rapidly (within 1 min), and a sustained current (S-current), which persisted for 10 min. Each type of 5-HT-evoked response was time-dependent after mRNA injection. The T-current was generated at 20-30 h and the S-current at 30–40 h. Although mianserin at 0.1 μ M completely inhibited the T-current, 10 μ M mianserin was required to suppress the S-current. 5-HT also caused Cl⁻ efflux from oocytes preloaded with ³⁶Cl⁻, Cl⁻ efflux during 1 min, corresponding to the T-current, was inhibited by 0.1 μ M mianserin. A higher concentration of mianserin (10 μ M) was required to block the efflux for 10 min, corresponding to the S-current, as well as the current response. Desipramine selectively inhibited the T-current and Cl⁻ efflux for 1 min. The mechanisms underlying the different sensitivity to mianserin of oocytes injected with rat brain mRNA are discussed.     

Biochemical evidence for the 5-HT agonist properties of PAT (8-hydroxy-2-(di-n-propylamino)tetralin) in the rat brain

In vitro investigations revealed that PAT (8-hydroxy-2-(n-dipropylamino)tetralin) interacted with postsynaptic 5-HT receptors in the rat brain: the drug stimulated 5-HT-sensitive adenylate cyclase in homogenates of colliculi from new-born rats (K_Aapp 8.6 μM) and inhibited the specific binding of [³H]5-HT to 5-HT₁ sites. The PAT-induced inhibition of [³H]5-HT binding showed marked regional differences compatible with a preferential interaction of PAT (IC₅₀ 2 nM) with the 5-HT_1A subclass. As previously seen with 5-HT agonists, the efficacy of PAT for displacing [³H]5-HT bound to hippocampal membranes was markedly increased by Mn²⁺ (1 nM) and reduced by GTP (0.1 nM). PAT also affected presynaptic 5-HT metabolism since it inhibited competitively (K_i 1.4 μM) [³H]5-HT uptake into cortical synaptosomes and reduced (in the presence of the 5-HT uptake inhibitor fluoxetine) the K⁺-evoked release of [³H]5-HT previously taken up or newly synthesized from [³H]tryptophan in cortical or striatal slices. This latter effect was prevented by 5-HT antagonists (methiothepin, metergoline) suggesting that it was mediated by the stimulation of presynaptic 5-HT autoreceptors by PAT. Like 5-HT, PAT counteracted the stimulatory effect of K⁺-induced depolarization on the synthesis of [³H]5-HT from [³H]tryptophan in cortical slices. It is concluded that PAT is a potent 5-HT agonist acting on both post- and presynaptic 5-HT receptors in the rat brain.     

Characterisation of the selective 5-HT1B receptor antagonist SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): in vivo neurochemical and behavioural evidence of anxiolytic/antidepressant activity

The 5-HT_1B receptor has attracted significant interest as a potential target for the development of therapeutics for the treatment of affective disorders such as anxiety and depression. Here we present the in vivo characterisation of a novel, selective and orally bioavailable 5-HT_1B receptor antagonist, SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride). SB-616234-A reversed the 5-HT_1/7 receptor agonist, SKF-99101H-induced hypothermia in guinea pigs in a dose related manner with an ED₅₀ of 2.4 mg/kg p.o. Using in vivo microdialysis in freely moving guinea pigs, SB-616234-A (3–30 mg/kg p.o.) caused a dose-related increase in extracellular 5-HT in the dentate gyrus. Evaluation of antidepressant- and anxiolytic-like effects of this 5-HT_1B receptor antagonist was performed in a variety of models and species. SB-616234-A produced a decrease in immobility time in the mouse forced swim test; an effect suggestive of antidepressant activity. Furthermore, SB-616234-A produced dose-related anxiolytic effects in both rat and guinea pig maternal separation-induced vocalisation models with an ED₅₀ of 1.0 and 3.3 mg/kg i.p., respectively (vs fluoxetine treatment ED₅₀ = 2.2 mg/kg i.p. in both species). Also a significant reduction in posturing behaviours was observed in the human threat test in marmosets; an effect indicative of anxiolytic activity. In summary, SB-616234-A is a novel, potent and orally bioavailable 5-HT_1B receptor antagonist which exhibits a neurochemical and behavioural profile that is consistent with both anxiolytic- and antidepressant-like activity in a variety of species. Taken together these data suggest that SB-616234-A may have therapeutic efficacy in the treatment of affective disorders.     

The action of single and repeated doses of p-bromo-methamphetamine on the monoamine content and turnover rate in rat brain

The effect of p-bromo-methamphetamine (pBrMA) on serotonergic and catecholaminergic neurones in the rat brain was studied. Acute (15 mg/kg, s.c.) and chronic (30 × 15 mg/kg, s.c.) administration of the drug caused a long-lasting decrease in serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) content of whole brain. In contrast the catecholamine (CA) levels remained unchanged. Detailed studies of the 5-HT and CA content of brain regions showed a time-dependent decrease in 5-HT after acute injection, and a marked and persistent reduction in 5-HT and 5-HIAA after chronic treatment. In both injection regimens the content of noradrenaline (NA) was enhanced in the cortex. The turnover rate of 5-HT, dopamine (DA) and NA was reduced after acute treatment. Repeated injections caused a decrease in 5-HT turnover, while that of NA remained unchanged. However, the turnover rate of DA was enhanced. The present data appears to confirm the previous suggestion that after chronic treatment, when the rats show improvement in their learning performances, the serotonergic tone of the brain is decreased while dopaminergic tone is increased.     

Studies of the antagonist actions of (RS)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO) on non-NMDA receptors in cultured rat neurones

1. Whole-cell patch-clamp recordings from single cultured cortical neurones have been used to study the action of (RS)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO), which has previously been proposed to be a potent selective antagonist of 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors.
2. ATPO competitively reduced peak responses evoked by semi-rapid applications of AMPA (K_i=16 μM) but had variable effects on plateau responses, which were on average unchanged. Following blockade of AMPA receptor desensitization by cyclothiazide (CTZ, 100 μM), the plateau responses were reduced by ATPO to a similar extent as the peak responses, indicating that ATPO reduces desensitization of AMPA receptors.
3. Semi-rapid application of kainic acid (KA) and the KA receptor-selective agonist, (2S,4R)-4-methylglutamic acid (MeGlu) evoked non-desensitizing responses which were competitively antagonized by ATPO (K_i values: 27 and 23 μM, respectively).
4. Responses to MeGlu were unaffected by CTZ (100 μM), but potentiated 3 fold following blockade of KA receptor desensitization by concanavalin A (Con A, 300 μg ml⁻¹). Responses of spinal cord neurones to MeGlu were blocked by ATPO to a similar extent before and after blockade of KA receptor desensitization by Con A.
5. Although selectively potentiated by Con A, plateau responses to MeGlu were reduced by 69.6% by the AMPA selective antagonist, GYKI 53655 (10 μM). The remaining component was further reduced by ATPO with a K_i of 36 μM, which was not significantly different from that in the absence of GYKI 53655, but was greater than that on responses to AMPA.
6. It is concluded that ATPO is a moderate-potency competitive inhibitor of naturally expressed non-NMDA receptors.

     

Differential effects of the new antipsychotic risperidone on sleep and wakefulness in the rat

The effects of risperidone, a new antipsychotic with potent 5-hydroxytryptamine₂ (5-HT₂) and dopamine-D₂ (DA-D₂) antagonistic properties, were studied on sleep-wakefulness patterns in rats. Administration of low doses (0.01–0.16 mg/kg i.p.) resulted in a significant increase of deep slow wave sleep (SWS2) and a decrease of wakefulness (W) and light slow wave sleep (SWSl). High doses (0.63–2.5 mg/kg) produced opposite effects. Paradoxical sleep (PS) was significantly reduced over the dose range tested. The increase of SWS2 after low doses of risperidone could be related to a predominant and potent 5-HT₂ receptor blocking activity.     

The pharmacology of the hypothermic response in mice to 8-hydroxy-2-(DI-n-propylamino)tetralin (8-OH-DPAT) : A model of presynaptic 5-HT1 function

In the mouse, injection (subcutaneously) of the putative 5-HT₁ agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), produced a dose-related hypothermia (ED₅₀:0.36mg/kg). A maximum response was elicited by intracerebroventricular (i.c.v.) injection of 8-OH-DPAT (3 μg) and almost abolished by lesion of 5-HT-containing terminals in the brain with 5,7-dihydroxytryptamine (5,7-DHT; i.c.v.) or long-term treatment with p-chlorophenylalanine. The response was unaltered by a range of neurotransmitter antagonists: prazosin (α₁-adrenoceptor), idazoxan (α₂-adrenoceptor), metoprolol (β₁-adrenoceptor), erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol (β₂-adrenoceptor), (?)propranolol or (±)pindolol (β-adrenoceptor), flupenthixol (dopamine) or Ro 15–1788 (benzodiazepine binding site). Classical 5-HT antagonists (methysergide, metergoline, cinanserin and methiothepin) were either without effect or facilitated the response and the 5-HT₂ antagonist, ritanserin was also without effect. In contrast, quipazine and haloperidol produced a dose-related antagonism of the response.Since the response was almost abolished by a lesion induced by 5,7-DHT and was antagonised by quipazine, which is known to antagonise presynaptic 5-HT function in vitro, it is suggested that the hypothermie response is due to 8-OH-DPAT acting as an agonist at a presynaptic 5-HT receptor, which also appears to be sensitive to butyrophenones (the antagonism elicited by haloperidol but not by flupenthixol). The hypothermie response of mice to 8-OH-DPAT, therefore, may provide a simple and convenient in vivo model in which to measure the function of the presynaptic 5-HT receptor.     

Effects of nimodipine on the amphetamine- and methamphetamine-induced decrease in tryptophan hydroxylase activity

The effects of nimodipine on the amphetamine- and methamphetamine-induced decrease in central tryptophan hydroxylase activity was examined. Rats were administered 4 or 5 injections of amphetamine or methamphetamine at 6-h intervals with or without nimodipine (1 mg/kg), and killed 1 or 18 h after the last drug administration. The decrease in hippocampal tryptophan hydroxylase activity induced by amphetamine and methamphetamine was potentiated by the administration of nimodipine. Moreover, while hippocampal tryptophan hydroxylase activity was not altered by 2.5 mg/kg methamphetamine alone, the coadministration of 1 mg/kg nimodipine decreased the enzymatic activity to 68% of control. The decrease in striatal tryptophan hydroxylase activity caused by these amphetamine analogues was not significantly altered by the coadministration of nimodipine. Interestingly, nimodipine increased hippocampal and striatal amphetamine concentrations to 187 and 162%, respectively, of the concentrations measured in animals treated with amphetamine alone. Nimodipine also increased by 2-fold the plasma concentration of methamphetamine and amphetamine measured 3 h after a single administration of methamphetamine, whereas the hippocampal concentrations of these compounds were raised to 354 and 516%, respectively, of that in animals treated with methamphetamine alone. These results suggest that nimodipine altered drug distribution and potentiated the methamphetamine-induced decrease in hippocampal tryptophan hydroxylase activity by increasing the cerebral methamphetamine concentration.     

间尼索地平对5-羟色胺诱导大鼠肺动脉平滑肌细胞增殖和迁移的影响及其机制

目的探讨间尼索地平(m-Nis)对5-羟色胺(5-HT)诱导的大鼠肺动脉平滑肌细胞(PASMCs)增殖和迁移的影响,并深入研究其作用机制。方法采用植块法培养大鼠PASMCs。实验分为6组:空白对照组、5-HT(1μmol·L-1)组,m-Nis(10-5、10-6、10-7、10-8mol.L-1)组。噻唑蓝(MTT)比色法、Transwell迁移小室法分别测定PASMCs的增殖和迁移,Western blot法检测大鼠PASMCs中增殖细胞核抗原(PCNA)的蛋白表达及细胞外信号调节激酶1和2(ERK1/2)的磷酸化水平,研究m-Nis对ERK1/2/MAPK信号通路的影响。结果不同浓度m-Nis明显抑制了5-HT诱导的大鼠PASMCs增殖(P<0.05或P<0.01)和迁移(P<0.01),并呈现一定的浓度依赖性;另外,Western blot结果显示m-Nis对5-HT诱导的大鼠PASMCs中PCNA的蛋白表达有不同程度的抑制作用(P<0.05或P<0.01),10-5,10-6,10-7mol.L-1m-Nis还明显抑制了5-HT诱导的大鼠PASMCs中ERK1/2磷酸化水平的升高,p-ERK1/2/ERK1/2比值均有不同程度地降低(P<0.05或P<0.01)。结论m-Nis对5-HT诱导的大鼠PASMCs增殖和迁移有明显的抑制作用,可能与其抑制PCNA蛋白表达及ERK1/2/MAPK信号通路有关。     

The reaction of (E)-2,4-pentadienoic acid with aqueous bromine re-evaluation of the product

The reaction of (E)-2,4-pentadienoic acid with aqueous bromine was reinvestigated to affirm the formation of (E)-5-bromo-4-hydroxy-2-pentenoic acid, whose structure was confirmed by the spectroscopic methods as well as the chemical modification.     

新型β_2受体激动剂2-(4-氨基-3-氯-5-三氟甲基苯基)-2-叔丁氨基-乙醇盐酸盐对映异构体抗哮喘作用的比较

目的用整体动物实验法,比较2-(4-氨基-3-氯-5-三氟甲基苯基)-2-叔丁氨基-乙醇盐酸盐(2-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylaminoethanol hydrochloride,SPFF)对映异构体抗哮喘作用的效果和作用强度。方法用豚鼠肺溢流方法观察SPFF及其对映异构体的扩张气道平滑肌作用和强度;用小鼠气管酚红排泌实验和家鸽气管纤毛运动实验考察SPFF异构体的祛痰作用。结果十二指肠给药后60 min时,(-)-SPFF(30、10、3μg.kg-1)、(±)-SPFF(100、30、10μg.kg-1)、(+)-SPFF(100、30、10μg.kg-1)对组胺诱导的豚鼠支气管收缩都具有不同程度的抑制作用,(-)-SPFF的作用强度分别是(±)-SPFF和(+)-SPFF的1.4倍和5.7倍;(±)-SPFF(10、7.5、5 mg.kg-1)及其异构体对小鼠气道黏液分泌没有影响;(-)-SPFF(0.04、0.1 mg.kg-1)、(±)-SPFF(0.1、0.25 mg.kg-1)可显著促进气管纤毛运动,而(+)-SPFF对纤毛运动没有明显的促进作用;口服或静脉给予(-)-SPFF对小鼠的急性毒性低于(+)-SPFF。结论(-)-SPFF的抗哮喘作用优于(+)-SPFF。     

Effect of some phosphodiesterase inhibitors on adenylate cyclase from the liver fluke, Fasciola hepatica.

The present investigation was prompted by our previous finding that in the liver fluke, Fasciola hepatica, some phosphodiesterase inhibitors, instead of potentiating the rise in endogenous cAMP caused by 5-hydroxytryptamine (5-HT), antagonized it. Papaverine, 1-ethyl-4-(isopropylidenehydrazino)-1H-pyrazolo-(3,4-b)-pyridine-5-carboxylic acid, ethyl ester, HCl (SQ 20009), 6,7-dimethyl-4 ethyl-quinazoline (Quazodine) and caffeine inhibited 5-HT-activated adenylate cyclase from particulate fractions of the liver fluke. This may explain their in vivo antagonism to the 5-HT-mediated rise in endogenous cAMP levels. Isobutylmethylxanthine (IBMX), which did not antagonize the 5-HT effect in vivo, did not inhibit 5-HT-activated adenylate cyclase in fluke particles. None of the above compounds inhibited the NaF-activated adenylate cyclase. Kinetic studies showed that inhibition of 5-HT-activated adenylate cyclase by papaverine or SQ 20009 was not competitive with the substrate, ATP, or with GTP. While high levels of 5-HT decreased the degree of inhibition by papaverin and SQ 20009. the kinetics of inhibition does not appear to be strictly competitive.     

The effects of 8-OH-DPAT on medulllary 5-HT neurons and sympathetic activity in baroreceptor-denervated animals

The effects of the 5HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on medullary 5-hydroxytryptamine (5-HT) neuronal firing and inferior cardiac sympathetic nerve activity were simultaneously determined in baroreceptor-denervated cats. 5-HT neuronal firing was inhibited by 50% at a 1 μg/kg i.v. dose of 8-OH-DPAT in the baroreceptor-denervated animal. Unit firing was completely inhibited by a 3 μg/kg dose. In contrast, 8-OH-DPAT inhibited inferior cardiac nerve activity between 10 and 100 μg/kg i.v. A similar relationship between the 8-OH-DPAT-induced inhibition of 5-HT unit activity and sympathetic nerve activity was observed in sham-operated control animals. These data suggest that the sympatholytic effects of 8-OH-DPAT cannot be explained on the basis of an autoreceptor effect of the drug.