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.     

Somatodendritic 5-HT1A receptors are critically involved in the anxiolytic effects of 8-OH-DPAT

In the rat shock-induced ultrasonic vocalization test, the anxiolytic effects of the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) obtained after systemic (IP) and intracerebral injection into the dorsal raphe nucleus (DRN) were selectively abolished by pretreatment with the 5-HT_1A receptor antagonist WAY-100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide trihydrochloride]. This blockade was demonstrated both after systemic and DRN application of WAY-100635. Therefore, it is concluded that the anxiolytic effects of 8-OH-DPAT are mediated by activation of somatodendritic 5-HT_1A receptors.     

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.     

Partial postsynaptic 5-HT1A agonist properties of the novel stereoselective 8-OH-DPAT analogue (+)cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin, (+)ALK-3

The present study assessed the pharmacological activity of the stereoisomers of the novel 8-OH-DPAT analogue cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin, ALK-3, at postsynaptic 5-HT_1A receptors involved in 5-HT-mediated behaviour. Reserpine-pretreated rats were injected with (+)8-OH-DPAT (0.03–1.0 mg/kg s.c), (+)ALK-3 (0.3–10.0 mg/kg s.c.) or (-)ALK-3 (3.0–10.0 mg/kg s.c.), and components of the ‘5-HT behavioural syndrome’ were scored. (+8-OH-DPAT dose dependently elicited forepaw treading, flattened body posture and hindlimb abduction. In this respect, (+)ALK-3 was significantly less efficacious although its beahvioural action was prevented by pindolol (8 mg/kg s.c.), indicating that it was 5-HT_1A receptor mediated. Following pretreatment, (+)ALK-3 dose dependently, but partially, attenuated the effect of (+)8-OH-DPAT. (-)ALK-3 did not elicit 5-HT behaviours per se, and only very weakly antagonized the behavioural actions of (+)8-OH-DPAT at the highest dose tried. Our data indicate that the (+) enantiomer of ALK-3 is a partial but stereoselective agonist at postsynaptic 5-HT_1A receptors.     

Gonadectomy changes the pituitary-adrenocortical response in mice to 5-HT1A receptor agonists.

The effects of 5-HT_1A receptor agonists such as 8-hydroxy-2-(ui-n-propylamino)tetralin (8-OH-DPAT), BP 554 and buspirone on the serum corticosterone level were significantly more pronounced in female than in male mice. A similar sex difference was observed for the effect of 8-OH-DPAT on the piasma ACTH level. Pretreatment with proadifen, an inhibitor of microsomal drug-metabolizing enzymes, did not affect the sex difference in the effect of 8-OH-DPAT. The corticosteione response to 8-OH-DPAT in female mice was attenuated by ovariectomy. The effect of 8-OH-DPAT in ovariectomized mice was enhanced by chronic estradiol and the enhancement was blocked by testosterone. In male mice the corticosterone response to 8-OH-DPAT increased at 5 weeks after castration but had not changed at 2 weeks. Chronic estradiol enhanced the corticosterone response to 8-OH-DPAT in castrated mice. There was no difference between sexes in [³H]8-OH-DPAT binding to membranes and in the contents of 5-HT and 5-hydroxyindoleacetic acid in the hypothalamus. Accumulation of 5-hydroxytryptophan after decarboxylase inhibition in the hypothalamus was however greater in female than in male mice.     

5-HT(1A) receptor full agonist, 8-OH-DPAT, exerts antidepressant-like effects in the forced swim test in ACTH-treated rats

We examined the effect of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test after administration of the 5-HT(1A) receptor agonist, 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT). Imipramine (3-30 mg/kg, i.p.) or 8-OH-DPAT (0.1-1 mg/kg, s.c.) significantly decreased the duration of immobility in normal rats. The immobility-decreasing effect of imipramine was blocked when ACTH was administered for 14 days. On the other hand, the immobility-decreasing effect induced by 8-OH-DPAT was not blocked by chronic administration of ACTH for 14 days. These findings indicate that 8-OH-DPAT can be useful in an animal model of depressive conditions resistant to antidepressant treatment.     

BIMT 17, a 5-HT1A receptor agonist/5-HT2A receptor antagonist,directly activates postsynaptic 5-HT inhibitory responses in the rat cerebral cortex

BIMT 17 (1-[2-[4-(3-trifluoromethyl phenyl) piperazin-1-yl] ethyl] benzimidazol- [1H]-2-one), a 5-HT_1A receptor agonist/5-HT_2A receptor antagonist (see Borsini et al., accompanying paper), in a dose range of 1–10 mg/kg i.v., dose-dependently inhibited the electrical activity of rat medial prefronto-cortical neurons, whereas buspirone, in a dose range of 0.1–1000 g/kg, increased it. 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and 1-[2-(2-thenoylamino)ethyl]-4[1-(7-methoxynaphthyl)] piperazine (S 14671) presented biphasic patterns of response; they increased electrical activity at doses in the range of 0.1–10 g/kg and 0.1–3 g/kg i.v. respectively, and reduced it at higher doses, 30–300 g/kg and 10–30 g/kg i.v., respectively.The inhibitory effect of BIMT 17 on the firing rate of neurons in the frontal cortex was antagonized by the 5-HT_1A antagonists tertatolol and WAY 100135, and was still present after destruction of serotonin (5-HT) containing neuronal endings by the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 150 g/rat, given intraventricularly), which reduced the cortical 5-HT content by 85%. This destruction of 5-HT neurons, while suppressing the ability of 8-OH-DPAT to inhibit the firing rate at high doses, did not change the excitatory action of this compound at low doses. The addition of ritanserin, a 5-HT2A receptor antagonist, potentiated both the excitatory and inhibitory effects of 8-OHDPAT on neuronal electrical activity. Direct microiontophoretic application (100 nA/20 s) of 5-HT and BIMT 17, but not that of 8-OH-DPAT, onto medial prefronto-cortical neurons, decreased the firing rate of these neurons.These findings suggest that BIMT 17 directly inhibits the electrical activity of medial prefronto-cortical neurons through its dual mode of receptor interaction.     

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.     

Cis-(+)-8-OH-1-CH3-DPAT, (+)ALK-3, a novel stereoselective pharmacological probe for characterizing 5-HT release-controlling 5-HT1A autoreceptors

Summary The somatodendritic 5-HT_1A autoreceptor regulating 5-HT neuronal activity is currently poorly defined pharmacologically because there are no specific antagonists, but also because potent and stereoselective agonists are scarce. Moreover, there have been few, if any, attempts to specifically investigate structure-activity relationships for agonists acting at this site. Employing brain microdialysis techniques, we have examined the effects of the enantiomers of cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (ALK-3; 0.01-0.3 mg/kg s.c.), its trans-1-methyl analogue (ALK-4; 0.3 mg/kg s.c.) and the pure enantiomers of the parent compound - 8-OH-DPAT (0.3 mg/kg s.c.) — in an attempt to address stereochemical agonist structure-activity requirements of 5-HT release-controlling 5-HT_1A autoreceptors in brain. The cis-1-methylated 8-OH-DPAT analogue (+)ALK-3 was comparable to the parent compound in reducing the 5-HT output from rat ventral hippocampus. In comparison, both (–)ALK-3 and the racemic rans-diastereomer to ALK-3, ALK-4, were inactive, while the two stereoisomers of 8-OH-DPAT strongly reduced 5-HT release. Pretreatment with (–)pindolol (8 mg/kg s.c.), which has high affinity for 5-HT_1A radioligand binding sites, blocked the reduction of hippocampal 5-HT release induced by a submaximally effective dose of (+)ALK-3. The direct intrahippocampal administration of (+)ALK3 (10 M) via the perfusion medium did not affect 5-HT output.In summary, the data indicate that (+)ALK-3, like 8-OH-DPAT, is a very potent 5-HT receptor agonist which inhibits terminal 5-HT release in rat hippocampus, probably via activation of somatodendritic 5-HT_1A autoreceptors. However, unlike 8-OH-DPAT, (+)ALK-3 is highly stereoselective and may therefore represent a useful probe in the further characterization of 5-HT_1A receptor-mediated mechanisms and function. The present study defines some of the stereochemical requirements for 5-HT_1A receptor interaction, emphasizing the importance of the receptor region complementary to the C₁ and C₂ carbons of the 8-OH-DPAT molecule. These findings contribute to the establishment of structure-activity relationships for the cell body 5-HT_1A autoreceptors and might be of value in resolving structural features that determine agonist/antagonist activity at central 5-HT_1A receptors. Finally, in conjunction with our recent finding that (+)ALK-3 is a partial agonist at postsynaptic 5HT_1A receptors, the present study extends previous observations suggesting that pre- and postsynaptic 5-HT_1A receptor populations differ in their characteristics. Send offprint requests to S. Hjorth at the above address     

Long lasting attenuation of 8-OH-DPAT induced corticosterone secretion after a single injection of a 5-HT1A receptor agonist

Summary The effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and some other 5-hydroxytryptamine_1A (5-HT_1A) receptor agonists (buspirone, ipsapirone and flesinoxan) on corticosterone secretion in rats were studied. The 5-HT_1A receptors mediating the corticosterone secretion appear to be postsynaptic to the 5-HT neurons, since the response to 8-OH-DPAT was not decreased but potentiated by depletion of 5-HT with p-chlorophenylalanine pretreatment of the animals. Rapid attenuation of the response was developed after a single dose of a 5-HT_1A receptor agonist. Thus, 1 mg/kg s.c. of 8-OH-DPAT attenuated the response of a challenge dose (0.1 mg/kg s.c.) of this compound within 4 h lasting between 7 and 14 d. The development of the subsensitivity was antagonized by pretreatment of the rats with the 5-HT_1A receptor antagonist S-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin ((–)-UH 301). This compound also antagonized the acute effect of 8-OH-DPAT in increasing serum corticosterone. The subsensitivity development was specific for the 5-HT_1A receptor-mediated corticosterone secretion, since the increase in serum corticosterone produced by stimulation of other receptor systems, e.g. ₂-adrenoreceptors (clonidine) or 5-HT₂ receptors [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (DOI)] was not affected. Send offprint requests to S. B. Ross at the above address     

Circadian rhythm in the response of central 5-HT1A receptors to 8-OH-DPAT in rats

Circadian rhythm in the behavioral responsiveness to the selective 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was studied in rats. Rats were subcutaneously injected with 8-OH-DPAT at one of the following times of day: 0000, 0400, 0800, 1200, 1600, 2000 hours. The postsynaptic 5-HT_1A receptor behavioral syndrome, that is, forepaw treading, head weaving, and flat body posture, were measured after the administration of 8-OH-DPAT. Circadian rhythms were found in each of the behavioral responses to 8-OH-DPAT. Peak responses were observed in the mid-dark phase (1200 hours) while the weakest responses were observed in the midlight phase (0000 hours). In a subsequent experiment, 8-OH-DPAT was administered intracerebroventricularly during the mid-dark phase and the mid-light phase. The behavioral responses to the drug in the middark phase were significantly higher than those in the mid-light phase. These results suggest that the function of central postsynaptic 5-HT_1A receptor exhibits circadian rhythm.     

The behavioural responses to 8-OH-DPAT,ipsapirone and the novel 5-HT1A receptor agonist Bay Vq 7813 in the pig

Summary In pigs, behavioural responses were examined after administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a full agonist at 5-hydroxytryptamine (5-HT) receptors of the 5-HT_1A subtype, and the pyrimidinylpiperazine derivatives ipsapirone and Bay Vq 7813 (2-[4-(2-pyrimidinyl)-1-piperazinylpropyl]-1,2-benzisothiazol-3(2H)one-1,1-dioxide), which act as partial agonists at 5-HT_1A receptors. The most prominent behavioural response examined after 8-OH-DPAT, 0.5 mg/kg i. m., ipsapirone, 2–5 mg/kg i.m., and Bay Vq 7813, 0.5–2 mg/kg i.m. or i.v., were head shakes. The potency of the three drugs to induce this behaviour correlated with their activity at 5-HT_1A receptors as determined by inhibition of forskolin-stimulated adenylate cyclase, substantiating that the head shake response has potential as a quantitative probe of in vivo receptor function. The 5-HT₂/5-HT_1C receptor antagonist ritanserin did not counteract the head shakes induced by ipsapirone, suggesting that neither 5-HT₂ nor 5-HT_1C receptors are involved in mediation of this response to this 5-HT_1A receptor agonist in pigs. Once daily administration of Bay Vq 7813 or ipsapirone for 3–5 days led to a reduction in the head shake response. 1-Pyrimidinylpiperazine (1-PP), a pharmacologically active metabolite shared by ipsapirone, Bay Vq 7813, and related pyrimidinylpiperazine derivatives, did not induce behavioural alterations in pigs. The data provide further evidence that marked species differences exist in functional responses to 5-HT receptor ligands. Send offprint requests to W. Löscher at the above address     

Chronic lithium treatment enhances the postsynaptic 5-HT1A receptor-mediated 5-HT behavioral syndrome induced by 8-OH-DPAT in rats via catecholaminergic systems

The effects of antimanic agents, including lithium, carbamazepine, clonazepam and zotepine, on the postsynaptic 5-HT_1A receptor-mediated behavioral and hypothermic responses induced by 8-OH-DPAT in rats, and on [³H]8-OH-DPAT binding to 5-HT_1A receptors in the rat hippocampus were examined. Treatment with lithium (3 mEq/kg, IP) for 14 days enhanced forepaw treading, one component of the 5-HT behavioral syndrome induced by 8-OH-DPAT, and this enhancement by lithium was abolished by catecholamine depletion with reserpine or -methyl-p-tyrosine, but not by 5-HT depletion withp-chlorophenylalanine. These data suggest that lithium enhances 5-HT_1A-mediated behavior via catecholaminergic systems. In contrast, chronic lithium treatment did not alter the hypothermic response to 8-OH-DPAT in untreated rats, as well as in rats treated with reserpine. These findings strengthen the suggestion that lithium has no direct influence on the postsynaptic 5-HT_1A-mediated response. Other antimanic agents had no effect on either forepaw treading or hypothermia induced by 8-OH-DPAT. Radioligand binding studies using [³H]-8-OH-DPAT demonstrated that chronic lithium treatment, but not other antimanic agents, caused 5-HT_1A receptor down-regulation in rat hippocampus. A discrepancy therefore exists between 5-HT_1A receptor down-regulation and unaltered 5-HT_1A-mediated behavioral and hypothermic responses in catecholamine-depleted rats after chronic lithium treatment.     

Evidence that 5-HT1A receptors are involved in the adrenaline-releasing effects of 8-OH-DPAT in the conscious rat

Summary 8-Hydroxy-2-(di-n-propylamino)tetralin (8OH-DPAT) is a 5-HT_1A receptor-selective agonist that has recently been reported to trigger adrenal catecholamine release and hyperglycemia. The aim of this study was to analyze in the conscious rat whether the 5-HT_1A receptor subtype is involved in these effects.8-OH-DPAT (0.1–1 mg/kg, i.v.) evoked dose-dependent increases in plasma adrenaline and glucose concentrations. Increases in plasma adrenaline levels peaked 5 min after administration of 8-OH-DPAT; in contrast, plasma glucose levels rose throughout the 20 min period of analysis. Prior administration of (–)pindolol, a beta-adrenoceptor antagonist that blocks 5-HT_1A receptors, markedly diminished the rise in plasma adrenaline levels and abolished the hyperglycemia triggered by 8-OHD-PAT. On the other hand, neither the selective beta 1-adrenoceptor antagonist, betaxolol, the selective beta 2-adrenoceptor antagonist, ICI 118.551, nor the 5-HT₂ receptor antagonist, ketanserin, affected 8-OH-DPAT-induced increases in plasma adrenaline levels. In addition, except for ICI 118.551 pretreatment, which delayed the hyperglycemic effect of 8-OH-DPAT, none of these antagonists affected the rise in glycaemia evoked by 8-OHD-PAT.The data suggest that the adrenaline-releasing and a major part of the hyperglycemic effects of 8-OH-DPAT are mediated by activation of 5-HT_1A receptors. Send offprint requests to F. Chaouloff at the above address     

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.     

A pharmacological analysis of the eating response induced by 8-OH-DPAT injected into the dorsal raphé nucleus reveals the involvement of a dopaminergic mechanism

Direct injection of the 5-hydroxytryptamine (5-HT) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into the dorsal raphé nucleus (DRN) dose dependently increased food intake in free feeding rats. The hypothesis that this effect is mediated by 5-HT_1A receptors was tested by investigating the abilities of the putative 5-HT_1A antagonists metergoline, propanolol and spiperone to prevent 8-OH-DPAT-induced eating. Metergoline failed to affect 8-OH-DPAT-induced eating when injected either peripherally or into the DRN. Peripherally injected propranolol and spiperone prevented 8-OH-DPAT-induced eating, but these drugs were ineffective when injected into the DRN. These results indicate that 8-OH-DPAT-induced eating may not involve 5-HT_1A receptors within the DRN. The ability of peripherally injected spiperone to prevent the eating response to 8-OH-DPAT reflects its dopamine blocking activity since haloperidol was an effective antagonist of 8-OH-DPAT-eating. This result may indicate that 8-OH-DPAT produces a general behavioural activation by reducing the inhibitory influence which 5-HT normally exerts over the nigrostriatal dopamine pathway, and that this behavioural activation is expressed as eating when food is the most salient goal object present.     

Blockade of the antidepressant-like effects of 8-OH-DPAT,buspirone and desipramine in the rat forced swim test by 5HT1A receptor antagonists

This study examined whether the antidepressant-like effect of serotonin (5-HT)_1A receptor agonists in the forced swim test (FST) is mediated by 5-HT_1A receptors. The 5-HT_1A receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and buspirone decreased immobility in the FST. The effect of 8-OH-DPAT was blocked by the 5-HT_1A receptor antagonists NAN 190, BMY 7378 and pindolol. The effect of buspirone was blocked by NAN 190 and pindolol. The antagonists produced no effects on their own. The norepinephrine (NE) uptake inhibitor desipramine (DMI) also reduced immobility, and this was also blocked by NAN 190, BMY 7378 and pindolol. The ₁, ₁ and ₂ adrenergic antagonists prazosin, betaxolol and ICI 118,551 did not block either 8-OH-DPAT or DMI, and produced no effects on their own. These results provide evidence that the antidepressant-like effects of 5-HT_1A receptor agonists in the FST are mediated through 5-HT_1A receptors, probably located postsynaptically. The finding that the 5-HT_1A receptor antagonists blocked the effect of DMI suggests that the NE and 5-HT systems interact in the FST.     

Tandospirone activates neuroendocrine and ERK (MAP kinase) signaling pathways specifically through 5-HT1A receptor mechanisms in vivo

Tandospirone, an azapirone, is a selective serotonin_1A (5-HT_1A) receptor agonist. The effects of tandospirone on plasma hormones and on mitogen-activated protein (MAP) kinase activity in the brain of male rats were studied. Tandospirone produced a time- and dose-dependent increase in plasma levels of oxytocin, adrenocorticotropin (ACTH), corticosterone, and prolactin. The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin, ACTH, and prolactin levels was 1.0 mg/kg (s.c.), while the minimal dose for corticosterone release was 3.0 mg/kg (s.c.). The ED₅₀ of tandospirone was 1.3 mg/kg for oxytocin, 1.2 mg/kg for ACTH, 3.0 mg/kg for corticosterone, and 0.24 mg/kg for prolactin. Pretreatment with the specific 5-HT_1A receptor antagonist WAY 100,635 (0.3 mg/kg, s.c.) completely blocked the effects of tandospirone on plasma levels of oxytocin, ACTH, and corticosterone but shifted the dose–response curve for prolactin to the right. Tandospirone injection (10 mg/kg, s.c.) stimulated the MAP kinase signaling cascade, specifically the phosphorylation of p42/44 extracellular signal-regulated kinase (ERK). Western blot analysis revealed a significant increase in phosphorylated ERK (p-ERK) levels in the hypothalamic paraventricular nucleus (PVN) as well as the dorsal raphé nucleus 5 min following tandospirone injection. These increases were blocked by pretreatment with WAY 100,635 (0.3 mg/kg). The results are the first evidence that systemic 5-HT_1A receptor agonist administration produces a rapid increase in p-ERK levels in vivo, providing further insight into the signaling mechanisms of the 5-HT_1A receptor.     

Ipsapirone and 8-OH-DPAT reduce ethanol preference in rats: involvement of presynaptic 5-HT1A receptors

The selective serotonin(5-HT)_1A receptor agonists 8-OH-DPAT and ipsapirone were tested in selectively inbred Wistar rats, with high preference [70–90%: defined as the ratio of ethanol (EtOH) to total fluid intake] for EtOH (10% v/v) over water in a two-bottle free choice situation. Rats were injected shortly before the overnight test session (8:00p.m.–8:00a.m.). EtOH and water consumption were determined in 20-min intervals; food consumption after the session. 8-OH-DPAT (ED₅₀: 2.4 mg/kg, SC) and ipsapirone (ED₅₀: 12.5 mg/kg, SC) reduced EtOH preference in a dose-dependent manner. In addition, 8-OH-DPAT increased total fluid intake, whereas ipsapirone enhanced total food intake. The EtOH preference reduction was time-dependent and reached a maximum within the second 4 h after application of 8-OH-DPAT (–73%) and ipsapirone (–72%). The preference reducing effect of ipsapirone (20 mg/kg, PO) was completely blocked by the nonselective 5-HT_1A antagonist spiperone (0.05 mg/kg, SC). Local application of 8-OH-DPAT (10 µg, 0.5 µl) into the dorsal raphe nucleus (DRN, a brain area rich in somatodendritic 5-HT_1A autoreceptors), reduced the EtOH preference significantly as compared to the saline injection in the same animal (–12%, 8:00–12:00p.m.). Only marginal effects on ingestion behavior were observed after micro-injection into the nucleus accumbens. Reduction of brain 5-HT levels by pretreatment with the 5-HT synthesis inhibitor pCPA (2×150 mg/kg, IP) resulted in a short lasting, marked reduction (–54%) and a long lasting, small attenuation of the EtOH preference. Total food consumption was strongly decreased but returned soon to normal; total fluid intake was only slightly decreased. The EtOH preference reducing effect of ipsapirone (5 and 20 mg/kg, SC) was attenuated in pCPA-pretreated rats. The present data suggest that 5-HT_1A receptor ligands reduce EtOH preference via stimulation of 5-HT_1A receptors in the DRN. The possibility of additional mechanism(s) is discussed.     

Inhibition of histamine turnover by 8-OH-DPAT,buspirone and 5-hydroxytryptophan in the mouse and rat brain

Summary The effects of 5-hydroxytryptamine (5-HT) receptor agonists on histamine turnover in mouse and rat brains were examined. The histamine turnover rate was estimated from the accumulation of tele-methylhistamine 90 min after i.p. injection of pargyline (65 mg/kg). In whole mouse brains, the histamine turnover was significantly inhibited by the 5-HT_1A agonists, 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) (> 0.5 mg/kg) and buspirone (> 2 mg/kg) injected s. c. 10 min before pargyline treatment. 5-hydroxytryptophan (20 mg/kg) also significantly inhibited histamine turnover. Injections of the 5-HT_1B agonist m-trifluoromethylphenylpiperazine (10 and 20 mg/kg) or the 5-HT₂ agonist (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (1, 2 and 5 mg/kg)), however, did not affect histamine turnover. The inhibitory effect of 8-OH-DPAT (1 mg/kg) on histamine turnover was significantly antagonized (by 40%) by pindolol (20 mg/kg) and slightly antagonized (by 29%) by spiperone (10 mg/kg), while methysergide (20 mg/kg) and ketanserin (10 mg/kg) demonstrated no antagonistic effects. 8-OH-DPAT (0.3 and 1 mg/kg) also showed an inhibiting effect on histamine turnover in various regions of rat brains. Although the extent of inhibition was slightly larger in the striatum and cerebral cortex, there was no marked regional difference. These results suggest that histaminergic activity in the brain is regulated by 5-HT_1A receptors. Send offprint requests to R. Oishi at the above address