Serotonin 5-HT3, 5-HT4, and 5-HT-M receptors

Serotonin (5-hydroxytryptamine [5-HT]) receptors can be classified either pharmacologically, into 5-HT1, 5-HT2, 5-HT3 and 5-HT4 receptors, or functionally, into G-protein-coupled receptors (5-HT1, 5-HT2, and 5-HT4) and ligand-gated ion channels (5-HT3). This article concentrates on the pharmacology, distribution, receptor-effector coupling, possible subtypes, and species differences of 5-HT3 receptors, which are equivalent to Gaddum and Picarelli's 5-HT-M receptor. Also presented here are some of the prominent features of the recently characterized 5-HT4 receptor. Although pharmacologic similarities have been suggested between 5-HT-M and 5-HT4 receptors (some potent 5-HT3 antagonists are active, with lower potency, at 5-HT4 receptors), it is clear that 5-HT4 receptors are different from 5-HT-M receptors.     

5-羟色胺及其受体与阿尔茨海默病的关系

5-羟色胺(5-hydroxytryptamine,5-HT)是一种重要的单胺类神经递质,其功能异常可能与包括阿尔茨海默病(Alzheimer disease,AD)在内的神经系统疾病密切相关。许多研究结果表明,5-HT受体在数量和分布等方面所发生的变化与AD的发生发展有关。本文就近年来5-HT与AD之间关系的研究进展进行综述,为药物治疗AD提供新思路。     

In the search for selective ligands of 5-HT5, 5-HT6 and 5-HT7 serotonin receptors

In recent years much attention has been focused on the functional importance of 5-HT5, 5-HT6 and 5-HT7 receptors in the pathogenesis of neuropsychiatric and other diseases. In this connection, intensive studies with ligands of these receptors are currently in progress. Recognition of the structural characteristics responsible for the binding of a ligand molecule to an appropriate receptor, and development of an active complex have reached an advanced stage in the search for selective compounds. This review was undertaken to summarize the results of structure-activity relationship studies with ligands of 5-HT5, 5-HT6 and 5-HT7 receptors. Additionally, some data on localization, pharmacological properties and the functional role of those receptors were reported.     

Interaction of arylpiperazines with 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors: do discriminatory 5-HT1B receptor ligands exist?

Summary The effects of several putative 5-HT₁ receptorsubtype selective ligands were investigated in biochemical models for 5-HT_1A, 5-HT_1B, and 5-HT_1D receptors (inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus, rat and calf substantia nigra, respectively) and 5-HT_1C receptors (stimulation of inositol phosphates production in pig choroid plexus). Following compounds were studied: 5-HT (5-hydroxytryptamine), TFMPP (1-(mtrifluoromethylphenyl)piperazine), mCPP (1-m-chlorophe-nyl)piperazine, 1 CGS 12066 (7-trifluoromethyl-4-(4-methyl1-piperazinyl)-pyrrolo[1,2-a]quinoxaline 1), isamoltane (CGP 361A, 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propranol), quipazine, 1-NP (1-(1-naphthyl)piperazine), and PAPP (LY165163, 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine). Among reported 5-HT_1B receptor selective drugs, TFMPP had similar potency at 5HT_1A, 5-HT_1B and 5-HT_1C receptors, mCPP did not separate between 5-HT_1B and 5-HT_1C receptors, CGS 12066 was equipotent at 5-HT_1B and 5-HT_1D receptors, and isamoltane was only slightly 5-HTIB versus 5-HT_1A selective. Quipazine showed equal potency at 5-HTIB and 5-HT_1C receptors and 1-NP did not discriminate between the four receptor subtypes. PAPP described as 5-HT_1A receptor selective, was equally potent at 5-HT_1A and 5-HT_1D receptors. The potencies determined in second messenger studies were in good agreement with the affinity values determined in radioligand binding studies. Thus 5-HT_1A, 5-HT_1B, 5-HT_1C and 5-HT_1D receptors have different pharmacological profiles as predicted from radioligand binding studies. Despite claims to the contrary, none of the tested compounds had actual selectivity for a given 5-HT₁ receptor subtype. Of interest were the properties of several of these drugs, which behaved as agonists at some receptors and as antagonists at others (e. g. quipazine, 1-NP, PAPP and isamoltane). Send offprint requests to D. Hoyer at the above address     

Effects of chronic treatment with fluoxetine and citalopram on 5-HT uptake, 5-HT1B autoreceptors, 5-HT3 and 5-HT4 receptors in rats

The effect in rats of chronic treatment with two specific 5-HT reuptake inhibitors (SSRI) with antidepressant properties, citalopram (10 mg/kg, i.p. twice a day for 14 days, one day washout) and fluoxetine (15 mg/kg, p.o. twice a day for 21 days, 7 days washout), was evaluated on some mechanisms involved in central 5-HT neurotransmission. No adaptive modifications of brain 5-HT uptake (sites) were found by measuring functional [³H]5-HT uptake and [³H]citalopram binding in cortical and hippocampal synaptosomes, and by [³H]citalopram binding autoradiography in the raphe nuclei (5-HT cell bodies) and the ventral tegmental area (5-HT axonal pathway). Chronic treatments had no effect on presynaptic 5-HT_1B autoreceptors, functionally evaluated by measuring 5-HT_1B-mediated inhibition of depolarization-induced [³H]5-HT release from cortical and hippocampal synaptosomes. Chronic citalopram or fluoxetine did not significantly affect the binding of [³H]BRL-43694 to 5-HT₃ receptors in the rat brain cortex. Citalopram had no effect on [¹²⁵I]SB-207710 binding to 5-HT₄ receptors, measured by autoradiography in the substantia nigra. Negative results, such as those reported in the present study, could be due to a number of variables including the animal species, the treatment schedule or the brain areas considered, thus explaining the differences from some previous reports of significant effects of SSRI. However, our negative data are in agreement with many other published studies, suggesting that adaptive modifications of brain 5-HT transporters, terminal 5-HT_1B receptors, 5-HT₃ and 5-HT₄ receptors may not be a general effect induced by all SSRI. Received: 9 December 1996 / Accepted: 1 March 1997     

Interaction of the alpha-adrenoceptor agonist oxymetazoline with serotonin 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors.

Oxymetazoline was recognized with nanomolar affinity by 5-HT1A, 5-HT1B and 5-HT1D binding sites and mimicked the effects of 5-hydroxytryptamine with about the same potency and intrinsic activity as the endogenous amine in the corresponding functional tests. At 5-HT1C receptors, oxymetazoline behaved as a mixed agonist-antagonist. Clonidine had minimal activity. Methiothepin antagonized the effects of oxymetazoline (7.4 less than pKB less than 8.8). Thus, oxymetazoline is a full and potent agonist at 5-HT1A, 5-HT1B and 5-HT1D receptors and a partial agonist at 5-HT1C receptors.     

Effect of reserpine on behavioural responses to agonists at 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptor subtypes.

Rats were given a single dose of reserpine (5 mg/kg s.c.) and behavioural responses to agonists at 5-HT receptor subtypes compared with those of control animals 21 days later. The following effects of activating postsynaptic 5-HT1A receptors by the agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) were significantly increased: tail-flick, reciprocal forepaw treading, flat body posture. The hyperphagic effect of activating presynaptic 5-HT1A receptors by 8-OH-DPAT tended to increase and hypothermia on activating postsynaptic 5-HT1A sites tended to decrease. The hyperlocomotor effect of activating 5-HT1A sites also tended to decrease possibly as a result of a dependence of this response on the known depletion of catecholamines by reserpine. Head shakes on activating 5-HT2A receptors by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and two effects of activating 5-HT2C receptors by 1-(3-chlorophenyl) piperazine (mCPP) were significantly increased (hypophagia, anxiety) and a third effect, hypolocomotion tended to increase but hypophagia on activating postsynaptic 5-HT1B receptors by CP-94, 253 was significantly attenuated. The results are discussed with particular reference to altered 5-HT function in depression.     

Characterization of the novel human serotonin receptor subunits 5-HT3C,5-HT3D, and 5-HT3E

Within the family of serotonin receptors, the 5-hydroxytryptamine-3 (5-HT(3)) receptor is the only ligand-gated ion channel. It is composed of five subunits, of which the 5-HT(3A) and 5-HT(3B) subunits are best characterized. Several studies, however, have reported on the functional diversity of native 5-HT(3) receptors, which cannot solely be explained on the basis of the 5-HT(3A) and 5-HT(3B) subunits. After our discovery of further putative 5-HT(3) serotonin receptor-encoding genes, HTR3C, HTR3D, and HTR3E, we investigated whether these novel candidates and the isoform 5-HT(3Ea) are able to form functional 5-HT(3) receptor complexes. Using immunofluorescence and immunoprecipitation studies of heterologously expressed proteins, we found that each of the respective candidates coassembles with 5-HT(3A). To investigate whether the novel subunits modulate 5-HT(3) receptor function, we performed radioligand-binding assays and calcium-influx studies in human embryonic kidney 293 cells. Our experiments revealed that the 5-HT(3C),5-HT(3D), 5-HT(3E), and 5-HT(3Ea) subunits alone cannot form functional receptors. Coexpression with 5-HT(3A), however, results in the formation of functional heteromeric complexes with different serotonin efficacies. Potencies of two agonists and antagonists were nearly identical with respect to homomeric 5-HT(3A) and heteromeric complexes. However, 5-HT showed increased efficacy with respect to 5-HT(3A/D) and 5-HT(3A/E) receptors, which is consistent with the increased surface expression compared with 5-HT(3A) receptors. In contrast, 5-HT(3A/C) and 5-HT(3A/Ea) receptors exhibited decreased 5-HT efficacy. These data show for the first time that the novel 5-HT(3) subunits are able to form heteromeric 5-HT(3) receptors, which exhibit quantitatively different functional properties compared with homomeric 5-HT(3A) receptors.     

Constriction of porcine arteriovenous anastomoses by indorenate is unrelated to 5-HT1A, 5-HT1B, 5-HT1C or 5-HT1D receptor subtypes

The study concerns the effects of indorenate, a tryptamine derivative with antihypertensive properties as well as high affinity for the 5-HT1A binding site, on carotid haemodynamics in anaesthetized pigs. Intracarotid infusions of indorenate (0.3, 1.0, 3.0 and 10.0 micrograms.kg-1.min-1 for 10 min each) caused dose-related decreases in total common carotid artery blood flow due almost exclusively to a reduction in arteriovenous anastomotic flow. These effects of indorenate were not appreciably modified after treatment with the 5-HT2 receptor antagonist ketanserin (0.5 mg.kg-1 i.a.), but were markedly reduced after treatment with methiothepin (1.0 mg.kg-1 i.a.), which antagonizes not only 5-HT2 receptors, but also the putative 5-HT1A, 5-HT1B 5-HT1C and 5-HT1D subtypes of 5-HT1-like receptors. Nonetheless, metergoline (1 mg.kg-1 i.a.), a drug with higher affinity than methiothepin for the above 5-HT1 receptor subtypes, failed to significantly modify the responses to indorenate. It is therefore concluded that, like 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969), indorenate reduces both total common carotid and cephalic arteriovenous anastomotic blood flow in the pig by stimulating 5-HT1-like receptors; these receptors, however, do not seem to correspond to either 5-HT1A, 5-HT1B, 5-HT1C or 5-HT1D binding sites.     

Modulation of the 5-HT1C receptor-mediated behavior by 5-HT2, but not 5-HT1A, receptor activation.

The effects of 5-HT1A-receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and gepirone, a 5-HT1A/5-HT2-receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and a 5-HT2-receptor agonist (+-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((+/)DOI) on the 5-HT1C-receptor-mediated exploratory hypoactivity in rats, induced by m-trifluoromethylphenylpiperazine (TFMPP) or m-chlorophenylpiperazine (m-CPP), were studied in the open field test. (+/-)DOI attenuated the effects of TFMPP and abolished those of m-CPP (not dose-dependently). 5-MeODMT showed a weak antagonistic action only at one, intermediate dose. The effects of TFMPP or m-CPP were not changed by 8-OH-DPAT or gepirone. At the same time, 8-OH-DPAT, gepirone, 5-MeODMT and (+/-)DOI themselves practically did not change the exploratory activity of rats. The obtained results permit an assumption that a functional interaction exists between 5-HT1C- and 5-HT2-receptors, but not between 5-HT1C- and 5-HT1A-ones.     

5-HT3 receptor antagonism by anpirtoline, a mixed 5-HT1 receptor agonist/5-HT3 receptor antagonist.

1. The aim of this study was to provide evidence that anpirtoline, which is an agonist at 5-HT1B and 5-HT1D receptors and also displays submicromolar affinity for 5-HT1A recognition sites, in addition, acts as an antagonist at 5-HT3 receptors. 2. In radioligand binding studies on rat brain cortical membranes, anpirtoline inhibited specific binding of [3H]-(S)-zacopride to 5-HT3 receptor recognition sites (pKi: 7.53). 3. In N1E-115 neuroblastoma cells in which [14C]-guanidinium was used as a tool to measure cation influx through the 5-HT3 receptor channel, the 5-HT-induced influx was concentration-dependently inhibited by anpirtoline. In this respect, anpirtoline mimicked other 5-HT3 receptor antagonists; the rank order of potency was ondansetron > anpirtoline > metoclopramide. 4. The concentration-response curve for 5-HT as a stimulator of [14C]-guanidinium influx was shifted to the right by anpirtoline (apparent pA2: 7.78). 5. In urethane-anaesthetized rats, anpirtoline inhibited (at lower potency than zacopride and tropisetron) the 5-HT- or phenylbiguanide-induced bradycardia (Bezold-Jarisch reflex), but did not induce this reflex by itself. 6. Intravenous infusion of cisplatin in the domestic pig caused a consistent emetic response which was antagonized by anpirtoline. 7. It is concluded that anpirtoline, which was previously characterized as a 5-HT1 receptor agonist also proved to be a 5-HT3 receptor antagonist in several experimental models and, hence, exhibits a unique pattern of properties at different 5-HT receptors.     

5-HT5 receptors

The 5-HT(5) receptor family consists of two members designated as 5-HT(5A) and 5-HT(5B). To date the 5-HT(5A) receptor has been identified in the mouse, rat, and human. The 5-HT(5B) receptor also is expressed in the mouse and rat, but not in the human where the coding sequence is interrupted by stop codons. Both receptors are essentially limited in distribution to the central nervous system (CNS), although the 5-HT(5A) receptor has also been found on neurons and neuronal-like cells of the carotid body. Within the CNS the 5-HT(5A) receptor shows a relatively broad distribution, while the 5-HT(5B) receptor has a very restricted distribution. The 5-HT(5A) receptor has been demonstrated to couple to G proteins, and the primary coupling appears to be through Gi/o to inhibit adenylyl cyclase activity. The 5-HT(5) receptors have not been extensively characterized pharmacologically. Both receptors show their highest affinity for LSD, which appears to act as a partial agonist at the 5-HT(5A) receptor. Amongst agonist-like molecules, 5-CT (5-carboxamidotryptamine) also has high affinity and has greater potency and affinity at the 5-HT(5A) receptor than does 5-HT itself. Both [(125)I]LSD and [(5)H]5-CT have been used as radioligands to study the receptors in vitro. Nothing is known about the role of the 5-HT(5B) receptor in vivo. A mouse line has been developed where the 5-HT(5A) receptor has been knocked out and these animals have been shown to have a diminished response to LSD-induced increases in locomotion. The 5-HT(5) receptors remain as two of the least studied and understood of the 5-HT receptor subtypes.     

Effects of cold stress on some 5-HT1A, 5-HT1C and 5-HT2 receptor-mediated responses.

The purpose of the present study was to analyze the influence of stress (24-h cold exposure) on presynaptic 5-HT1A receptors, and on postsynaptic 5-HT1A, 5-HT1C and 5-HT2 receptors. Cold exposure for 24 h affected neither pargyline-induced decreases in 5-hydroxyindoleacetic acid (5-HIAA) levels in midbrain and rest of brain, nor plasma glucose and corticosterone levels. Treatment with the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.5-1 mg/kg), 3-5 h after the end of cold exposure triggered less intense flat body posture and forepaw treading in cold-exposed rats than in controls. On the other hand, 15- and 30-min plasma glucose responses to 8-OH-DPAT (0.25-0.5 mg/kg, 3-5 h after cold) or to the alpha 2-adrenoceptor agonist, clonidine (0.025 mg/kg), were not affected by cold, while the 15-min, but not the 30 min, plasma corticosterone response to 8-OH-DPAT was slightly amplified in cold-exposed rats. Cold exposure affected neither the inhibitory effect of 8-OH-DPAT (0.25-0.5 mg/kg, 3-5 h after cold) on midbrain 5-HIAA levels, nor the hypothermic effect of 8-OH-DPAT (0.5-1 mg/kg, 3-5 h after cold). Lastly, the hypoactivity elicited by the 5-HT1C receptor agonist, m-chlorophenyl-piperazine (1.5-3 mg/kg, 3-5 h after cold), or head shakes elicited by the 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (1-2 mg/kg, 3-5 h after cold), were of similar intensities in control and in cold-exposed rats.     

Pharmacological characterization of the 5-HT1A, 5-HT2 and 5-HT3 receptors in the bovine ciliary muscle

We aimed to investigate the effects of serotonin (5-hydroxytryptamine, 5-HT) on the bovine ciliary muscle and subsequently to characterize and identify the subtypes of 5-HT receptors involved in the serotonin-evoked contractility muscle. The binding of [3H]ketanserin, [3H]granisetron and [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) was analyzed. All labelled compounds bound with high affinity to a single site in the membrane preparations studied. The affinity (K(d)) of the binding site was 7.5+/-1.2 nM for [3H]ketanserin, 6.9+/-0.8 nM for [3H]granisetron and 4.4+/-0.31 nM for [3H]8-OH-DPAT. The density of receptors (B(max)) was 1062+/-43.0 fmol/mg protein for [3H]ketanserin, 566+/-2.32 fmol/mg protein for [3H]granisetron and 205+/-4.63 fmol/mg protein for [3H]8-OH-DPAT. The serotonin-induced contraction appeared to be competitively antagonized by ketanserin (0.1, 1 and 10 microM) and ondansetron (0.1, 10 and 100 microM) which produced a pA(2) value of 8.5+/-0.12 and 8.0+/-0.19, respectively. 8-OH-DPAT and 5-carboxamidotryptamine (5-CT) proved to be completely ineffective. We conclude that serotonin induces bovine ciliary muscle contraction via 5-HT(2) and 5-HT(3) receptors while the 5-HT(1A) receptors, although present, do not mediate the contractile response.     

5-HT7, but not 5-HT2B, receptors mediate hypotension in vagosympathectomized rats

This study evaluated the possible involvement of 5-HT(2B) receptors in long-lasting hypotension to 5-hydroxytryptamine (5-HT), which is predominantly mediated by 5-HT7 receptors, in anaesthetised vagosympathectomized rats. Intravenous injections of 5-HT and 5-carboxamidotryptamine (5-CT) elicited a dose-dependent hypotension that was dose-dependently antagonised by (R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl) ethyl] pyrrolidine (SB-269970; a selective 5-HT7 receptor antagonist), but not by saline. Interestingly, alpha-methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine (BW723C86; a 5-HT(2B) receptor agonist) produced vasopressor responses without affecting hypotension to 5-HT. These results suggest that hypotension to 5-HT and 5-CT is mainly mediated by 5-HT7 receptors, whilst the role of 5-HT(2B) receptors seems unlikely.     

SB-649915, a novel, potent 5-HT1A and 5-HT1B autoreceptor antagonist and 5-HT re-uptake inhibitor in native tissue

An increase in brain 5-HT levels is thought to be the key mechanism of action which results in an antidepressant response. It has been proven that selective serotonin re-uptake inhibitors are effective antidepressants but the delay to therapeutic onset of these agents is thought to be due to the time required for 5-HT1A, and possibly 5-HT1B, autoreceptor desensitisation. Therefore an agent incorporating 5-HT re-uptake inhibition coupled with 5-HT1A and/or 5-HT1B autoreceptor antagonism may provide a fast acting clinical agent. The current studies describe the in vitro profile of SB-649915 (6-[(1-{2-[(2-methylquinolin-5-yl)oxy]ethyl}piperidin-4-yl)methyl]-2H-1,4-benzoxazin-3(4H)-one), a novel compound which has high affinity for human recombinant 5-HT1A, 5-HT1B and 5-HT1D receptors (pKi values of 8.6, 8.0, 8.8, respectively) and the human recombinant 5-HT transporter (pKi value of 9.3). SB-649915 also displays high affinity for rat, guinea pig, mouse and marmoset native tissue 5-HT1A, 5-HT1B and 5-HT1D receptors and rat native tissue 5-HT transporters (pKi values>or=7.5). In functional [35S]GTPgammaS binding studies, SB-649915 (up to 1 microM) does not display intrinsic activity in HEK293 cells expressing human recombinant 5-HT1A receptors but acts as a partial agonist at human recombinant 5-HT1B and 5-HT1D receptors with intrinsic activity values of 0.3 and 0.7, respectively, as compared to the full agonist 5-HT. From Schild analysis, SB-649915 caused a concentration-dependent, rightward shift of 5-HT-induced stimulation of basal [35S]GTPgammaS binding in cells expressing human recombinant 5-HT1A or 5-HT1B receptors to yield pA2 values of 9.0 and 7.9, respectively. In electrophysiological studies in rat dorsal raphe nucleus, SB-649915 did not affect the cell firing rate up to 1 microM but attenuated (+)8-hydroxy-2-(di-n-propylamino) tetralin-induced inhibition of cell firing with an apparent pKb value of 9.5. SB-649915 (1 microM) significantly attenuated exogenous 5-HT-induced inhibition of electrically-stimulated [3H]5-HT release from guinea pig cortex. In studies designed to enhance endogenous 5-HT levels, and therefore increase tone at 5-HT1B autoreceptors, SB-649915 significantly potentiated [3H]5-HT release at 100 and 1000 nM. In LLCPK cells expressing human recombinant 5-HT transporters and in rat cortical synaptosomes, SB-649915 inhibited [3H]5-HT re-uptake with pIC50 values of 7.9 and 9.7, respectively. In summary, SB-649915 is a novel, potent 5-HT1A/1B autoreceptor antagonist and 5-HT re-uptake inhibitor in native tissue systems and represents a novel mechanism that could offer fast acting antidepressant action.     

5-HT1A, 5-HT1B and 5-HT2 receptor agonists induce differential behavioral responses in neonatal rat pups

Sprague-Dawley rat pups at 3–4 days prenatally were tested in both the absence and presence of milk following administration of various doses of either the 5-HT_1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT), the 5-HT_1B agonist 1-(3-chlorophenyl)piperazine (mCPP), or the 5-HT₂ agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Administration of 8-OHDPAT decreased mouthing, increased probing and increased behavioral activation. Conversely, the 5-HT₂ agonist DOI and the 5-HT_1B agonist mCPP increased mouthing and decreased probing. mCPP and DOI differed in their effects on behavioral activation, with mCPP decreasing and DOI increasing this composite behavioral score. mCPP increased grooming, whereas DOI elicited a characteristic unusual positioning of the limbs. Thus it appears that 5-HT_1A, 5-HT_1B and 5-HT₂ receptor subtypes are present in the neonate and elicit differential behavioral responses upon stimulation with selective agonists. Ontogenetic variations in the balance among these receptor subtypes during development may be related to the ontogenetic reversal that has been previously reported in the impact of serotonin manipulations on mouthing and suckling behavior during the neonatal to weanling age period.     

5-HT1A, 5-HT1B and 5-HT2 receptor agonists induce differential behavioral responses in preweanling rat pups

Preweanling (postnatal day 17-18) Sprague-Dawley rat pups were tested in both the absence and presence of milk following administration of various doses of the 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) or ipsapirone, the 5-HT1B agonist 1-(3-chlorophenyl)piperazine (mCPP) or the 5-HT2 agonist 1-(2,5-dimethoxy-4-iodo-phenyl)-2-aminopropane (DOI). 8-OH-DPAT decreased mouthing while ipsapirone, mCPP and DOI had no effect upon this behavior. However, all four agonists significantly decreased grooming. Both 8-OH-DPAT and mCPP produced alterations in limb positioning, with 8-OH-DPAT administration resulting in a poor control of the hindlimbs and mCPP inducing a hindlimb straddle position. These functional responses to 5-HT1A, 5-HT1B and 5-HT2 agonists in preweanling pups vary from those observed previously in neonates. For instance, whereas inhibitory effects of 5-HT1A stimulation on mouthing are observed in both neonatal and preweanling pups, facilitory effects of 5-HT1B and 5-HT2 stimulation are only seen in neonates. These ontogenetic alterations may be related to the previously reported ontogenetic reversal in the effect of serotonergic activation upon mouthing and suckling that occurs during the neonatal to weanling age period.     

Anxiolytic-like effect of a serotonergic ligand with high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors

S-(-)-2-[[4-(napht-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-alpha]-pyrazine (CSP-2503) is a serotonin (5-HT) receptor ligand with selectivity and high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors. CSP-2503 reduced rectal temperature and 5-HT neuronal hypothalamic activity in mice, decreased electrical activity of raphe nuclei cells in rats and blocked the enhancement of adenylate cyclase activity induced by forskolin in HeLa cells transfected with the human 5-HT1A receptor. This compound also blocked head-twitches induced by the 5-HT(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Contractions of guinea pig ileum induced by the 5-HT3 receptor agonist 2-methyl-5-HT were prevented by CSP-2503. Moreover, it reduced the bradycardia reflex induced by 2-methyl-5-HT in anaesthetized rats. In the light/dark box and social interaction tests, CSP-2503 presented anxiolytic activity, an action shared by 5-HT1 agonists and 5-HT3 antagonists. Taken together, these results suggest that CSP-2503 is a new 5-HT1 receptor agonist with 5-HT2A and 5-HT3)receptor antagonist activities that might be useful in a number of conditions associated with anxiety.