Antidepressant-like activity of 5-HT1A agonists measured with the forced swim test

This study examined the abilities of 5-hydroxytryptamine (5-HT) agonists with varying selectivity for different subtypes of 5-HT receptors to produce antidepressant-like behavioral effects in the forced swim test in rats. The 5-HT_1A agonists 8-OH-DPAT (0.125–1.0 mg/kg, SC) and tandospirone (SM-3997) (5–20 mg/kg, SC) both produced dose-related decreases in immobility time following subchronic treatment in rats. These effects were similar to those of the tricyclic antidepressants imipramine (5–15 mg/kg) and desipramine (5–15 mg/kg). In addition, the 5-HT_1A agonists, buspirone (20 mg/kg), gepirone (20 mg/kg) and ipsapirone (10 and 20 mg/kg) demonstrated antidepressant-like effects. Other groups of rats treated subchronically with each of the 5-HT_1A agonists or antidepressants showed no increase in locomotor activity, so that general changes in activity could not account for the reduction of immobility time in the forced swim test. 5-HT agonists selective for other receptor subtypes, such as the 5-HT_1B/1C agonistm-CPP (5 mg/kg) and the 5-HT_2/1C agonist DOB (1 mg/kg), were not effective in this behavioral test. The benzodiazepine diazepam (5 mg/kg) also failed to reduce immobility time, suggesting that anxiolytic properties of 5-HT_1A agonists did not mediate this behavioral effect. A common metabolite of some of the 5-HT_1A agonists, 1-PP, was ineffective in reducing immobility time. The stimulantd-amphetamine (2 mg/kg) significantly reduced immobility time but also significantly increased locomotor activity. Pretreatment with the 5-HT synthesis inhibitor PCPA alone did not alter immobility time, and did not alter the antidepressant-like effects of 8-OH-DPAT or tandospirone, suggesting that the 5-HT_1A agonists are producing their antidepressant-like effects through postsynaptic 5-HT_1A receptors. These results suggest that 5-HT_1A agonists may have antidepressant efficacy and act as a novel class of antidepressant drug.     

5-HT1A receptor activation and antidepressant-like effects: F 13714 has high efficacy and marked antidepressant potential

To examine further the hypothesis that the magnitude of the intrinsic activity of agonists at 5-HT_1A receptors determines the magnitude of their psychotropic activity, we studied the relationship between the maximal receptor activation produced by various 5-HT_1A receptor ligands and their antidepressant-like effects (i.e., decreased immobility in the forced swimming test in rats). Using three different in vitro assays suitable to measure differences among high, intermediate, and low efficacy 5-HT_1A receptor agonists, ligands were identified with intrinsic activities ranging from low-negative (i.e., the inverse agonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane-carboxamide (WAY 100635)) to high-positive (i.e., 3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone (F 13714)). In addition, novel compounds with intermediate intrinsic activity, like buspirone, but with high selectivity for 5-HT_1A receptors, unlike buspirone, were identified. The maximal effects of the 5-HT_1A receptor ligands in the forced swimming test correlated positively (r_S=0.91, P<0.005) with the rank order of their intrinsic activity at 5-HT_1A receptors. This relationship constitutes evidence that the magnitude of the psychotropic activity of 5-HT_1A receptor ligands is a positive function of their intrinsic activity at the receptor, and suggests that F 13714, which had maximal effects in the forced swimming test significantly larger than any of the other compounds examined here, did so because of its higher intrinsic activity at 5-HT_1A receptors.     

Effect of acute and repeated versus sustained administration of the 5-HT1A receptor agonist ipsapirone: electrophysiological studies in the rat hippocampus and dorsal raphe

The present study was aimed at examining the adaptation of presynaptic 5-HT_1A autoreceptors in the dorsal raphe and of postsynaptic 5-HT_1A receptors in the dorsal hippocampus during long-term administration of the 5-HT_1A receptor agonist ipsapirone given either repeatedly or in a sustained fashion. Concurrent microiontophoretic application of ipsapirone did not attentuate the suppressant effect of 5-hydroxytyptamine (5-HT) on 5-HT neurons, but markedly decreased it when co-applied on CA₃ pyramidal neurons in the dorsal hippocampus. Thus, ipsapirone acted as a full agonist in the dorsal raphe and as a partial agonist in the dorsal hippocampus. Ipsapirone (15 mg/kg/day, s.c. × 2 days) delivered by osmotic minipumps markedly decreased the firing activity of the dorsal raphe 5-HT neurons. After 14 days of treatment, there was a complete recovery of their firing activity and a desensitization of their somatodendritic 5-HT_1A autoreceptors, as assessed using microiontophoretic applications of 5-HT and 8-hydroxy-2(di-n-propylamino)tetraline (8-OH-DPAT) onto 5-HT neurons. The same degree of desensitization was obtained when ipsapirone was administered with repeated injections (7.5 mg/kg b.i.d., s.c. × 14 days). In contrast, the two modalities of ipsapirone adminsitration left unaltered the responsiveness of CA₃ pyramidal neurons to microiontophoretic applications of 5-HT and 8-OH-DPAT. In conclusion, long-term administration of ipsapirone most likely increases 5-HT neurotransmission by enhancing the tonic activation of postsynaptic 5-HT_1A receptors. Therefore, the use of sustained release preparation of 5-HT_1A receptor agonists should not alter their therapeutic effectiveness in anxiety and affective disorders since the same effects on 5-HT_1A receptor functions were produced in this rat model by the sustained and the repeated modes of administration of ipsapirone. Received: 24 September 1996 / Accepted: 28 April 1997     

Pharmacodynamic and Pharmacokinetic Studies in Rats of S-8-(2-Furyl)- and R-8-Phenyl-2-(di-n-Propylamino)Tetralin,Two Novel 5-HT1A Receptor Agonists In-vitro with Different Properties In-vivo

R- and S-8-(2-Furyl)- and R- and S-8-phenyl-2-(di-n-propylamino)tetralins (R- and S-LY-55 and R- and S-LY-49, respectively), novel enantiopure dipropylaminotetralins, have been screened as 5-HT_1A receptor ligands. All had nanomolar affinities for 5-HT_1A receptors and fully inhibited forskolin-stimulated adenylyl cyclase in-vitro (i.e. the four compounds appeared to be 5-HT_1A agonists). It was also found that the enantiomers of LY-55 behaved as typical 5-HT_1A receptor agonists in rats in-vivo by inducing a typical behavioural 5-HT syndrome, hypothermia and a decrease in 5-HT synthesis and turnover, indicating effects both on postsynaptic 5-HT_1A receptors and somatodendritic 5-HT_1A autoreceptors. In contrast, R- and S-LY-49 did not cause any 5-HT_1A receptor-related effects in-vivo except for a partial inhibition of 5-HT synthesis after high doses. The 5-HT_1A receptor antagonist WAY-100635 was shown to attenuate the R-LY-49-induced inhibition of 5-HT synthesis, indicating the compound to be a weak agonist at somatodendritic 5-HT_1A autoreceptors. R-LY-49 at a high dose and with a long pre-treatment time interval inhibited the hypothermic and behavioural effects, but not the inhibition of 5-HT synthesis induced by the 5-HT_1A receptor agonist R-8-hydroxy-(dipropylamino)tetralin (R-8-OH-DPAT). Taken together, these findings seem to indicate, that R-LY-49 is a weak partial agonist at 5-HT_1A receptors. A comparative pharmacokinetic study showed that the enantiomers of LY-55 entered the brain rapidly after subcutaneous administration and reached peak brain tissue/plasma concentration ratios within 15–30 min of injection, whereas the brain concentrations of R-LY-49 increased slowly, reaching a relatively low peak brain tissue/plasma concentration ratio 90 min after injection despite their similar lipophilicity. The differences between the pharmacological activity of the two compounds in-vivo seem to be explained by their different abilities to cross the blood-brain barrier, and a weak agonistic activity of R-LY-49 on 5-HT_1A receptors, both pre- and postsynaptically, compared with S-LY-55. Further studies are, however, needed for a deeper understanding of these differences.     

An evaluation of the elevated plus-maze test using the novel anxiolytic buspirone

Previous work suggests that the elevated plusmaze test of anxiety is insensitive to the anxiolytic effects of the novel anxiolytic buspirone, which shows an anxiogenic-like profile in this test. This paper examines some of the possible reasons for this and the role that buspirone's agonist activity at 5-HT_1A receptors plays in this effect. A variety of 5-HT_1A receptor agonists (p-aminophenylethylm-trifluromethylphenyl piperazine, (+)- and (-)-MDL 72832) showed similar activity to buspirone, as did the related compound ipsapirone. (-)-MDL 72832 was more potent than (+)-MDL 72832, in keeping with its stereoselective action at 5-HT_1A receptors. The ₂-adrenoceptor antagonist properties of 1-pyrimidinyl piperazine, a metabolite of buspirone, did not appear to be relevant to this action of buspirone as neither it nor idazoxan showed an anxiogenic-like profile. Neither chronic treatment with buspirone (1 mg/kg SC twice a day for 16 days) nor depletion of 5-HT withp-chlorophenylalanine changed the anxiogenic-like activity of buspirone in the elevated plus-maze test. These results suggest that an agonist action at postsynaptic 5-HT_1A receptors mediates the anxiogenic-like effects of buspirone in the elevated plus-maze test and that this test may either be insensitive to certain classes of anxiolytics or is measuring something unrelated to human anxiety states.     

Pharmacology of the hypothermic response to 5-HT1A receptor activation in humans

Summary The selective 5-HT_1A receptor ligand ipsapirone (IPS) caused dose-related hypothermia in humans. The response was attenuated by the nonselective 5-HT_1/2 receptor antagonist metergoline and was completely antagonized by the nonselective [3-adrenoceptor antagonist pindolol, which interacts stereoselectively with the 5-HT_1A receptor. The selective β₁-adrenergic antagonist betaxolol had no effect. The findings indicate that IPS-induced hypothermia specifically involves activation of (presynaptic) 5-HT_1A receptors. Therefore, the hypothermic response to IPS may provide a convenient in vivo paradigma to assess the function of the presynaptic 5-HT receptor in affective disorders and its involvement in the effects of psychotropic drugs.     

5-HT1C receptors in the serotonergic control of periaqueductal gray induced aversion in rats

The functional role of brain 5-HT and 5-HT receptor subtypes in periaqueductal gray (PAG) induced aversion has been investigated in rats. Antiaversive effects were found with the serotonin agonists TFMPP, mCPP and DOI but not with RU 24969 which was found to facilitate PAG aversion. The first three serotonin agonists share potent 5-HT_1C activity while RU 24969 differs with a high 5-HT_1A activity. Proaversive effects were found with the mixed 5-HT_1C/5-HT₂ antagonists cyproheptadine and ritanserin; this effect was already reported for the mixed 5-HT_1C/5-HT₂ antagonists metergoline and mianserin and is opposite to the effects of the selective 5-HT₂ antagonists ketanserin, pirenperone, trazodone and spiperone. The antiaversive effects of mCPP (1 mg/kg) could be prevented by pretreatment of the animals with mianserin (1 and 10 mg/kg). These results suggest that 5-HT_1C receptors play an important role in the serotonergic control of PAG aversion. 5-HT_1C receptor activation seems to mediate antiaversive effects whereas acute 5-HT_1C receptor blockade appears to facilitate PAG aversion. Functional interactions take place between several receptor types in the in vivo control of PAG aversion, where 5-HT_1C receptors appear to play a predominant function.     

Social instigation and aggressive behavior in mice: role of 5-HT1A and 5-HT1B receptors in the prefrontal cortex

Rationale  Social instigation is used in rodents to induce high levels of aggression, a pattern of behavior with certain parallels to that of violent individuals. This procedure consists of a brief exposure to a provocative stimulus male, before direct confrontation with an intruder. Studies using 5-HT_1A and 5-HT_1B receptor agonists show an effective reduction in aggressive behavior. An important site of action for these drugs is the ventral orbitofrontal cortex (VO PFC), an area of the brain which is particularly relevant in the inhibitory control of aggressive and impulsive behavior. Objectives  The objectives of the study are to assess the anti-aggressive effects of 5-HT_1A and 5-HT_1B agonist receptors [8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT) and CP-93,129] in the VO PFC of socially provoked male mice. To confirm the specificity of the receptor, 5-HT_1A and 5-HT_1B antagonist receptors (WAY-100,635 and SB-224,289) were microinjected into the same area, in order to reverse the agonist effects. Results  8-OH-DPAT (0.56 and 1.0 μg) reduced the frequency of attack bites. The lowest dose of CP-93,129 (0.1 μg) also decreased the number of attack bites and lateral threats. 5-HT1A and 5-HT1B receptor agonists differed in their effects on non-aggressive activities, the former decreasing rearing and grooming, and the latter, increasing these acts. Specific participation of the 1A and 1B receptors was verified by reversal of anti-aggressive effects using selective antagonists WAY-100,635 (10.0 μg) and SB-224,289 (1.0 μg). Conclusions  The decrease in aggressiveness observed with microinjections of 5-HT_1A and 5-HT_1B receptor agonists into the VO PFC of socially provoked mice, supports the hypothesis that activation of these receptors modulates high levels of aggression in a behaviorally specific manner.     

Agonist/antagonist interactions with cloned human 5-HT1A receptors: variations in intrinsic activity studied in transfected HeLa cells

Summary The characteristics of 5-HT_1A-recognition sites and receptor-mediated release of intracellular calcium were established in two transfected HeLa cell lines (HA 6 and HA 7) expressing different levels of human 5-HT_1A receptors (about 3000 and 500 fmol/mg protein, Fargin et al. 1989; 1991; Raymond et al. 1989).The pharmacological profiles of the binding (determined with [³H]8-OH-DPAT) and the calcium response (measured using Fura-2) were clearly of the 5-HT_1A type. Compounds such as 5-HT, 5-CT and 8-OH-DPAT acted as full agonists on the calcium response in both HeLa cell lines. In addition, methiothepin, pindolol, NAN 190 and SDZ 216-525 (Seiler et al. 1991) acted as silent and potent antagonists.Marked differences were observed in the responses mediated in the two cell lines. EC₅₀ values of agonists (particularly 5-HT, 5-CT, flesinoxan and 8-OH-DPAT) were higher in HA 7 cells (up to 80-fold) than in other 5-HT_1A receptor models (e.g. inhibition of adenylate cyclase in calf hippocampus). Further, a variety of compounds (ipsapirone, buspirone, spiroxatrine, MDL 73005) acted as agonists in HA 6 cells, whereas they behaved as silent antagonists in HA 7 cells (which express fewer receptors). By contrast, K_B values for antagonists were comparable in HA 6 and HA 7 cells.The present data show that EC₅₀ values and intrinsic activity for a given drug are subject to large variations depending on the number of receptors expressed in the target tissue. The results obtained in HA 6 cells are comparable with respect to both potency and efficacy to those observed, in calf or mouse hippocampus (inhibition of forskolin stimulated adenylate cyclase), whereas the results obtained in HA 7 cells are similar to those reported in mouse cortex (which was suggested to represent an atypical subtype of the 5-HT_1A receptor).Since the agonist activity of a given compound at the same receptor can vary markedly, the present data show that intrinsic activity is not only ligand-dependent but also varies with the receptor-effector system studied. In addition, there seems to be no simple way to make predictions about intrinsic activity, since that feature is model-dependent. Send offprint requests to D. Hoyer at the above addressJ. R. Raymond was supported by the American Heart Association (Grant in Aid) and by a V. A. Merit Award     

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     

5-HT(1A)-receptor over-expressing mice: genotype and sex dependent responses to antidepressants in the forced swim-test

Deficiencies in serotonergic neurotransmission are involved in the pathophysiology of depression. Due to its modulatory effect on serotonin (5-HT) release, the 5-HT_1A-receptor is thought to play a decisive role in the therapy of this mood disorder. However, it is not fully understood how antidepressant effects are mediated by pre- and postsynaptic receptor sites. In this study we examined the impact of postsynaptic 5-HT_1A-receptor over-expression in corticolimbic areas of male and female mice on the performance in the forced swim-test (FST). Furthermore, we investigated their response to the serotonin selective reuptake inhibitor (SSRI) citalopram in comparison to the selective noradrenaline reuptake inhibitor reboxetine, as well as the partial 5-HT_1A-receptor agonists, buspirone and S 15535. Additionally, these drugs were evaluated in the open field-test in order to observe effects on motor activity. The density of 5-HT_1A-receptors in discrete corticolimbic regions was determined in detail by quantitative autoradiography with [³H]8-OH-DPAT to investigate genotype as well as sex dependent differences in the expression pattern. [³H]8-OH-DPAT binding differed depending on sex with female mice of both genotypes displaying higher receptor binding in distinct brain areas. In the FST untreated male but not female over-expressing (OE) mice showed an antidepressant-like behaviour compared to wild-type (WT) mice. Citalopram yielded an antidepressant effect without influencing locomotor activity in OE mice but not in WT mice. Reboxetine had no antidepressant-like effect in OE mice, but sex-dependently in WT mice. The two partial agonists, buspirone and S 15535 produced no antidepressant-like activity in both genotypes and sexes, but aberrant motor effects. The antidepressant-like phenotype of male transgenic mice accounts for an involvement of postsynaptic 5-HT_1A-receptors in the FST behaviour. In addition, the selective over-expression of postsynaptic 5-HT_1A-receptors in mice contributes to the antidepressant response to citalopram in the FST. Although further pharmacological analysis is required, the data provide novel support for a role of postsynaptic 5-HT_1A-receptors in the effects of SSRIs.This article is part of a Special Issue entitled ‘Serotonin’.     

Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders

Rationale Current treatments for schizophrenia adequately treat the positive symptoms of schizophrenia but only modestly improve cognitive deficits. This review provides evidence for and against the use of selective 5-HT receptor drugs as cognition enhancing agents for schizophrenia and other disorders.Methods Pre-clinical and clinical literature concerned with the role of the serotonergic system in cognition and memory as it relates to schizophrenia is reviewed. Individual 5-HT receptor subtypes for which selective drugs are available that are likely to improve cognition are reviewed. Recommendations for clinical testing are proposed.Results and conclusions Four 5-HT receptor systems (5-HT_1A, 5-HT_2A, 5-HT₄, 5-HT₆) are highlighted as suitable targets for enhancing cognition and memory. Because many clinically available antipsychotic drugs already target 5-HT_1A, 5-HT_2A and 5-HT₆ receptors, design of clinical trials will need to take into account the serotonergic pharmacology of concurrently administered antipsychotic medications. 5-HT_1A partial agonists and 5-HT_2A antagonists have shown modest effectiveness in improving cognition in schizophrenia. 5-HT₆-selective compounds for cognition enhancement are in late-stage clinical trials, while 5-HT₄ compounds have not yet been tested in humans for cognition enhancement.Recommendations For stand-alone therapy for enhancing cognition, 5-HT_1A partial agonists, 5-HT_2A antagonists, 5-HT₄ partial agonists and 5-HT₆ antagonists are all likely to induce at least modest improvement in cognition in schizophrenia. If add-on therapy is contemplated, antipsychotic drugs with weak affinities for serotonin receptors should be used to avoid confounds. It is likely that serotonergic drugs will soon be available as cognition enhancing medications for disorders other than schizophrenia (e.g. dementia).     

Implication of 5-HT<Subscript>2</Subscript> receptor subtypes in the mechanism of action of antidepressants in the four plates test

Rationale The selective serotonin reuptake inhibitors (SSRIs) and the serotonin and noradrenaline reuptake inhibitors (SNRIs) increase synaptic levels of serotonin, leading to an increased activation of a multitude of specific postsynaptic 5-HT receptors. However, it is not yet known which 5-HT receptor subtypes mediate the therapeutic effects of antidepressants.Methods The effects of the SSRI, paroxetine and the SNRI, venlafaxine were evaluated in the mouse four plates test (FPT).Results Paroxetine administered intraperitoneally (IP) (0.5, 2–8 mg/kg) potently augmented the number of punished passages accepted by mice in this paradigm. The effects of paroxetine (8 mg/kg) were not reversed by the selective 5-HT_2C receptor antagonist, RS 10-2221 (0.1 mg/kg and 1 mg/kg) or the selective 5-HT_2B/2C receptor antagonist SB 206553 (0.1 mg/kg and 1 mg/kg), at doses which lack an effect when administered alone. In contrast, the selective 5-HT_2A receptor antagonist, SR 46349B (0.1 mg/kg and 1 mg/kg) completely abolished the paroxetine-induced increase in punished passages. The acute administration of venlafaxine induced an anxiolytic-like effect in the FPT at the doses of 2–16 mg/kg. This effect was reversed by the 5-HT_2B/2C receptor antagonist as did SR 46349B, for both doses administered. Our results strongly suggest that activation of 5-HT_2A receptors is critically involved in the anxiolytic activity of paroxetine, whereas the 5-HT_2A and 5-HT_2B receptors are involved in the anti-punishment action of venlafaxine in the FPT. The co-administration of selective 5-HT_{2A, 2B, 2C} receptor agonists (DOI, 0.06 mg/kg and 0.25 mg/kg; BW 723C86, 0.5 mg/kg and 2 mg/kg and RO 60-0175, 0.06 mg/kg and 0.25 mg/kg), respectively, was subsequently investigated. The effects of sub-active doses of paroxetine (0.25 mg/kg and 1 mg/kg) were augmented by BW 723C86 and RO 60-0175 receptor agonist challenge. The anti-punishment effects of venlafaxine (0.25 mg/kg and 1 mg/kg) were potentialised only by DOI co-administration.Conclusion These results indicate that the co-administration of 5-HT₂ receptor agonists with paroxetine and venlafaxine may provide a powerful tool for enhancing the clinical efficacy of these antidepressants.     

BIMT 17, a 5-HT2A receptor antagonist and 5-HT1A receptor full agonist in rat cerebral cortex

In the search for antidepressant agents with a rapid onset of action, we have found that compound BIMT 17 (1-[2-[4-(3-trifluoromethylphenyl)piperazin1-yl]ethyl]benzimidazol-[1H]-2-one) shows a good affinity for cerebral cortical 5-HT_1A (pK _i = 7.72) and 5-HT_2A (pK _i = 6.90) receptors, with no appreciable affinity for the other 5-HT receptor subtypes, including 5-HT_2C. BIMT 17 reduced forskolin-stimulated cAMP accumulation in the cerebral cortex (pEC₅₀ = 6.09) and in the hippocampus (pEC₅₀ = 6.50), and antagonized 5-HT-induced phosphatidylinositol turnover (pK _i = 6.96) in the cerebral cortex. The effect on cAMP accumulation was blocked by the 5-HT_1A receptor antagonist tertatolol. Buspirone, 8-OH-DPAT and S 14671 {1-[2-(2-thenoylamino)ethyl]-4[1-(7-methoxynaphtyl)]piperazine, claimed to be 5-HT_1A receptor agonists, did not reduce forskolin-stimulated cAMP formation in the cerebral cortex.On the basis of these data, it was concluded that BIMT 17 was the only compound that behaved as a full agonist with respect to the CAMP response in the cortex, while exerting concurrent agonism at 5-HT_1A receptors and antagonism at 5-HT_2A receptors. These characteristics might explain the peculiar behaviour of BIMT 17 in mimicking the inhibitory action of 5-HT on the basal firing rate of the cortical neurons (see accompanying paper).     

Effects of blockade of 5-HT2 receptors and activation of 5-HT1A receptors on the exploratory activity of rats in the elevated plus-maze

Acute administration of gepirone, a 5-HT_1A agonist, caused a dose dependent (1–10 mg/kg, IP) reduction in the locomotor activity (open and closed arms) of rats tested in the elevated plus-maze. However, rats housed in individual cages and submitted to chronic treatment with gepirone (10 mg/kg PO) showed a marked increase in the percentages of number and time spent in the open arms as compared to controls. These results are compatible with the idea that the antiaversive effect due to long-term treatment with 5-HT_1A agonists is the result of a progressive desensitization of the somatodendritic 5-HT autoreceptor with the consequent recovery of firing rate of 5-HT neurons along with an activation of normosensitive postsynaptic 5-HT neurons. Ketanserin caused a biphasic effects on the exploratory behavior of rats in the plus-maze. The lower dose (0.5 mg/kg) decreased the aversion to the open arms and the higher dose (1.0 mg/kg) caused an unspecific decrease in the overall activity of the animals. Ketanserin is supposed to have antagonistic action on 5-HT₂ and on -adrenergic receptors. As prazosin (0.5–1.0 mg/kg), an -adrenergic receptor blocker, did not present any significant effect in the present work it is suggested that the effects of the lower dose of ketanserin was due to its high antagonistic action on 5-HT₂ receptors.     

Comparison of 5-HT4 receptors in guinea-pig colon and rat oesophagus: effects of novel agonists and antagonists

5-HT₄ receptors in isolated distal colon myenteric plexus of guinea-pig, mediating contraction of longitudinal smooth muscle, have been further characterized by selective agonists and antagonists. The indole agonists, 5-HT and 5-methoxytryptamine (5-MeOT), were full agonists (relative to 5-HT) with potency values (pEC₅₀) of 8.0 ± 0.1 (n = 50) and 7.8 ± 0.1 (n = 12), respectively. 5-HT₄ receptor agonists of other structural classes, including benzimidazolones (BIMU 1 and BIMU 8), and benzamides ((S)-zacopride, (R)-zacopride, renzapride, SC 49518) were partial agonists with intrinsic activities less than that of 5-HT. In general, the potencies for these compounds at 5-HT₄ receptors in guinea-pig colon were similar to the potencies seen in the rat isolated oesophagus, where 5-HT₄ receptors mediate relaxation.GR 113808 {[1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl1-methyl-1H-indole-3-carboxylat}, RS 39604 {1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-3-[1-[2-[(methylsulfonyl)amino] ethyl]-4-piperidinyl]-1-propanone hydrochloride and SB 204070 {(1-n-butyl-4-piperidinyl)methyl 8-amino-7-chloro-1,4-benzodioxane-5-carboxylate} antagonized 5-HT responses with pA₂ values of 9.1 ± 0.1, 9.0 ± 0.2 and 11.0 ± 0.1, respectively. These affinity values were similar to those obtained at 5-HT₄ receptors in isolated rat oesophagus (9.0 ± 0.4, 9.3 ± 0.1 and 10.6 ± 0.1, respectively).Despite these operational similarities between 5-HT₄ receptors in guinea-pig colon and rat oesophagus, several novel compounds have revealed important differences between 5-HT₄ receptors in the two tissues. For example, the substituted benzoate, RS 23597 {3-(piperidine-1-yl) propyl-4-amino-5-chloro-2-methoxybenzoate hydrochloride, acted as a partial agonist (intrinsic activity 0.5) in guinea-pig colon with a potency of 7.6 ± 0.1 (n = 16). In isolated rat oesophagus, however, this compound was a surmountable antagonist (pA₂ = 7.8 ± 0.1) with no intrinsic activity. In contrast, the substituted naphthalimide (S)RS 56532 {(S)6-amino-5-chloro-2-(1-azabicyclo[2, 2, 2]octan-3-yl)2,3-dihydro-1H-benz isoquinoline-1,3-dione hydrochloride}, was a potent (pEC₅₀ = 7.9 ± 0.1), efficacious partial agonist (intrinsic activity = 0.8) in the rat oesophagus. However, in guinea-pig colon, it was a surmountable antagonist with an affinity (pK_B) of 9.4 ± 0.1. Furthermore, several novel, selective, 5-HT₄ compounds also showed opposing patterns of intrinsic activities similar to those described for RS 23597 and (S)RS 56532.It is concluded that these differences are inconsistent with differences in 5-HT₄ receptor reserves, and may suggest that 5-HT₄ receptors in the guinea-pig colon and the rat oesophagus can be operationally distinguished.     

Role of spinal serotonin1 receptor subtypes in thermally and mechanically elicited nociceptive reflexes

The ability of 5-HT_1A and 5-HT_1B agonists to alter a spinal animal's nociceptive threshold was examined using two analgesiometric tests. In the spinal withdrawal reflex test, administration of the selective 5-HT_1A agonists ipsapirone, gepirone and PAPP resulted in significant dose-dependent increases in receptive field (RF) area for withdrawal reflexes when compared to predrug baseline values, indicating an increase in nociceptive sensitivity. The average overall percent maximal increase in RF area following administration of 5-HT_1A selective compounds was: 80±16% for the ventroflexion reflex, 90±6% for the dorsiflexion reflex and 87±8% for the lateral flexion reflex. Similar to the effects noted with 5-HT_1A agonists, administration of 5-HT_1B agonists RU24969, mCPP and TFMPP resulted in a hyperalgesic response with an overall percent maximal increase of 43±6% for the ventroflexion reflex, 51±6% for the dorsiflexion reflex and 38±9% for the lateral flexion reflex. In the tail-flick analgesiometric test, administration of the 5-HT_1A agonists 8-OH-DPAT and ipsapirone and the 5-HT_1B agonists RU24969 and mCPP resulted in a significant dose-dependent increase in tail-flick latencies when compared to predrug baseline values, indicating a decrease in nociceptive sensitivity to noxious thermal stimuli. No differences in magnitude of the effect of the two receptor subtypes were found, indicating that stimulation of either 5-HT_1A or 5-HT_1B receptors was equipotent in producing the antinociceptive tail-flick response. Administration of the 5-HT_1A antagonist meter-goline completely reversed the increase in TFL produced by RU24969, providing further evidence that the effects seen here are mediated by spinal 5-HT receptors. The results of this study indicate that spinal 5-HT₁ receptor subtypes may either facilitate or inhibit nociceptive input depending upon the type of nociceptor that is activated, as opposed to the type of receptor subtype that is stimulated.     

N-Methyl-D-aspartate receptor antagonists counteract the long lasting 5-HT1A receptor-induced attenuation of postsynaptic responses in the rat in vivo

Summary The effect of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists dizocilpine and phencyclidine, the competitive NMDA antagonist 3-(2-carboxypiperazin-4-yl)-propyl-l-phosphonic acid (CPP) and the antagonist at the glycine modulatory site of the NMDA receptor, 3-amino-l-hydroxy-2-pyrrolidone (HA-966) on the long lasting attenuation of some postsynaptic 5-HT_1A receptor-mediated responses in rats (increased corticosterone secretion and inhibition of the cage leaving response) produced by a single injection of the 5-hydroxytryptamine_1A 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was studied. It was found that these antagonists counter-acted the attenuation of these responses at dose levels known to block the NMDA receptor-ion channel complex in vivo. It is concluded that the long lasting attenuation of postsynaptic responses after a 5-HT_1A receptor agonist is initiated through stimulation of glutamate NMDA receptors indicating a functional interaction between the 5-HT and glutamate systems in at least two different models. Send offprint requests to S. B. Ross at the above address     

The role of serotonin receptor subtypes in treating depression: a review of animal studies

Rationale

Serotonin reuptake inhibitors (SSRIs) are effective in treating depression. Given the existence of different families and subtypes of 5-HT receptors, multiple 5-HT receptors may be involved in the antidepressant-like behavioral effects of SSRIs.

Objective

Behavioral pharmacology studies investigating the role of 5-HT receptor subtypes in producing or blocking the effects of SSRIs were reviewed.

Results

Few animal behavior tests were available to support the original development of SSRIs. Since their development, a number of behavioral tests and models of depression have been developed that are sensitive to the effects of SSRIs, as well as to other types of antidepressant treatments. The rationale for the development and use of these tests is reviewed. Behavioral effects similar to those of SSRIs (antidepressant-like) have been produced by agonists at 5-HT_1A, 5-HT_1B, 5-HT_2C, 5-HT₄, and 5-HT₆ receptors. Also, antagonists at 5-HT_2A, 5-HT_2C, 5-HT₃, 5-HT₆, and 5-HT₇ receptors have been reported to produce antidepressant-like responses. Although it seems paradoxical that both agonists and antagonists at particular 5-HT receptors can produce antidepressant-like effects, they probably involve diverse neurochemical mechanisms. The behavioral effects of SSRIs and other antidepressants may also be augmented when 5-HT receptor agonists or antagonists are given in combination.

Conclusions

The involvement of 5-HT receptors in the antidepressant-like effects of SSRIs is complex and involves the orchestration of stimulation and blockade at different 5-HT receptor subtypes. Individual 5-HT receptors provide opportunities for the development of a newer generation of antidepressants that may be more beneficial and effective than SSRIs.     

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