Antagonism of 5-hydroxytryptamine1A (5-HT1A) receptor-mediated modulation of adenylate cyclase activity by pindolol and propranolol isomers

The interactions of the stereoisomers of pindolol and propranolol with 5-hydroxytryptamine1A (5-HT1A) binding sites and adenylate cyclase activity were examined in rat hippocampus. (-)Pindolol and (-)propranolol displayed high affinity for 5-HT1A binding sites, and their affinities were not affected significantly by the addition of 10(-4) M GTP to the radioligand assay. The selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) decreased forskolin-stimulated adenylate cyclase activity. The (-)isomers of pindolol and propranolol did not affect basal or forskolin-stimulated activity but, at a concentration of 10(-5) M, they reversed the 8-OH-DPAT inhibition of the forskolin-stimulated cyclase activity. The (+)isomers were less potent in producing this effect. These data suggest that (-)pindolol and (-)propranolol are potent antagonists at 5-HT1A receptors in rat hippocampus.     

2-(Alkylamino)tetralin derivatives: interaction with 5-HT1A serotonin binding sites

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is a selective 5-HT1A serotonin agonist. Derivatives of 8-OH-DPAT with amine substituents larger or more bulky than n-propyl appear to be inactive in a presynaptic biochemical assay measuring agonist-induced feedback inhibition of 5-HT synthesis but have never been examined in brain binding assays. A series of N-phenylalkyl derivatives of 8-methoxy-2-aminotetralin was evaluated at [3H]-8-OH-DPAT-labeled 5-HT1A sites in rat brain hippocampal membranes. All of the phenylalkyl derivatives displayed significant affinity for these sites and, of the agents examined, the 3-phenylpropyl 8-hydroxy analogue appears to be optimal and had an affinity (Ki = 1.9 nM) comparable to that of 8-OH-DPAT (Ki = 1.2 nM). In addition, the presence of an oxygen-containing substituent at the 8-position of the tetralin ring is not necessary for good affinity, and secondary amines and tertiary amines displayed equal affinity at central 5-HT1A binding sites. 5-HT1A sites are found both pre- and postsynaptically; thus, differences observed in the biochemical assay as compared to the results of the present binding study could be due to different structural requirements of these two receptors. This seems unlikely, however, because there was little difference in the affinities of several selected analogues for striatal versus hippocampal binding sites. Because we have now demonstrated that amine substituents larger than propyl, and an unsubstituted 8-position, are well tolerated by central 5-HT1A sites, future studies aimed at the development of new serotonergic tetralin analogues need not be limited to N-propyl or 8-hydroxy derivatives of 2-aminotetralin.     

(+)-cis-8-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin: a potent and highly stereoselective 5-hydroxytryptamine receptor agonist

C1-Methylated derivatives of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1) were synthesized and tested for central 5-HT and dopamine receptor activity by use of a biochemical test method in rats. cis-8-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin (8) was found to be a 5-HT receptor agonist. The (+)-enantiomer of 8 had a potency equal to that of 1, whereas (-)-8 and the trans isomer (+/-)-9 were inactive.     

Differential interactions of dimethyltryptamine (DMT) with 5-HT1A and 5-HT2 receptors.

The interactions of the indolealkylamine N,N-dimethyltryptamine (DMT) with 5-hydroxytryptamine1A (5-HT1A) and 5-HT2 receptors in rat brain were analyzed using radioligand binding techniques and biochemical functional assays. The affinity of DMT for 5-HT1A sites labeled by [3H]-8-hydroxy-2-(di-n-propylamino)tetralin ([3H]-8-OH-DPAT) was decreased in the presence of 10(-4) M GTP, suggesting agonist activity of DMT at this receptor. Adenylate cyclase studies in rat hippocampi showed that DMT inhibited forskolin-stimulated cyclase activity, a 5-HT1A agonist effect. DMT displayed full agonist activity with an EC50 of 4 x 10(-6) M in the cyclase assay. In contrast to the agonist actions of DMT at 5-HT1A receptors, DMT appeared to have antagonistic properties at 5-HT2 receptors. The ability of DMT to compete for [3H]-ketanserin-labeled 5-HT2 receptors was not affected by the presence of 10(-4) M GTP, suggesting antagonist activity of DMT at 5-HT2 receptors. In addition, DMT antagonized 5-HT2-receptor-mediated phosphatidylinositol (PI) turnover in rat cortex at concentrations above 10(-7) M, with 70% of the 5-HT-induced PI response inhibited at 10(-4) M DMT. Micromolar concentrations of DMT produced a slight PI stimulation that was not blocked by the 5-HT2 antagonist ketanserin. These studies suggest that DMT has opposing actions on 5-HT receptor subtypes, displaying agonist activity at 5-HT1A receptors and antagonist activity at 5-HT2 receptors.     

The effects of 8-hydroxy-2-(di-n-propylamino)tetralin and other serotonergic agonists on performance in a radial maze: a possible role for 5-HT1A receptors in memory

A group of ten rats was trained to obtain food pellets in an 8-arm radial maze. The effects of pretreatment with (+)-Lysergic acid diethylamide (+)-tartrate (LSD), m-trifluoromethylphenylpiperazine (TFMPP), 5-methoxy-N,N-dimethyltryptamine oxalate (5-MeO-DMT), racemic 8-hydroxy-2-(di-n-propylamino)tetralin HBr (8-OH-DPAT), and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole succinate (RU 24969) were then evaluated. All drugs were administered IP 15 min before testing. With the exception of an increased rate of responding at a dose of 0.1 mg/kg of 8-OH-DPAT, all drugs produced a dose-related decline in response rate. In addition, LSD, RU 24969, and 8-OH-DPAT caused a statistically significant decrease in efficiency of responding. Of the three, 8-OH-DPAT was clearly the most active. Doses of 0.3, 1.0, and 3.0 mg/kg resulted in efficiencies of 61%, 53%, and 44%, respectively. The present results taken in light of 8-OH-DPAT's preferential binding to 5-HT1A receptors, the high density of these receptors in hippocampus, and the observation that the number of 5-HT1A receptors is decreased in Alzheimer's disease, suggest a possible role for this serotonergic receptor subtype in memory.     

Central 5-HT1A receptors and the mechanism of the central hypotensive effect of (+)8-OH-DPAT, DP-5-CT, R28935, and urapidil

This study investigated the central hypotensive effects of drugs that possess a high affinity for central 5-hydroxytryptamine (5-HT1A) binding sites; (+)8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), N,N-dipropylcarboxamidotryptamine (DP-5-CT), erythro-1-(1-[2(1,4-benzodioxan-2-yl)-2-hydroxyethyl]- 4-piperidyl)-2-benzimidazolinone (R28935) and urapidil proved to possess high affinity and selectivity for central 5-HT1A binding sites, labeled by [3H]8-OH-DPAT. (+)8-OH-DPAT (0.1-10 micrograms/kg) given through the left vertebral artery of chloralose-anesthetized cats, lowered blood pressure by a biphasic dose-response curve. When given systemically, 10- to 100-fold higher doses of (+)8-OH-DPAT were necessary to obtain the same hypotensive effect when compared with central administration. Besides 8-OH-DPAT, R28935, DP-5-CT and urapidil also lowered blood pressure by a central mechanism in doses that were ineffective when given systemically. The central hypotensive effect of 0.3 micrograms/kg (+)8-OH-DPAT, 3 micrograms/kg DP-5 CT, and 3 micrograms/kg R28935 could be blocked by 100 micrograms/kg (-)pindolol, indicating that central 5-HT1A receptors are involved. High doses of (+)8-OH-DPAT (3-10 micrograms/kg) can also lower blood pressure by activating central alpha 2-adrenoceptors. The hypotensive effect of 300 micrograms/kg urapidil given through the vertebral artery could not be blocked by (-)pindolol. These results indicate the involvement of central 5-HT1A receptors in the mechanism of the central hypotensive activity of (+)8-OH-DPAT, DP-5-CT, and R28935.     

Stimulation of corticosterone and beta-endorphin secretion in the rat by selective 5-HT receptor subtype activation

Changes in plasma concentrations of corticosterone and beta-endorphin (beta-END) were determined in male rats after treatment with the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) or the non-selective 5-HT agonist 6-chloro-2-(1-piperazinyl)pyrazine (MK-212). The administration of either 8-OH-DPAT or MK-212 increased plasma concentrations of both corticosterone and beta-END in a dose-related manner. The corticosterone and beta-END responses to 8-OH-DPAT were antagonized by spiperone and (-)-pindolol, both of which have been shown to have high affinity for the 5-HT1A binding site. In contrast, antagonist which are selective for the 5-HT2 receptor or non-selective 5-HT antagonists were without effect on the hormone responses to 8-OH-DPAT. The MK-212-induced increase in plasma concentrations of corticosterone and beta-END were not affected by treatment with the 5-HT1A antagonists spiperone and (-)-pindolol. However, the corticosterone and beta-END responses to MK-212 were attenuated by the selective 5-HT2 antagonists ketanserin, ritanserin and altanserin, as well as by the non-selective 5-HT antagonist metergoline. It is concluded that stimulation of either 5-HT1A or 5-HT2 receptors results in an activation of the hypothalamic-pituitary-adrenal axis in the rat.     

In vitro profile of the antidepressant candidate OPC-14523 at rat and human 5-HT1A receptors

This study determined the in vitro functional profile of 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2-quinolinone monomethanesulfonate (OPC-14523) at rat and human serotonin (5-HT) 5-HT1A receptors and binding affinity of OPC-14523 at human frontocortical 5-HT1A receptors. OPC-14523 (1 microM) increased guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS) binding to 5-HT1A receptor-containing regions of rat brain tissue sections (approximately 53% of the effect of 1 microM (+)8-hydroxy-2-(di-n-propylamino)tetralin ((+)8-OH-DPAT) that were blocked by the selective 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635). OPC-14523 also behaved as a partial agonist in its stimulation of [35S]GTPgammaS binding to membranes from rat hippocampus (pEC50=7.60+/-0.23, Emax=41.1% of the effect of 10 microM (+)8-OH-DPAT), human frontal cortex (pEC50=7.89+/-0.08; Emax=64% of the effect of 10 microM (+)8-OH-DPAT), and Chinese Hamster Ovary cells expressing cloned human 5-HT1A receptors (pEC50=8.0+/-0.11; Emax=85.5% of the effect of 10 microM 5-HT), and all of these effects of OPC-14523 were blocked by WAY-100635. Taken together, these data support the development of OPC-14523 as an antidepressant whose mechanism of action involves potent partial agonist activity at 5-HT1A receptors.     

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-HT1A receptors are differentially involved in the anxiolytic- and antidepressant-like effects of 8-OH-DPAT and fluoxetine in the rat

Fluoxetine, a selective serotonin reuptake inhibitor, shows moderate efficacy and potency in the rat forced swimming depression test and the shock-induced ultrasonic vocalization anxiety test, whereas the 5-HT(1A) receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is highly efficient and potent in both models. Whereas the 5-HT(1A) receptor antagonist WAY 100,635 abolishes the effect of 8-OH-DPAT in both models, it only attenuates the antidepressant-like effect of fluoxetine. Pretreatment with the 5-HT-depleting agent parachlorophenylalanine attenuates the antidepressant-like effect of fluoxetine, but not that of 8-OH-DPAT. This suggests that the antidepressant-like effect of fluoxetine and 8-OH-DPAT results from indirect (via increased synaptic availability of 5-HT) and direct stimulation of postsynaptic 5-HT(1A) receptors, respectively; whereas the anxiolytic-like effect of fluoxetine is not mediated by 5-HT(1A) receptors. The data support the hypothesis that the antidepressant- and anxiolytic-like effect of 8-OH-DPAT is predominantly mediated by post- and presynaptic 5-HT(1A) receptors, respectively, and that 5-HT(1A) receptors are only partially involved in the antidepressant-like effect of fluoxetine.     

Inactivation of 5-HT(1A) receptors in hippocampal and cortical homogenates

5-HT(1A) receptor function can be assessed in rat hippocampal and cortical membrane preparations as agonist-stimulated [35S]GTPgammaS binding. Membranes were preincubated in vitro with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). R(+)-8-hydroxy-2-(di-n-propylamino)tetralin [R(+)-8-OH-DPAT]-stimulated [35S]GTPgammaS binding and [3H]8-OH-DPAT binding assays were used to assess 5-HT(1A) receptor function and density, respectively. EEDQ decreased both R(+)-8-OH-DPAT-stimulated [35S]GTPgammaS and [3H]8-OH-DPAT binding in hippocampal and cortical membranes. The E(max) but not the EC(50) of R(+)-8-OH-DPAT to stimulate [35S]GTPgammaS binding was decreased by EEDQ in both preparations. Additionally, the IC(50) for EEDQ to reduce R(+)-8-OH-DPAT-stimulated [35S]GTPgammaS and [3H]8-OH-DPAT binding was the same for both brain regions in both assays. In contrast to EEDQ alone, agonist-stimulated [35S]GTPgammaS binding was not reduced in hippocampal membranes preincubated with EEDQ and the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl- cyclohexanecarboxamide maleate (WAY 100,635), suggesting that EEDQ acts directly on the receptor. Due to parallel reductions in receptor density and maximal functional response, it is concluded that there is little or no reserve for 5-HT(1A) receptor coupling to G(alpha) in these preparations. In addition, the sensitivity of hippocampal and cortical 5-HT(1A) receptors to inactivation by EEDQ in vitro is the same.     

8-Hydroxy-2-(di-n-propylamino)-tetralin inhibits food intake in fasted rats by an action at 5-HT1A receptors

The effects of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) on food intake were investigated in food-deprived rats. 8-OH-DPAT (25-100 microg/kg) administered subcutaneously immediately prior to the presentation of food produced a dose-related decrease in food intake in rats that had been fasted for 22 h. The hypophagic effect of 8-OH-DPAT (50 microg/kg) was abolished by pretreatment with the selective 5-HT1A receptor antagonist n-[2-(4-2-methoxyphenyl)-1-piperazinyl]-n-(2-pyridyl) cyclohexanecarboxamide (WAY 10063; 0.3 mg/kg). The results of this study show that the acute dose-dependent depressant effect of 8-OH-DPAT on food intake in fasted rats is mediated by an action at 5-HT1A receptors.     

Involvement of hypothalamic serotonin in activation of the sympathoadrenomedullary system and hypothalamo-pituitary-adrenocortical axis in male Wistar rats.

Infusion of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (2.5-20 micrograms in 1 microliter during 15 min), into the paraventricular nucleus of the hypothalamus (PVN) in the rat dose dependently increased plasma adrenaline and corticosterone concentrations, without affecting plasma noradrenaline concentrations. The highest dose also increased plasma glucose levels significantly. The results suggest that both the sympathoadrenomedullary system and the hypothalamo-pituitary-adrenocortical axis are activated after stimulation of 5-HT1A receptors in the PVN.     

Serotonin increases the production of inositol phosphates and mobilises calcium via the 5-HT2 receptor in A7r5 smooth muscle cells

Serotonin (5-HT) induces inositol phosphate production and the efflux of 45Ca2+ in a smooth muscle cell line (A7r5) derived from rat aorta. These effects were pharmacologically characterised and compared to data obtained in radioligand binding studies performed with the 5-HT2 ligand [3H]ketanserin in rat brain cortex membranes. 5-HT causes in increase in the levels of inositol trisphosphate (InsP3), inositol bisphosphate (InsP2) and inositol phosphate (InsP1). InsP3 production was rapid and transient whereas InsP1 accumulated in a time and concentration dependent manner. The 5-HT stimulated InsP1 accumulation (pEC50 = 6.48) was potently and competitively inhibited by the 5-HT2 specific antagonists, pirenperone and ketanserin, whereas antagonists of other 5-HT receptors were active only at high concentrations. There was a significant correlation between inhibition of 5-HT stimulated InsP1 accumulation and 5-HT2 binding (r = 0.98, P = 0.0035). 5-HT stimulated the efflux of 45Ca2+ from preloaded cells with a pEC50 of 7.59. The rank order of potency for agonist induced Ca2+ efflux, 5-HT greater than alpha-methyl-5-HT greater than 1-methyl-5-HT greater than RU 24969 (5-methoxy-3[1,2,3,6,-tetrahydropyridin-4-yl]-1-H indole) greater than 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)-tetralin) greater than 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)-tetralin) greater than 5-CT (5-carboxamidotryptamine) is typical for a 5-HT2 receptor mediated event. The effect of 5-HT was competitively blocked by ketanserin (pA2 = 8.22).(ABSTRACT TRUNCATED AT 250 WORDS)     

Estrogen modulates 5-HT(1A) agonist inhibition of lordosis behavior but not binding of [(3)H]-8-OH-DPAT

Previous studies showed that repeated estrogen treatment reduces the ability of the 5-HT(1A) receptor agonist, 8-hydroxy-2(di-n-propylamino) tetralin (8-OH-DPAT), to inhibit lordosis behavior of female rats. The present study evaluated the effects of repeated estrogen treatment on lordosis behavior and 5-HT(1A) receptor binding and coupling to G protein in the hypothalamus-preoptic area using the agonist ligand [3H]-8-OH-DPAT, which binds selectively to G-protein-coupled 5-HT(1A) receptors. Rats were injected twice with 25 or 50 microg of estradiol benzoate (EB) 7 days apart followed by 500 microg of progesterone (P) 48 h after the second EB injection. Controls received a single injection of 25 or 50 microg EB followed 48 h later by 500 microg of P. Four hours after P, 0.15 mg/kg 8-OH-DPAT was injected, and lordosis behavior examined for 30 min. Rats treated twice with EB showed significantly less 8-OH-DPAT inhibition of lordosis behavior than rats receiving a single EB injection. For receptor binding, rats received EB without P treatment. None of the estrogen treatments reduced [3H]-8-OH-DPAT binding density or affinity in the hypothalamus-preoptic area or hippocampus. These studies suggest that estrogen modulates 5-HT(1A) agonist potency without a measurable change in 5-HT(1A) receptor density or coupling to G protein.     

Selective 5-HT1A and 5-HT2 receptor-mediated adrenocorticotropin release in the rat: effect of repeated antidepressant treatments.

The 5-HT receptor agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) produced dose-dependent increases in plasma adrenocorticotropin (ACTH) in the male rat by activation of 5-HT1A and 5-HT2 receptors respectively. The ACTH response to DOI was enhanced by repeated administration of electroconvulsive shock (five over 10 days) but abolished by the tricyclic antidepressant, amitriptyline (20 mg/kg for 14 days). In contrast 21 days lithium treatment failed to alter DOI-induced ACTH release. Neither repeated electroconvulsive shock, nor amitriptyline, nor lithium altered the ACTH response to 8-OH-DPAT. These data are consistent with results from ligand binding and behavioural studies which suggest that the sensitivity of brain 5-HT2 receptors is increased by repeated electroconvulsive shock but attenuated by tricyclic antidepressant treatment. In contrast, our data suggest that the antidepressant treatments studied do not alter the sensitivity of the 5-HT1A receptors involved in ACTH release.     

Pharmacological characterization of release-regulating serotonin autoreceptors in rat cerebellum

The release of [3H]5-hydroxytryptamine ([3H]5-HT) evoked by 15 mM KCl in superfused rat cerebellum synaptosomes was inhibited by 5-HT (pEC30 = 8.73). Methiothepin antagonized 5-HT (pA2 = 9.28); ketanserin, methysergide, cinanserin and spiperone were ineffective. The receptors involved were activated (pEC30 = 8.90) by the 5-HT1 agonist 5-methoxy-3-[1,2,3,6-tetrahydropyridin-4-yl]-1H-indole (RU 24969) X (-)Propranolol shifted to the right (pA2 = 8.05) the dose-response curve of 5-HT. The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was ineffective. In conclusion, autoreceptors are present on 5-HT nerve endings in rat cerebellum and appear to belong to the 5-HT1B subtype.     

Chloroamphetamine did not prevent the effects of chronic antidepressants on 5-hydroxytryptamine inhibition of forskolin-stimulated adenylate cyclase in rat hippocampus.

Administration of p-chloroamphetamine (PCA, 10 mg/kg i.p. on two occasions) to rats resulted in a severe depletion of [3H]paroxetine binding sites, a measure of presynaptic serotonergic terminals, in both cortex and hippocampus, but did not affect [3H]8-hydroxy-2-(di-n-propylamino)tetralin [( 3H]8-OH-DPAT) binding or 5-hydroxytryptamine (5-HT)-induced inhibition of forskolin-stimulated adenylate cyclase in hippocampal membranes. Administration of either imipramine (15 mg/kg i.p. for 2 weeks) or lithium (0.2% for 2 weeks) to PCA-treated rats did not affect [3H]8-OH-DPAT binding but reduced the degree of inhibition of forskolin-stimulated adenylate cyclase by 5-HT in hippocampal membranes. It is concluded that the effects of imipramine and Li+ on 5-HT1A receptor-mediated responses in the hippocampus are exerted postsynaptically, possibly at a level distal to the receptor.     

Anticonflict effect of the putative serotonin receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)

The putative 5-HT agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) produced in rats an increase in the number of shocks accepted in a modified Vogel's conflict test design. Subchronic pretreatment with p-chlorophenylalanine (PCPA) similarly caused release of the punished behavior. This anticonflict effect of PCPA was antagonized by both 5-hydrotryptophan and 8-OH-DPAT. Thus in naive animals 8-OH-DPAT exerting anticonflict effects acted like a 5-HT antagonist, whereas in subchronically PCPA-pretreated animals with presumably supersensitive 5-HT receptors, 8-OH-DPAT decreasing the number of accepted shocks acted like a 5-HT agonist.