Serotonergic influences on male sexual behavior of rhesus monkeys: effects of serotonin agonists

Although numerous studies in rats have demonstrated an influence of serotonin (5-HT) on male copulation, no studies have yet to demonstrate whether such a relationship exists in primate species. The present study sought to characterize 5-HT influences on male copulatory behavior of rhesus monkeys by using three different 5-HT agonists: a full 5-HT_1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT); a partial 5-HT_1A agonist, ipsapirone; and a 5-HT_1C/1D agonist, m-chlorophenylpiperazine (m-CPP). 8-OH-DPAT had a biphasic effect upon ejaculation latency, with low doses (5–10 µg/kg) producing a shortening of ejaculation latency (time from initiation of copulation to ejaculation), and the highest dose (100 µg/kg) producing a lengthening of ejaculation latency. Intromission frequency (number of intromissions preceding ejaculation) was affected only at 10 µg/kg 8-OH-DPAT with monkeys requiring fewer intromissions to ejaculation at this dose. Ipsapirone administration led to a shortening of ejaculation latency at all doses tested (50–800 µg/kg), and a reduction in intromission frequency at 200–800 µg/kg ipsapirone. Administration of the 5-HT_1C/1D agonist, m-CPP, resulted in an increase in ejaculation latency at 200–400 µg/kg m-CPP and mount latency at 400 µg/kg m-CPP, but did not affect intromission frequency. In summary, stimulation of 5-HT_1A receptors lowered the ejaculatory threshold of the monkeys, while stimulation of 5-HT_1C/1D receptors interfered with copulatory behavior and raised the ejaculatory threshold. These results provide evidence that copulatory behavior of rhesus monkeys is influenced by 5-HT receptor stimulation, however, the direction of the effect depends upon the subtype of 5-HT receptor being stimulated.     

Effect of the 5-HT1A agonist, 8-OH-DPAT on instrumental performance in rats

These experiments assessed whether reported increases in food consumption and food-reinforced instrumental performance in undeprived rats by the 5-HT_1A agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) are due to an increment in the incentive value of foods. Against this hypothesis, we found that when undeprived rats were trained to lever press for the food pellets and then allowed to consume the pellets under 8-OH-DPAT, this reexposure decreased subsequent instrumental extinction performance regardless of test drug condition relative to reexposure under vehicle. Although both food consumption and reinforced lever press performance were incremented, 8-OH-DPAT was found generally to reduce instrumental extinction performance and lever pressing during a period when the reinforcer was delivered non-contingently. Rats injected with 8-OH-DPAT were, however, more sensitive to delay of reinforcement, and increased their lever press performance at a 3-s delay but decreased performance at 6-s and 12-s delays relative to animals injected with vehicle. These results are consistent with the hypothesis that 8-OH-DPAT modifies arousal processes in a manner similar to mild stress, thereby acting both to elevate rewarded instrumental performance and to increase sensitivity to the effects of non-reward.     

Monoaminergic mediation of masculine and feminine copulatory behavior in female rats.

Ovariectomized rats treated with testosterone propionate (TP; 100 mug/kg X 6 days) and para-chlorophenylalanine (pCPA; 100 mg/kg X 3 days), a serotonin synthesis inhibitor, showed more masculine copulatory behavior (including the ejaculatory pattern) than did females receiving either TP or pCPA alone. The facilitatory effect of pCPA on the masculine copulatory behavior in females was not potentiated by pargyline (50 or 100 mg/kg), a monoamine oxidase inhibitor; instead, pargyline antagonized the effect of pCPA. Apomorphine (100 mug/kg), a dopamine receptor stimulant, did not increase masculine copulatory behavior in TP treated females. Adopaminergic facilitatory effect was therefore not demonstrated. These results suggest a serotonin-mediated inhibition of masculine copulatory behavior in female rats. When feminine copulatory behavior was tested, females receiving TP plus pCPA plus pargyline, TP plus pargyline, or TP plus apomorphine displayed lordosis in response to mounting by male rats. Lordosis did not occur after administration of TP, PCPA, or pargyline, individually or in any other combination. The responses in pargyline groups are consistent with the hypothesis of a noradrenergic facilitatory system for lordotic behavior. The responses in the apomorphine group are discussed in terms of a possible role for low level dopaminergic stimulation in facilitating lordosis.     

Gestational manganese intoxication and anxiolytic-like effects of diazepam and the 5-HT1A receptor agonist 8-OH-DPAT in male Wistar rats

In the present study, the effects of prenatal manganese (Mn) intoxication on the anxiolytic-like effects of diazepam and the 5-HT_1A receptor agonist R-(+)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) were examined. Wistar dams were exposed to MnCl₂?4H₂O at 5, 000 ppm in the drinking water for the duration of pregnancy. On the day of parturition, Mn was discontinued as an additive in the drinking water. Control rats were derived from dams that consumed tap water and had no exposure to Mn. Male offspring were tested at the age of 12 weeks. The anxiolytic-like effect was assessed in an elevated plus maze device and with the Vogel conflict test. The benzodiazepine anxiolytic diazepam (5 mg/kg, ip) increased the percentage of time spent in open arms in control rats (in comparison to saline treatment) (p < 0.05); no such effect was seen in Mn-exposed rats. Conversely, the serotoninergic 5-HT_1A agonist 8-OH-DPAT (0.3 mg/kg, ip) increased the percentage of time spent in open arms in both experimental groups. In the Vogel drinking test, an anxiolytic-like effect was also observed in both test groups (in controls this was of borderline significance). In contrast, 8-OH-DPAT did not evoke an anxiolytic-like action in control or in Mn-exposed rats in the anticonflict test. In conclusion, findings indicate that gestational Mn exposure attenuated benzodiazepine-mediated anxiolytic-like effects but not those of the 5-HT_1A receptor agonist 8-OH-DPAT.     

Para-chlorophenylalanine prevents feeding induced by the serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)

The effects of para-chlorophenylalanine pre-treatment (PCPA, 150 mg/kg IP daily for 3 days) on feeding and stereotyped behaviour elicited by the serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in rats were investigated. PCPA depleted brain serotonin and 5-hydroxyindoleacetic acid concentrations by 90% and increased feding during a 2-h day-time test. 8-OH-DPAT (60–4000 μg/kg SC) increased food intake in control animals but decreased in in PCPA-treated animals during the 2-h test. PCPA treatment had no effect on 8-OH-DPAT-induced locomotion or serotonin-related stereotyped behaviour (i.e. forepaw treading, headweaving, wet dog shakes, etc). Since PCPA prevents the operation of pre-synaptic serotonergic mechanisms, the failure of 8-OH-DPAT to increase food intake in PCPA-treated rats suggests that 8-OH-DPAT-induced hyperphagia is autoreceptor mediated.     

Low doses of the putative serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) elicit feeding in the rat

The effects of the putative serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on food intake in non-deprived male rats were investigated. Low doses of 8-OH-DPAT (15–60 g/kg) significantly increased food intake, without affecting drinking, grooming, rearing or locomotion. Microstructural analysis of the elicited feeding behaviour revealed that the rate of eating after 8-OH-DPAT treatment was very similar to that previously reported following 16 h food deprivation. Higher drug doses (250–4,000 g/kg) also elicited feeding and caused locomotor stimulation and serotonin-related stereotyped behaviour (i.e. forepaw padding, headweaving, wet dog shakes, flat body posture). When feeding and stereotypy were observed concurrently, response competition was evident and feeding behaviour was fragmented into numerous short eating bouts. As drug-induced stereotypy declined with time, this fragmented pattern of eating was succeeded by long bouts of eating which were similar to those observed at doses of 15–60 g/kg 8-OH-DPAT. The induction of feeding by a serotonin agonist appears paradoxical, since drugs which enhance brain serotonergic activity usually inhibit feeding.     

An ethopharmacological analysis of the behavioral effects of 8-OH-DPAT

Several behaviors associated with the serotonin syndrome have been reported in rats following administration of the 5-HT_1A receptor agonist 8-OH-DPAT. The present investigation approached this phenomenon from an ethopharmacological perspective, and provided a detailed temporal analysis of the behavioral effects of this compound over a 2-h period, in both male and female rats in the home cage. In addition, in order to further characterize the nature of the forepaw-treading and locomotor elements, and assess the extent of influence of the physical characteristics of the test arena, this study provided a detailed analysis of these behaviors in both the home cage and a large oval runway. In the initial analysis, the data indicate a distinct chronological sequence of effects following 8-OH-DPAT treatment. For example, flat back activity and lower lip retraction were apparent within a few minutes post-injection, the former dissipating after about 30 min and being replaced as the prepotent response by a more general (curved back) locomotor enhancement, while the latter effect remained throughout the 2-h test period. Interestingly, there were reliable gender differences in terms of the onset and disappearance of several behavioral components, with females generally being more rapidly affected, but recovering earlier than males. The detailed analysis of locomotor activity and forepaw treading would suggest that the locomotor syndrome primarily involves forward movement, heavily guided by the physical environment. Furthermore, forepaw-treading would seem only to occur when an animal reaches a barrier and forward movement is briefly interrupted, as no reliable incidence of this behavior was observed in the open area of the test area. Together, these findings provide further characterization of the behavioral syndrome induced by 8-OH-DPAT, and indicate the importance of time post-administration, gender of the subject, and the physical characteristics of the test environment, when considering stereotypical drug effects.Supported by NIH Grant MH42803 and RCMI Grant RR03061     

Effects of a new type of 5-HT receptor agonist on male rat sexual behavior

8-Methoxy-2-(di-n-propylamino) tetralin (8-OMe-DPAT) and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) are two new drugs exerting selective actions on brain 5-HT neurotransmission. In the present experiments we have investigated the effects of these two drugs on male rat sexual behavior. It was found that both drugs reduce the number of intromissions preceding ejaculation and shorten the ejaculation latency. These effects are extremely pronounced and several animals ejaculate at the first intromission. In addition 8-OH-DPAT produced a slight reduction of the post-ejaculatory interval. There were no significant effects on latency to initiate copulation or in the number of mounts preceding ejaculation. Finally, sexual behavior was partly or completely restored in castrated male rats after injection with 8-OMe-DPAT or 8-OH-DPAT.     

The 5-HT1A agonist 8-OH-DPAT increases consumption of palatable wet mash and liquid diets in the rat

The 5-HT_1A agonist 8-OH-DPAT, at a dose of 30 g/kg, enhanced the consumption of sweetened wet mash and sweetened milk in non-deprived rats. In partially satiated rats, sensitivity to the hyperphagic effect of 8-OH-DPAT on wet mash intake was substantially increased, so that the minimally effective dose was reduced to 3 g/kg. Similarly, 8-OH-DPAT was more efficacious in increasing milk intake in satiated rats. Thus, 30 and 40 g/kg 8-OH-DPAT produced a 4-fold increase of milk intake in completely satiated rats compared to a 2-fold increase in partially satiated animals at a dose of 30 g/kg. The increased intake of liquid and wet mash diets observed after treatment with low doses of 8-OH-DPAT argues against the involvement of non-specific gnawing in the increased consumption of solid food produced by the drug. Rather, the data suggest that 8-OH-DPAT may specifically stimulate appetite by counteracting a tonic serotonergic inhibition of feeding. The present experiments also showed that 8-OH-DPAT attenuates fenfluramine-induced anorexia which is thought to depend on increased serotonergic neurotransmission.     

Rotational behavior induced by 8-hydroxy-DPAT,a putative 5HT-1A agonist,in 6-hydroxydopamine-lesioned rats

Rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the ascending nigro-striatal pathway have been shown to rotate in response to dopamine (DA) agonists that are not considered to have postsynaptic DA stimulant properties in intact animals, suggesting a relative loss of DA receptor selectivity in the denervated striatum. The present experiments assessed the possibility that this loss of selectivity may extend to serotonin (5HT) agonist drugs. The 5HT-1a agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), at doses of 0.3–3 mg/kg SC, induced robust contralateral rotational behavior (RB) in 6-OHDA-lesioned rats that had been preselected on the basis of high responsiveness to the atypical DA agonists 3-PPP and SKF 38393. Rats with unilateral dorsal raphe lesions induced by 5,7-dihydroxytryptamine (5,7-DHT) showed contralateral RB in response to similar doses of 8-OH-DPAT but with a different behavioral pattern. The putative 5HT-1b agonist RU 24969 produced contralateral RB in 5,7-DHT-lesioned rats while showing a much weaker effect in 6-OHDA-lesioned rats. Striatal DA levels were depleted by 99% in representative 6-OHDA-lesioned rats but striatal 5HT levels were unaffected. The effects of 8-OH-DPAT in 6-OHDA-lesioned rats were therefore not attributable to destruction of ascending 5HT-containing neurons. These effects may result from indirect actions, mediated by 5-HT neurons or neuronal receptors, that result from asymmetry of brain DA systems. Alternatively, it is proposed that rats with highly denervated striatal DA receptors show a loss of apparent molecular selectivity such that weak partial DA agonist properties of 8-OH-DPAT, although not demonstrable in normal rats, become manifested under these conditions. Offprint requests to: J.M. Liebman     

Differential coupling of 5-HT1A receptors occupied by 5-HT or 8-OH-DPAT to adenylyl cyclase

Summary Human serotonin (5-hydroxytryptamine, 5-HT)-1A receptors have been transfected in NIH-3T3 cells, and their coupling to adenylyl cyclase was analysed depending on (1) the number of receptor expressed, (2) the experimental conditions used, (3) the nature of the agonists. Two monoclonal cell lines were used, expressing low (45 fmol/mg) and high (500 fmol/mg) levels of 5-HT_1A receptor. Two methods were tested to study the negative coupling of the transfected 5-HT_1A receptors to adenylyl cyclase: (1) measurement of CAMP production in intact cells, (2) measurement of adenylyl cyclase activity in vitro on membrane preparations. Studies on intact cells revealed that an increase in the receptor concentration was followed by (1) an increase in the efficacies of 5-HT, 5-CT (5-carboxamidotryptamine) and 8-hydroxy2-(di-n-propylamino)tetralin (8-OH-DPAT), (2) a 2 to 3-fold increase in the potency of 5-CT and 8-OH-DPAT, but no change in the potency of 5-HT. In membrane preparations, 8-OH-DPAT dose-response curve was shifted leftwards when the receptor concentration became higher whereas the corresponding shift was smaller for 5-HT and absent for 5-CT. Surprisingly, on membrane preparations, 8-OH-DPAT was a partial agonist relative to 5-HT. The relative efficacy of 8-OH-DPAT was lower in the clone expressing the lowest level of receptor. This partial agonist behavior of 8-OH-DPAT could be modulated by the ionic conditions under which the adenylyl cyclase activity was measured. When physiological intracellular concentrations of Na⁺, Mg²⁺ and K⁺ were used, 8-OH-DPAT became an almost full agonist relative to 5-HT.These data indicate that (1) the classical pharmacological models do not exactly fit with characteristics of the negative coupling between transfected 5-HT_1A receptors and adenylyl cyclase; (2) on membranes, the experimental procedures (ionic conditions) can modify this coupling differently depending on the nature of the agonist.Abbreviations 5-HT 5-hydroxytryptamine (serotonin) - 8-OHDPAT 8-hydroxy-2-(di-n-propylamino)-tetraline - 5-CT 5-carboxamidotryptamine - IBMX isobutyl methyl xanthine - BSA bovine serum albumine - EC₅₀ half maximal efficacy - DXM dexamethasone - PTX Bordetella pertussis toxin - G protein GTP-binding protein Correspondence to A. Varrault at the above address     

Discriminative stimulus effects of the 5HT1A agonist 8-OH-DPAT: attenuation by mu but not by kappa opioids

The ability of mu and kappa opioids to alter the discriminative-stimulus and rate-decreasing effects of the 5-HT_1A receptor agonist 8-OH-DPAT was examined in rats trained to discriminate either a low (0.1 mg/kg) or a high (0.3 mg/kg) dose of 8-OH-DPAT from water using a two-lever food-reinforced drug discrimination procedure. The mu opioids, morphine and fentanyl, and the kappa opioids, U50,488 and bremazocine, failed to substitute for the 8-OH-DPAT stimulus, even when tested up to doses that substantially reduced rates of responding. During antagonism tests, selected doses of the mu opioids, morphine and fentanyl, administered at various pretreatment times, attenuated the stimulus effects of both training doses of 8-OH-DPAT. Moreover, morphine (135-min pretreat) and fentanyl (15-min pretreat) produced rightward shifts in the 8-OH-DPAT dose-effect curve that were partially surmountable and naltrexone-reversible. In contrast to the effects of the mu opioids, the kappa opioids, U50,488 and bremazocine, failed to alter the stimulus effects of the training dose of 8-OH-DPAT, regardless of dose or pretreatment time. The ratedecreasing effects of 8-OH-DPAT were not altered substantially by either the mu or kappa opioids examined. The present study demonstrates that the stimulus effects, but not the rate-decreasing effects, of 5-HT_1A receptor agonists can be modulated by mu opioids, whereas neither of these effects are changed by kappa opioids.     

Potential anxiolytic properties of 8-hydroxy-2-(Di-N-propylamino)tetralin,a selective serotonin1A receptor agonist

The effects of a selective serotonin_1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), were studied in two animal models of anxiety. Peripherally injected 8-OH-DPAT in doses ranging from 0.125 to 2.0 mg/kg did not increase black-white transitions (BWT) and black square entries (BSE) in a two-compartment exploratory test or punished responding in a test of conditioned suppression of drinking. With 2.0 mg/kg 8-OH-DPAT BSE and unpunished responding were reduced. In an investigation of the drinking time of water-deprived rats, naive or habituated to the test environment, 1.0 and 2.0 mg/kg 8-OH-DPAT increased the drinking time of naive rats but 2.0 mg/kg 8-OH-DPAT reduced that of habituated animals. In animals deprived of water for 48 h or subjected to immobilization stress for 2 h, 1.0 mg/kg 8-OH-DPAT increased BWT and BSE values in the two-compartment exploratory test. Infusions of 5 g/0.5 l 8-OH-DPAT in the nucleus raphe medianus increased BWT and BSE values in the exploratory test and punished responding in the test of conditioned suppression of drinking, whereas the same dose of 8-OH-DPAT injected in the nucleus raphe dorsalis had no effect on punished but suppressed unpunished responding. The effects of 8-OH-DPAT are only detectable in the appropriate experimental conditions. When injected systemically, the effects are evident when a state of arousal of the animals contributes to the overall behavioural output. 8-OH-DPAT shows effects comparable to those of established anxiolytics such as benzodiazepines and barbiturates when it is injected in the nucleus raphe medianus, but not in the dorsalis. The data support the hypothesis that brain serotonin is involved in the mechanisms mediating behavioural suppression in the presence of aversive stimuli.     

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.     

Dimerization of 8-OH-DPAT increases activity at serotonin 5-HT1A receptors

[³⁵S]GTPγS binding responses can be used to measure differences between the intrinsic activity of ligands at human 5-hydroxytrypamine-_1A (h 5-HT_1A) receptors expressed in recombinant cell lines. The maximal [³⁵S]GTPγS binding response to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was lower than that to 5-HT in a recombinant C6-glial membrane preparation and dependent on the GDP concentration: it was attenuated by about 60% vs 5-HT by increasing the concentration of GDP from 0.3 to 30 and 300 μM. Whereas dimerization of 8-OH-DPAT almost did not affect its potency at h 5-HT_1A receptors (pEC₅₀: 7.45 and 7.40 for 8-OH-DPAT and its dimer at 30 μM GDP), it increased efficacy at h 5-HT_1A receptors. The maximal response to the 8-OH-DPAT dimer was systematically greater than the response to 8-OH-DPAT and identical to that to 5-HT; moreover in contrast to the 8-OH-DPAT monomer, the maximal response to the dimer was unaffected by increasing the GDP concentration. An enhanced [³⁵S]GTPγS binding response (44 to 63% vs 8-OH-DPAT) was also observed in the hippocampus, lateral septum, dorsal raphe and cingulate cortex of guinea-pig brain sections using autoradiography of 5-HT_1A receptor-activated G-proteins. Hence, the 8-OH-DPAT dimer shows increased efficacy at 5-HT_1A receptors compared to 8-OH-DPAT. The differential regulation of the maximal agonist responses by GDP suggests that the [³⁵S]GTPγS binding responses to these two ligands could be mediated by different G-protein subtypes upon activation of the 5-HT_1A receptor. Received: 23 June 1998 / Accepted: 29 July 1998     

8-OH-DPAT, a 5-HT1A agonist and ritanserin, a 5-HT2A/C antagonist, reverse haloperidol-induced catalepsy in rats independently of striatal dopamine release

In this study, both catalepsy and changes in extracellular levels of striatal dopamine (DA) and dihydroxyphenyl acetic acid (DOPAC) induced by the typical neuroleptic haloperidol (HAL) were simultaneously assessed, using intracerebral microdialysis in freely moving rats, in the presence of either the 5-HT_1A agonist 8-OH-DPAT or the 5-HT_2A/C antagonist ritanserin. HAL (1 mg/kg, SC) elicited a strong cataleptic state, reaching its maximal intensity (about 240 s) 2 h after the drug administration. This effect was paralleled by a long-lasting enhancement of striatal DA and DOPAC extracellular levels, reaching 230 and 350% of basal values, respectively. 8-OH-DPAT (0.1 mg/kg, SC) given 2.5 h after, and ritanserin (0.63 and 1.25 mg/kg, IP), given 15 min prior to HAL, significantly reduced the neuroleptic-induced catalepsy. However, both 5-HT agents failed to modify basal DA and DOPAC striatal outflow as well as the stimulatory effect of HAL on these parameters. It can thus be concluded that the anticataleptic effect of these compounds is not related to an alteration of DA release within the striatum. Received: 29 August 1996/Final version: 25 November 1996     

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.     

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     

Direct effects of indorenate and 8-OH-DPAT on the blood pressure of pithed rats

Indorenate is a 5-HT_1A receptor agonist with antihypertensive properties. This study was aimed to determine if indorenate, like other 5-HT_1A receptor agonists, may also interact with α-adrenoceptors. Therefore, the effects of indorenate and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; which has affinity for 5-HT_1A receptors and, to a lesser extent, for α₁-adrenoceptors) on the blood pressure of pithed rats were compared. Both compounds produced dose-dependent increases in blood pressure; 8-OH-DPAT was the most potent whereas indorenate produced a higher maximum effect. Metitepine (a mixed 5-HT₁/5-HT₂ receptor antagonist), but not pindolol (a β-adrenoceptor and 5-HT₁ receptor blocker), antagonized the pressor responses produced by both agonists; only the pressor effects of 8-OH-DPAT, however, were antagonized by prazosin (an α₁-adrenoceptor antagonist). Interestingly, ketanserin (a 5-HT₂ and α₁-adrenoceptor blocker) strongly antagonized the pressor responses to indorenate whereas only a slight inhibition of 8-OH-DPAT responses was observed. Further, in pithed rats intravenously infused with norepinephrine (NE), 8-OH-DPAT, but not indorenate, produced dose-dependent hypotensive effects and both compounds were inactive in rats infused with quipazine. In conclusion, 8-OH-DPAT behaved as a partial agonist at α₁-adrenoceptors whereas indorenate produced pressor effects probably due to stimulation of 5-HT₂ receptors. Thus, 8-OH-DPAT, but not indorenate, showed activity at α₁-adrenoceptors in the pithed rat. © 1994 Wiley-Liss, Inc.     

Guamanian Suncus murinus responsiveness to emetic stimuli and the antiemetic effects of 8-OH-DPAT

The Japanese Suncus murinus, the house musk shrew, is a small insectivore commonly used in emetic research. The Guamanian S. murinus has not had extensive testing as an emetic model, but it is readily available for use in emetic experiments in the United States, unlike the Japanese Suncus. This study determined that Guamanian S. murinus is an acceptable model for emesis research and its differences from the Japanese strain were examined. Motion and nicotine were used as emetic stimuli and comparable doses of 8-OH-DPAT were used to compare emetic susceptibility to the Japanese strain. The Guamanian strain had decreased susceptibility to motion and increased susceptibility to nicotine as compared to the Japanese, as well as increased sensitivity to 8-OH-DPAT, with lower doses of the recovery drug eliminating retching episodes. The study also determined that Guamanian S. murinus are smaller and more aggressive than the Japanese strain, but just as effective as a model for emetic research.