Effects of N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) on shock elicited fighting in rats.

Rats were tested for shock elicited fighting under various doses of N,N-dimethyltryptamine (0.12, 0.25, 0.50, 1.0, 4.0, 8.0 mg/kg) and 5-methoxy-N,N-dimethyltryptamine (0.06, 0.12, 0.5, 2.0 mg/kg). Both drugs produced an inhibition of fighting at higher doses but no significant effects at lower doses. The effects of these drugs on shock elicited fighting, as well as on other behaviors, thus differ from those of another indole hallucinogen, d-lysergic acid diethylamide, and are discussed in relation to their effects on single unit activity of the raphe-serotonin system and their interaction with other neurotransmitter systems.     

Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5-HT1A and 5-HT1B receptor agonists 8-OH-DPAT and anpirtoline,as evidenced by use of the corresponding new and selective receptor antagonists NAD-299 and NAS-181

1. Ejaculatory problems and anorgasmia are well-known side-effects of the SSRI antidepressants, and a pharmacologically induced increase in serotonergic neurotransmission inhibits ejaculatory behaviour in the rat. In the present study the role of 5-HT_1A and 5-HT_1B receptors in the mediation of male rat ejaculatory behaviour was examined by use of selective agonists and antagonists acting at these 5-HT receptor subtypes.
2. The 5-HT_1A receptor agonist 8-OH-DPAT (0.25–4.00 μmol kg⁻¹ s.c.) produced an expected facilitation of the male rat ejaculatory behaviour, and this effect was fully antagonized by pretreatment with the new selective 5-HT_1A receptor antagonist (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R) tartrate monohydrate (NAD-299) (1.0 μmol kg⁻¹ s.c.). NAD-299 by itself (0.75–3.00 μmol kg⁻¹ s.c.) did not affect the male rat ejaculatory behaviour.
3. The 5-HT_1B receptor agonist anpirtoline (0.25–4.00 μmol kg⁻¹ s.c.) produced a dose-dependent inhibition of the male rat ejaculatory behaviour, and this effect was fully antagonized by pretreatment with the 5-HT_1B receptor antagonist isamoltane (16 μmol kg⁻¹ s.c.) as well as by the new and selective antagonist (R)-(+)-2-(3-morpholinomethyl-2H-chromene-8-yl)oxymethylmorpholino methansulphonate (NAS-181) (16 μmol kg⁻¹ s.c.). Isamoltane (1.0–16.0 μmol kg⁻¹ s.c.) and NAD-181 (1.0–16.0 μmol kg⁻¹ s.c.) had no, or weakly facilitatory effects on the male rat ejaculatory behaviour. The non-selective 5-HT₁ receptor antagonist (−)-pindolol (8 μmol kg⁻¹ s.c.), did not antagonize the inhibition produced by anpirtoline.
4. The present results demonstrate opposite effects, facilitation and inhibition, of male rat ejaculatory behaviour by stimulation of 5-HT_1A and 5-HT_1B receptors, respectively, suggesting that the SSRI-induced inhibition of male ejaculatory dysfunction is due to 5-HT_1B receptor stimulation.

     

Repeated administration of 5-methoxy-N,N-dimethyltryptamine to male rats potentiates stimulation of prolactin secretion by serotonin agonists

Repeated administration of 5-methoxy-N,N-dimethyltryptamine (5MeODMT, 5 mg/kg, a serotonin agonist, every 3 h for a total of 4 injections) potentiated its prolactin (PRL)-releasing effect and that of two other serotonin agonists, quipazine and N,N-dimethyltryptamine. This pretreatment schedule had no effect on PRL response to anti-dopaminergic drugs. The onset of enhanced PRL response to serotonin agonists was gradual and appears to be due to sensitization of the serotonergic mechanism involved in the regulation of PRL secretion. The possible mechanisms underlying this phenomenon are discussed.     

Blockade of the discriminative stimulus effects of ethanol with 5-HT3 receptor antagonists

The ability of selective 5-HT₃ receptor antagonists to block the discriminative stimulus effects of ethanol was investigated in pigeons trained with food reinforcement to discriminate ethanol (1.5 g/kg; IG) from water. The 5-HT₃ receptor antagonists that are substituted tropines, ICS 205-930 (0.1–0.56 mg/kg) and MDL 72222 (3.0–17.0 mg/kg), blocked ethanol-appropriate responding, in a dose-dependent manner, suggesting that some of the discriminative stimulus effects of ethanol are mediated via the 5-HT₃ receptor. The blockade the discriminative stimulus effects of ethanol occurred in the presence of approximately 25–40 mM blood ethanol levels. Furthermore, the ethanol dose-effect function was shifted to the right by increasing doses of MDL 72222, suggesting a surmountable antagonism of the discriminative stimulus effects of ethanol. However, the benzamide zacopride (0.56–1.7 mg/kg), which is also a 5-HT₃ receptor antagonist, did not block the discriminative stimulus effects of ethanol. In addition, the dopaminergic antagonist haloperidol and the 5-HT₂ receptor antagonist ketanserin also failed to block the ethanol discrimination. The results suggest that 5-HT₃ mediated neurotransmission is an important component of ethanol's discriminative stimulus effects, but that the structural characteristics of the selective 5-HT₃ receptor antagonists influence their ability to block this action of ethanol. Furthermore, these findings implicate a significant role of 5-HT₃ activity in the behavioral effects of ethanol that may provide a pharmacological means for therapeutic intervention of alcohol abuse.     

Acute and chronic tryptophan depletion differentially regulate central 5-HT1A and 5-HT2A receptor binding in the rat

Rationale Tryptophan depletion is used to reduce central serotonergic function and to investigate its role in psychiatric illness. Despite widespread clinical use, its effects on serotonin (5-HT) receptors have not been well characterized. Objective The aim of this study was to examine the effect of acute (ATD) and chronic tryptophan depletion (CTD) on free-plasma tryptophan (TRP), central TRP and 5-HT and brain 5-HT_1A and 5-HT_2A receptor binding in the rat. Methods TRP and 5-HT were measured by high-performance liquid chromatography and receptor levels determined by homogenate radioligand binding and in-vitro receptor autoradiography. Results Free-plasma TRP, central TRP and central 5-HT levels were significantly and similarly reduced by ATD and 1- and 3-week CTD compared to controls. ATD significantly reduced 5-HT_1A binding in the dorsal raphe (14%) but did not significantly alter postsynaptic 5-HT_1A binding (frontal cortex, remaining cortex and hippocampus) or 5-HT_2A binding (cortex and striatum). One-week CTD did not significantly alter cortical 5-HT_2A binding or postsynaptic 5-HT_1A binding. Furthermore, 3-week CTD did not significantly alter 5-HT_1A binding but significantly increased cortical 5-HT_2A binding without affecting striatal or hippocampal levels. In the CTD 1 and 3-week groups, rat body weight was significantly decreased as compared to controls. However, weight loss was not a confounding factor for decreased cortical 5-HT_2A-receptor binding. Conclusion ATD-induced reduction in somatodendritic 5-HT_1A autoreceptor binding may represent an intrinsic ‘homeostatic response’ reducing serotonergic feedback in dorsal raphe projection areas. In contrast, the increase in 5-HT_2A receptor after CTD may be a compensatory response to a long-term reduction in 5-HT.     

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

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

5-HT7 receptor deletion enhances REM sleep suppression induced by selective serotonin reuptake inhibitors, but not by direct stimulation of 5-HT1A receptor

5-HT₇ receptors are involved in REM sleep and possibly in mood disorders. REM sleep suppression and antidepressant-like behavior is observed in 5-HT₇^−/− mice and in rats treated with 5-HT₇ receptor antagonists. We recently demonstrated that pharmacological blockade of 5-HT₇ receptors enhances REM sleep suppression and antidepressant-like behavior induced by citalopram in rodents. It has been hypothesized that the effect of citalopram on sleep is essentially mediated by the activation of 5-HT_1A receptors. The present study investigates the impact of 5-HT₇ receptor gene deletion on the effect of various reuptake inhibitors on REM sleep and probes the role of 5-HT_1A receptors in this response. Three SSRIs (citalopram, fluoxetine and paroxetine) but not the tricyclic antidepressant desipramine had a significantly stronger REM sleep suppressive effect in 5-HT₇^−/− mice compared to 5-HT₇^+/+ mice. In contrast, REM sleep was similarly reduced in 5-HT₇^+/+ mice and 5-HT₇^−/− mice after treatment with the 5-HT_1A receptor agonist ipsapirone. Furthermore, both 5-HT₇^+/+ and 5-HT₇^−/− mice displayed the same increase in REM sleep duration produced by the 5-HT_1A receptor antagonist WAY-100635. These findings indicate that 5-HT₇ receptor deletion augments the effect of various SSRIs on REM sleep suppression and that this effect is distinct from those mediated via 5-HT_1A receptors.     

Attenuation of chemically induced defence response by 5-HT1 receptor agonists administered into the periaqueductal gray

The ability of 5-HT₁ receptor agonists to modulate a chemically induced defence response has been studied in Lister hooded rats. Microinjections of the excitatory amino acidd,l-homocysteic acid (DLH) in both rostral and caudal dorsal periaqueductal gray matter (PAG) caused explosive motor behaviour characteristic of defence. This behaviour was quantified in terms of response duration, arena revolutions and number of defensive jumps. Direct administration into the PAG of either 5-carboxamidotryptamine (5-CT) or 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) produced behaviours (decreased exploratory rearing, dose related onset of flat body posture) indicative of 5-HT_1A receptor activation. Pretreatment with either 5-CT or 8-OHDPAT directly in the PAG caused a significant attenuation, and in some cases a complete abolition, of the DLH evoked response. These agonists share high affinity in vitro for the 5-HT_1A receptor. Thus the results suggest that in vivo activation of 5-HT_1A receptors mediates an antiaversive reponse with respect to defensive behaviour elicited by specific chemical stimulation of the dorsal PAG.     

Impulsive action induced by amphetamine, cocaine and MK801 is reduced by 5-HT(2C) receptor stimulation and 5-HT(2A) receptor blockade

Previous work has shown that 5-HT_2C receptor agonists and 5-HT_2A receptor antagonists reduce impulsive action, as well as the locomotor stimulant effect of psychomotor stimulants. Since psychomotor stimulants also increase impulsive action we examined the effects of the 5-HT_2C receptor agonist Ro60-0175, and the 5-HT_2A receptor antagonist M100907 on impulsive action induced by amphetamine, cocaine and the NMDA receptor antagonist MK801 (dizocilpine). Impulsive action was measured in adult male Long-Evans rats as premature responding in the 5-choice serial reaction time (5-CSRT) test. Initially, we determined that amphetamine (0.3 mg/kg), cocaine (15 mg/kg) and MK801 (0.03 mg/kg) induced comparable premature response rates of approximately 50-70 per session, compared to 10-15 responses under baseline conditions. Each drug and its vehicle were then tested in combination with Ro60-0175 (0.1 and 0.6 mg/kg) or its vehicle, or M100907 (0.5 mg/kg) or its vehicle. At 0.1 mg/kg Ro60-0175 did not modify the effects of amphetamine, cocaine or MK801. In contrast, the 0.6 mg/kg dose reduced premature responses induced by amphetamine, cocaine and MK801. M100907 also reduced premature responding induced by all three of these drugs. In general, treatment with Ro60-0175 or M100907 by itself did not consistently alter any of the other aspects of task performance in the 5-CSRT test including number of trials completed, and accuracy of responding. These data show that activation of 5-HT_2C receptors and blockade of 5-HT_2A receptors have seemingly similar functional effects on a measure of impulsive action.     

Complex discriminative stimulus properties of (+)lysergic acid diethylamide (LSD) in C57Bl/6J mice

Rationale The drug discrimination procedure is the most frequently used in vivo model of hallucinogen activity. Historically, most drug discrimination studies have been conducted in the rat. With the development of genetically modified mice, a powerful new tool has become available for investigating the mechanisms of drug-induced behavior. The current paper is part of an ongoing effort to determine the utility of the drug discrimination technique for evaluating hallucinogenic drugs in mice.Objective To establish the training procedures and characterize the stimulus properties of (+)lysergic acid diethylamide (LSD) in mice.Methods Using a two-lever drug discrimination procedure, C57Bl/6J mice were trained to discriminate 0.45 mg/kg LSD vs saline on a VI30 sec schedule of reinforcement, with vanilla-flavored Ensure serving as the reinforcer.Results As in rats, acquisition was orderly, but the training dose was nearly five-fold higher for mice than rats. LSD lever selection was dose-dependent. Time-course studies revealed a rapid loss of the LSD stimulus effects. The 5-HT_2A/2C receptor agonist, 2,5-dimethoxy-4-bromoamphetamine [(–)DOB] (1.0 mg/kg), substituted fully for LSD and the 5-HT_1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) (1.6 mg/kg), substituted partially for LSD. Pretreatment with the 5-HT_2A receptor-selective antagonist, MDL 100907, or the 5-HT_1A-selective antagonist WAY 100635, showed that each antagonist only partially blocked LSD discrimination. Substitution of 1.0 mg/kg (–)DOB for LSD was fully blocked by pretreatment with MDL 100907 but unaltered by WAY 100635 pretreatment.Conclusions These data suggest that in mice the stimulus effects of LSD have both a 5-HT_2A receptor and a 5-HT_1A receptor component.     

Bivalent Ligands for the Serotonin 5-HT3 Receptor

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The interoceptive discriminative stimuli induced by the novel putative anxiolytic TVX Q 7821: behavioral evidence for the specific involvement of serotonin 5-HT1A receptors

Repeated exposure to nicotine increases both the number of central nicotinic receptors and the behavioral stimulant effect of nicotine. In the present experiments, the behavioral response to nicotine was examined in photocell activity cages. Groups of rats were tested using doses from 0.1 to 1.6 mg/kg both before and after all rats were exposed for 5 days to a common dose of 0.2 mg/kg/day. Prior to the 5-day exposure, there was a dose-related stimulant response to nicotine, with a maximum response seen at 0.4 mg/kg. After the 5-day exposure, the dose-effect curve was shifted upward, so that greater stimulation was produced at each test dose of nicotine.Other groups of rats were exposed for 5 days to doses of nicotine ranging from 0.01 to 0.30 mg/kg/day. On the 6th day all rats received a common test dose of 0.2 mg/kg and their response was measured in the activity cages. In animals exposed to 0.01 mg/kg/day, the test day response was not different from saline controls, but the groups exposed to higher doses showed increased stimulation in response to the common test dose. Measurements of nicotinic receptor binding using [³H]-acetylcholine found increased binding in groups receiving 0.03 mg/kg/day or more, but not in the group that received 0.01 mg/kg/day.The correspondence between the doses that increase behavioral stimulant reactions to nicotine and the doses that increase nicotinic binding suggest that increased receptor numbers may be responsible for the increased behavioral stimulation. However, rats given high doses (1.6 mg/kg, twice per day) did not show increased behavioral stimulation to a test dose of 0.2 mg/kg. In those rats, receptor binding was increased even more than in rats exposed to lower chronic doses. Several hypotheses are offered for this apparent discrepancy.     

Circadian variation in behavioural responses to central 5-HT receptor stimulation in the mouse

The intensity of the head-twitch response and the 5-hydroxytryptamine (5-HT) syndrome (tremor, fore-paw treading, head-weaving and hind-limb abduction) was measured in male CFLP mice following IP injection of 5 mg/kg 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). The results of separate experiments carried out at 1.5-h intervals throughout the light-dark cycle showed a clear circadian variation in head-twitch, with highest scores mid-light. No circadian variation in the 5-HT syndrome, or in any individual element of it, was observed. Dose-response curves constructed for 5-MeODMT mid-light and mid-dark over the range 2–64 mg/kg IP confirmed the difference in head-twitch response, showing a parallel shift to the right for mid-dark compared to mid-light up to 32 mg/kg. Again, no difference was seen between the two curves for the 5-HT syndrome. Measurement of the time course of behavioural activity following 5-MeODMT failed to show any differences between mid-light and mid-dark, making it unlikely that pharmacokinetic differences account for the observed circadian variation. It is suggested that the demonstration of a circadian rhythm in the head-twitch response and the failure to show any comparable rhythm in the 5-HT syndrome provides further evidence that these behaviours are mediated by different 5-HT-receptor subtypes.     

Characterization of prejunctional 5-HT1 receptors that mediate the inhibition of pressor effects elicited by sympathetic stimulation in the pithed rat

1. A study was made of the effects of 5-carboxamidotryptamine (5-CT) on pressor responses induced in vivo by electrical stimulation of the sympathetic outflow from the spinal cord of pithed rats. All animals had been pretreated with atropine. Sympathetic stimulation (0.1, 0.5, 1 and 5 Hz) resulted in frequency-dependent increases in blood pressure. Intravenous infusion of 5-CT at doses of 0.01, 0.1 and 1 μg kg⁻¹ min⁻¹ reduced the pressor effects obtained by electrical stimulation. The inhibitory effect of 5-CT was significantly more pronounced at lower frequencies of stimulation. In the present study we characterized the pharmacological profile of the receptors mediating the above inhibitory effect of 5-CT.
2. The inhibition induced by 0.01 μg kg⁻¹ min⁻¹ of 5-CT on sympathetically-induced pressor responses was partially blocked after i.v. treatment with methiothepin (10  μg kg⁻¹), WAY-100,635 (100 μg kg⁻¹) or GR127935T (250 μg kg⁻¹), but was not affected by cyanopindolol (100 μg kg⁻¹).
3. The selective 5-HT_1A receptor agonist 8-OH-DPAT and the selective 5-HT_1B/1D receptor agonists sumatriptan and L-694,247 inhibited the pressor response, whereas the 5-HT_1B receptor agonists CGS-12066B and CP-93,129 and the 5-HT_2C receptor agonist m-CPP did not modify the pressor symapthetic responses.
4. The selective 5-HT_1A receptor antagonist WAY-100,635 (100 μg kg⁻¹) blocked the inhibition induced by 8-OH-DPAT and the selective 5-HT_1B/1D receptor antagonist GR127935T (250 μg kg⁻¹) abolished the inhibition induced either by L-694,247 or sumatriptan.
5. None of the 5-HT receptor agonists used in our experiments modified the pressor responses induced by exogenous noradrenaline (NA).
6. These results suggest that the presynaptic inhibitory action of 5-CT on the electrically-induced pressor response is mediated by both r-5-HT_1D and 5-HT_1A receptors.

     

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

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

Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2C receptor

Interactions of the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine and its main metabolite norfluoxetine, and the tricyclic anti-depressant (TCA) imipramine with the rat serotonin 5-HT_2C receptor in a clonal cell line and in the rat choroid plexus were investigated by radioligand binding and phosphoinositide (PI) hydrolysis assays. For comparison, the affinities of a variety of other antidepressants of different chemical classes for the cloned rat 5-HT_2C and 5-HT_2A receptors were also determined by radioligand binding assays. Fluoxetine displayed relatively high affinity for the 5-HT_2C receptor in the choroid plexus, with a K_i value for inhibition of [³H]mesulergine binding of 55.4 nM. The K_i values for imipramine, norfluoxetine and citalopram were 136 nM, 203 nM, and 298 nM, respectively. Similar rank order of potency was detected in PI hydrolysis assays, which showed that these drugs are antagonists at the 5-HT_2C receptor without exhibiting inverse agonist activity. [³H]Ketanserin (5-HT_2A) binding assays revealed that the SSRIs fluoxetine, norfluoxetine and citalopram show 10- to 23-fold selectivity for the 5-HT_2C receptor in vitro, whereas the TCA imipramine does not. Many other TCAs also had high to intermediate affinity for both 5-HT_2A and 5-HT_2C receptors. The present data provide evidence that fluoxetine, norfluoxetine and citalopram, along with many other antidepressant compounds, interact directly with the 5-HT_2C receptor.     

Stimulus control by 5-methoxy-N,N-dimethyltryptamine in wild-type and CYP2D6-humanized mice

In previous studies we have observed that, in comparison with wild type mice, Tg-CYP2D6 mice have increased serum levels of bufotenine [5-hydroxy-N,N-dimethyltryptamine] following the administration of 5-MeO-DMT. Furthermore, following the injection of 5-MeO-DMT, harmaline was observed to increase serum levels of bufotenine and 5-MeO-DMT in both wild-type and Tg-CYP2D6 mice. In the present investigation, 5-MeO-DMT-induced stimulus control was established in wild-type and Tg-CYP2D6 mice. The two groups did not differ in their rate of acquisition of stimulus control. When tested with bufotenine, no 5-MeO-DMT-appropriate responding was observed. In contrast, the more lipid soluble analog of bufotenine, acetylbufotenine, was followed by an intermediate level of responding. The combination of harmaline with 5-MeO-DMT yielded a statistically significant increase in 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice; a comparable increase occurred in wild-type mice. In addition, it was noted that harmaline alone was followed by a significant degree of 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice. It is concluded that wild-type and Tg-CYPD2D6 mice do not differ in terms of acquisition of stimulus control by 5-MeO-DMT or in their response to bufotenine and acetylbufotenine. In both groups of mice, harmaline was found to enhance the stimulus effects of 5-MeO-DMT.     

Repeated administration of the 5-HT<Subscript>1B</Subscript> receptor antagonist SB-224289 blocks the desensitisation of 5-HT<Subscript>1B</Subscript> autoreceptors induced by fluoxetine in rat frontal cortex

Desensitisation of 5-HT_1A and 5-HT_1B autoreceptors is thought to be the mechanism underlying the therapeutic effects of fluoxetine and other selective serotonin re-uptake inhibitors (SSRIs) when these are administered chronically, while blockade of these autoreceptors occurring on administration of an SSRI together with an autoreceptor antagonist is responsible for the acute increase in 5-HT levels in vivo observed under these circumstances. The effects of repeated administration of SSRIs together with 5-HT_1B receptor antagonists on 5-HT levels and autoreceptor activity have not been studied previously with an in vivo method. In this work we found, using in vivo microdialysis that the effect of fluoxetine (5 mg/kg i.p. daily for 7 days) to desensitise 5-HT_1B autoreceptors in frontal cortex, as measured by the action of CP 93129 (10 M) to reduce 5-HT levels, was prevented by concomitant administration of the 5-HT_1B receptor antagonist SB 224289 (2.5 mg/kg s.c.). 5-HT_1B receptor activity in hypothalamus and 5-HT_1A autoreceptor activity, as determined by the effects of s.c. 8-OH-DPAT to reduce 5-HT levels, were not altered either by fluoxetine alone at this dose or by fluoxetine in the presence of SB 224289. We conclude that the effects obtained when 5-HT_1B autoreceptor antagonists are administered acutely together with SSRIs may not be maintained after repeated administration.     

Inhibition of noradrenaline release from the sympathetic nerves of the human saphenous vein via presynaptic 5-HT receptors similar to the 5-HT1D subtype

Summary The human saphenous vein preincubated with [³H]noradrenaline was used to determine the pharmacological properties of the release-inhibiting presynaptic serotonin (5-HT) receptor on the sympathetic nerves. The overflow of tritium evoked by transmural electrical stimulation (2 Hz) was concentration-dependently inhibited by drugs known to stimulate 5-HT receptors in the following rank order: oxymetazoline 5-HT 5-carboxamidotryptamine = 5-methoxytryptamine = sumatriptan > tryptamine > N,N(CH₃)₂-5-HT = yohimbine = 8-hydroxy-2-(di-n-propylamino)-tetraline. The potencies of these agonists in inhibiting overflow were significantly correlated with their affinities for 5-HT_1B and 5-HT_1D binding sites, but not with those for 5-HT_1A or 5-HT_1C binding sites. 5-Aminotryptamine, methysergide, ipsapirone, cyanopindolol, SDZ 21009 and metergoline dit not produce a significant inhibition. Metitepine and methysergide antagonized the inhibitory effect of 5-HT, whereas spiroxatrine, propranolol, ketanserin and ICS 205-930 did not.These data exclude the idea that the inhibitory presynaptic 5-HT receptor on the sympathetic nerves belongs to the 5-HT₂ and 5-HT₃ receptor class; the pattern of agonist potencies suggests that the receptor is very similar to the 5-HT_1D receptor subtype. Send offprint requests to M. Gothert at the above address     

Effect of the selective 5-HT3 receptor antagonists ICS 205-930 and MDL 72222 on 5-HTP-induced head shaking and behavioral symptoms induced by 5-methoxy-N,N,dimethyltryptamine in rats: comparison with some other 5-HT receptor antagonists

The effect of the selective 5-HT₃ receptor antagonists ICS 205-930 and MDL 72222 on head shaking behavior induced by l-5-HTP and behavioral symptoms induced with 5-methoxy-N,N,-dimethyltryptamine (5-MeODMT) in rats was evaluated. Both drugs dose-dependently reduced l-5-HTP-induced head shaking but were at least 600 times less potent than pirenperone and ketanserin and at least 50 times less potent than methysergide. ICS 205-930 and MDL 72222 were more than 1000 times less potent than pirenperone or methysergide and 100 times less potent than ketanserin in blocking 5-MeODMT-induced forepaw treading and tremor. Since it appears that head shakes induced by l-5-HTP are mediated by 5-HT₂ receptors, these data suggest that ICS 205-930 and MDL 72222 do not significantly interact with 5-HT₂ receptors in the brain. Furthermore, the data suggest that ICS 205-930 and MDL 72222 lack appreciable antagonistic activity at the 5-HT receptor(s) mediating those behavioral effects induced by 5-MeODMT.