Infusion of the 5-hydroxytryptamine agonists RU24969 and TFMPP into the paraventricular nucleus of the hypothalamus causes hypophagia

The 5-HT_1B agonist RU24969 when given either systemically (1 mg/kg SC) or by infusion (0.5, 1.0, 2.0 g) into the region of the paraventricular nucleus of the hypothalamus caused dose-dependent hypophagia in rats previously deprived of food for 18 h. Similar results were obtained at the above dosages of 1-[3-(trifluoromethyl) phenyl] piperazine (TFMPP), which acts on 5-HT_1B and possibly also on 5-HT_1C receptors. Neither drug significantly affected locomotion following central administration. Food intake was significantly decreased when the 5-HT_1A agonist 8-OH-DPAT was given systemically (1 mg/kg SC) to rats previously deprived of food but was unaffected when 8-OH-DPAT (1 g) was infused into the paraventricular nucleus of both food-deprived and free feeding rats. Therefore, hypophagia occurs when hypothalamic 5-HT_1B (and possibly 5-HT_1C) but not 5-HT_1A receptors are activated.     

5-HT4 receptor mediated stimulation of gastric emptying in rats

It is well documented that certain substituted benzamides, such as cisapride, and benzimidazolones, such as BIMU 8, enhance gastric emptying in rats. As these compounds possess 5-HT₃ antagonistic and 5-HT₄ agonistic properties, the precise mechanisms (5-HT₃ or 5-HT₄) underlying their gastroprokinesic effects is still unclear. In the present study, we used SC 49518 (a benzamide and selective 5-HT₄ receptor agonist) and two selective 5-HT₄ receptor antagonists (RS 23597-190 and SB 204070) to elucidate the role of 5-HT₄ receptors in gastroprokinesis. SC 49518 (1–316 g/kg; ip) produced significant and dose-dependent stimulation of gastric emptying in rats (ED₅₀ = 2.3 g/kg; ip). SC 49518 also produced dose-dependent inhibition of bradycardia induced by 2-methyl 5-HT (von Bezold-Jarisch reflex) but with a 156 fold lower potency (ID₅₀ = 0.36 mg/kg; ip). The gastroprokinetic effects of SC 49518 (3–316 g/kg; ip) were significantly antagonized by the selective 5-HT₄ receptor antagonist RS 23597-190 (0.1 mg/kg/min; iv). SB 204070 (0.003-1 mg/kg; ip), another selective 5-HT₄ receptor antagonist, produced dose-dependent inhibition of the gastroprokinesic effects of SC 49518 (10 g/kg; ip), the inhibition attaining statistical significance at the dose of 0.1 mg/kg; ip. RS 23597-190 had no effects on gastric emptying per se whereas SB 204070 significantly increased gastric emptying by itself at 1 mg/kg; ip but not at 0.1 mg/kg; ip. These findings show, for the first time, that SC 49518, a selective 5-HT₄ receptor agonist, produces potent stimulation of gastric emptying in rats via a mechanism involving activation of 5-HT₄ receptors. It is suggested that a similar mechanism may account for the gastroprokinetic effects of other non-selective benzamides and benzimidazolones.     

Effects of fenfluramine on free-operant timing behaviour: evidence for involvement of 5-HT<Subscript>2A</Subscript> receptors

Rationale Temporal differentiation in the free-operant psychophysical procedure is sensitive to the 5-hydroxytryptamine (5-HT)_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the 5-HT₂ receptor agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI); both drugs shift the psychophysical curve leftwards, reducing the indifference point, T ₅₀. We have examined the effect of the 5-HT releasing agent fenfluramine on temporal differentiation.Objective We examined whether fenfluramines effect on temporal differentiation can be antagonised by the 5-HT_1A receptor antagonist N-[2-(4-[2-methoxy-phenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexane-carboxamide (WAY-100635) and the 5-HT_2A receptor antagonist ketanserin, and compared the effects of fenfluramine, DOI and 8-OH-DPAT in intact rats and rats whose 5-HTergic pathways had been destroyed by 5,7-dihydroxytryptamine.Methods Rats were trained under the free-operant psychophysical procedure to press levers A and B in 50-s trials in which reinforcers were provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic psychophysical curves were fitted to the data for derivation of timing indices (T ₅₀, time corresponding to %B=50%, and Weber fraction). Experiment 1 examined the effects of acute treatment with fenfluramine, and the interaction between fenfluramine and the 5-HT_1A and 5-HT_2A receptor antagonists WAY-100635 and ketanserin; experiment 2 compared the effects of fenfluramine, 8-OH-DPAT and DOI in intact rats and rats whose 5-HTergic pathways had been destroyed by intra-raphe injection of 5,7-dihydroxytryptamine. Concentrations of 5-HT and catecholamines in the brain were measured by high-performance liquid chromatography.Results Experiment 1: fenfluramine (2 mg/kg) reduced T ₅₀; this effect was attenuated by ketanserin (1.0 mg/kg) but not by WAY-100635 (100 g/kg). Experiment 2: 8-OH-DPAT (100 g/kg) and DOI (250 g/kg) reduced T ₅₀ in both groups; fenfluramine reduced T ₅₀ only in the sham-lesioned group. Levels of 5-HT were reduced by 80% in the lesioned group; catecholamine levels were not affected.Conclusions The results suggest that fenfluramine affects temporal differentiation via the release of endogenous 5-HT which acts mainly on postsynaptic 5-HT_2A receptors.     

Behavioural evidence thatd-fenfluramine-induced anorexia in the rat is not mediated by the 5-HT1A receptor subtype

These studies investigated the involvement of the 5-HT_1A receptor in mediatingd-fenfluramine-induced anorexia in the rat. Non-deprived,d-fenfluramine-treated (3.0 mg/kg) rats consumed a reduced amount of a palatable wet mash and showed a temporal advance in the behavioural sequence consistent with satiety. Thus, rats treated withd-fenfluramine ceased feeding and began resting before corresponding controls. Pretreatment with the selective 5-HT_1A receptor antagonist WAY-100635 (1.0 mg/kg) had no effect on either the reduced mash consumption or behavioural satiety sequence ofd-fenfluramine-treated animals at a dose which was found to attenuate the anorexia induced by the 5-HT_1A receptor agonist 8-OH-DPAT (0.5 mg/kg). Pretreatment with the nonselective 5-HT antagonist metergoline (1.0 mg/kg) attenuated thed-fenfluramine-induced reduction of mash consumption and the advanced offset of feeding. Metergoline pretreatment had no effect on the advanced onset of resting observed ind-fenfluramine-treated animals. These data suggest thatd-fenfluramine reduces food intake, perhaps by enhancing satiety, via a mechanism which does not involve the 5-HT_1A receptor subtype. The implications of these results to the utility of the behavioural satiety sequence as a measure of postprandial satiety are discussed.     

Pharmacological profile of 5-hydroxytryptamine-induced inhibition on the pressor effect elicited by sympathetic stimulation in long-term diabetic pithed rats

We analysed the type and/or subtype of 5-hydroxytryptamine (5-HT) receptors involved in the inhibitory mechanisms of 5-HT on the pressor responses induced by stimulation of sympathetic vasopressor outflow in long-term diabetic pithed rats. Diabetes was induced in male Wistar rats by a single subcutaneous injection of alloxan. Eight weeks later, rats were anaesthetized, pre-treated with atropine, and pithed. The effect of 5-HT on the pressor responses elicited by stimulation of the sympathetic outflow was analysed in eight-week alloxan-induced diabetic pithed rats. 5-HT (20 μg/kg/min) reduced the pressor action obtained by electrical stimulation of the sympathetic outflow. However, there was no effect on exogenous noradrenaline-induced pressor responses. 5-CT (5 μg/kg/min), 8-OH-DPAT (5 μg/kg/min), and α-methyl-5-HT (5 μg/kg/min), selective 5-HT₁, 5-HT_1A and 5-HT₂ receptor agonists, respectively, reproduced the 5-HT inhibitory action. Nevertheless, infusion of 5 μg/kg/min of 1-phenylbiguanide, CGS-12066B, L-694,247, BW273C86 or MK212 (5-HT₃, 5-HT_1B, 5-HT_1D, 5-HT_2B and 5-HT_2C receptor agonists, respectively) had no effect on the pressor responses elicited by stimulation of the sympathetic outflow. Methiothepin (100 μg/kg) and a cocktail of WAY-100,635 (100 μg/kg) and spiperone (125 μg/kg) blocked the 5-HT inhibitory effect on the pressor action obtained by sympathetic stimulation. Moreover, WAY-100, 635 abolished the 8-OH-DPAT inhibitory effect and spiperone blocked α-methyl-5-HT action. In conclusion, this study revealed that long-term experimental diabetes induces changes in the receptor type/subtype involved in the 5-HT inhibitory action on the sympathetic pressor responses produced by electrical stimulation. This is mainly mediated by pre-junctional 5-HT_1A and 5-HT_2A receptors.     

Aripiprazole (OPC-14597) fully substitutes for the 5-HT<Subscript>1A</Subscript> receptor agonist LY293284 in the drug discrimination assay in rats

Rationale Aripiprazole (OPC-14597) is a novel atypical antipsychotic drug with a low incidence of side effects. The therapeutic action of aripiprazole has been attributed to its unique agonist/antagonist effects at D₂ dopamine receptors; however, aripiprazole also has significant in vitro affinity at 5-HT_1A receptors.Objectives The 5-HT_1A agonist property of aripiprazole has so far not been evaluated in any in vivo assay.Methods Thirteen male Sprague Dawley rats trained to discriminate the 5-HT_1A agonist LY 293284 (75 nmol/kg) from saline, using a fixed ratio (FR) 50 schedule of food-reinforcement in a two-lever operant-conditioning task, were used to evaluate the behavioral effect of aripiprazole at 5-HT_1A receptors.Results Aripiprazole fully mimicked LY 293284 in a drug-discrimination assay with an ED₅₀ of 1.39 mol/kg (0.62 mg/kg). In combination tests, aripiprazole did not block the LY 293284 cue but at 8.92 mol/kg (4 mg/kg) significantly reduced the response rate by lowering the threshold for induction of the 5-HT syndrome produced by the training dose of LY 293284. Moreover, the selective 5HT_1A receptor antagonist WAY 100635 was able to block the substitution of aripiprazole in LY-293284 trained rats.Conclusion Although the efficacy of aripiprazole against the positive symptoms of schizophrenia may be related to its dopamine receptor interactions, it seems possible that its atypical profile may derive, at least in part, from its 5-HT_1A agonist effect, rather than from unusual D₂ receptor properties.     

Evidence that 5-HT2C receptor antagonists are anxiolytic in the rat Geller-Seifter model of anxiety

Four non-selective 5-HT_2C/5-HT_2A receptor antagonists, mianserin (2–8 mg/kg), 1-naphthyl piperazine (1-NP) (0.5–1 mg/kg), ICI 169,369 (20 mg/kg) and LY 53857 (5 mg/kg), increased punished responding for a food reward in the rat Geller-Seifter test 30 min after subcutaneous (SC) administration. This property was shared by the benzodiazepine anxiolytic chlordiazepoxide (5 mg/kg SC). However, the selective 5-HT_2A receptor antagonists ketanserin (0.2–1 mg/kg SC) and altanserin (0.5, 1 mg/kg SC) had little effect. The 5-HT_1A, 5-HT_1B and-adrenergic receptor antagonists pindolol and cyanopindolol (6 mg/kg SC) did not affect punished responding either, nor did the 5-HT_1D receptor partial agonist and ₂ adrenergic receptor antagonist yohimbine (2.5 mg/kg SC) or the histamine H₁ receptor antagonist mepyramine (1 mg/kg SC). Unpunished responding was also modestly increased after some doses of the 5-HT_2C/5-HT_2A receptor antagonists. However, this effect was inconsistent and was also seen after chlordiazepoxide. Furthermore, it was not associated with the increase in punished responding observed in rats orally treated with mianserin (10, 20 mg/kg), 1-NP (10, 20 mg/kg) or ICI 169,369 (50 mg/kg). The action of the 5-HT_2C/5-HT_2A receptor antagonists tested is therefore consistent with anxiolysis. The results also strongly suggest that this effect is mediated by blockade of the 5-HT_2C receptor, although the possibility of 5-HT_2B receptor mediation is discussed.     

Reduction of feeding behavior by the serotonin uptake inhibitor sertraline

Administration of the selective serotonin (5-HT) uptake inhibitor sertraline produced a dose-dependent reduction of food intake in rats. Doses of sertraline of 10 mg/kg or greater reduced the intake of solid pellets significantly (P<0.01) during the 1st hour of a 4-h feeding test in rats deprived of food and water for 24 h. Food intake during the remaining 3 h and water intake during the feeding test was unaffected by sertraline. Sertraline (2–18 mg/kg IP) also reduced milk consumption in food-deprived rats. Pretreatment with the nonselective 5-HT antagonists metergoline (2 mg/kg IP) or methysergide (3.3 mg/kg IP) blocked sertraline's inhibition of dry food intake, whereas pretreatment with the selective 5-HT₂ receptor antagonist ketanserin (3.3 mg/kg IP) or the peripheral 5-HT₂ antagonist xylamidine (2.5 mg/kg IP) failed to block sertraline's anorexic effect. The feeding-suppressant effect of 10 mg/kg sertraline was prevented following the destruction of central 5-HT neurons by the 5-HT neurotoxic agent, 5,7-dihydroxytryptamine (200 g ICV). This result is consistent with sertraline's anorexic effect depending on intact 5-HT neurotransmission. Therefore, sertraline appears to reduce feeding by enhancing the action of endogenous serotonin at central synapses mediated by 5-HT₁ rather than 5-HT₂ receptors.     

Inhibition of median and dorsal raphe neurones following administration of the selective serotonin reuptake inhibitor paroxetine

Acute systemic injection of selective serotonin reuptake inhibitors (SSRIs) decreases 5-HT neuronal firing in the dorsal raphe nucleus (DRN). Recent data, however, question whether these drugs also inhibit the firing of 5-HT neurones in the median raphe nucleus (MRN). Using in vivo extracellular electrophysiological recording techniques in the chloral hydrate anaesthetised rat, we have tested the effect of acute administration of the SSRI, paroxetine, on 5-HT neuronal activity in the MRN and DRN. Presumed 5-HT neurones in the MRN displayed the same electrophysiological characteristics as those in the DRN, the only detectable difference being that MRN neurones showed a significantly (p < 0.001) slower mean ( ± SEM(n)) spontaneous firing rate (MRN, 5.6 ± 0.9 (14) spikes/10 s; DRN, 13.5 ± 1.6 (24) spikes/10 s). Paroxetine caused a dose-related (0.1–0.8 mg/kg i.v.) inhibition of all MRN neurones tested (n = 8), producing a complete cessation of cell-firing at the highest doses. DRN neurones (n = 9) responded in a similar fashion. Furthermore, paroxetine inhibited MRN and DRN neurones with almost identical potency (MRN ED₅₀ 259 ± 57 g/kg i.v.: DRN ED₅₀ 243 ± 49 g/kg i.v.). In the majority of cells tested, the effect of paroxetine was reversed by the 5-HT_1A receptor antagonists spiperone or (+)WAY100135, implicating the involvement of the 5-HT_1A autoreceptor. The selective 5-HT_1A receptor agonist 8-OH-DPAT also inhibited the firing of MRN (n = 5) and DRN (n = 12) neurones and with equal potency (MRN ED₅₀, 1.32 ± 0.40 g/kg i.v.: DRN ED₅₀, 1.19 ± 0.23 g/kg i.v.). Our data indicate that paroxetine not only inhibits the firing of 5-HT neurones in the MRN but does so with equal potency to those in the DRN.     

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.     

The effects of ageing on prejunctional 5-hydroxytryptamine receptors in the rat vas deferens

Summary The prejunctional inhibitory effects of a series of 5-HT₁ receptor agonists were examined against the isometric contraction of epididymal portions of rat vas deferens evoked by single stimulus pulses in the presence of nifedipine (10 mol/l). The 5-HT_1A ligand flesinoxan produced inhibition of contractions which was not inhibited by cyanopindolol or yohimbine. However, the prejunctional inhibitory concentration response curve for the 5-HT₁ agonist 5-carboxamidotryptamine (5-CT) was biphasic in tissues from 1.5 month old animals but monophasic in tissues from 24 months animals. Cyanopindolol (1 mol/l) antagonised the inhibitory effects of 5-CT in tissues from 1.5 and 3 month animals but not in tissues from 8 or 24 months animals. Inhibitory actions of 5-CT were not prevented by pretreating animals with pertussis toxin (6 g/kg i. v.), a dose which abolished the negative inotropic response to acetylcholine in rat left atria. It is concluded that the nerve terminals of vas deferens from 1.5 month old animals contain both 5-HT_1B and other as yet unclassified 5-HT₁ receptors, but that this 5-HT_1B-mediated response is lost in maturation and ageing.Send offprint requests to J. R. Docherty at the above address     

Operational characteristics of the 5-HT1-like receptors mediating external carotid vasoconstriction in vagosympathectomized dogs

It has recently been shown that the external carotid vasoconstrictor response to 5-HT in the dog is primarily mediated by sumatriptan-sensitive 5-HT₁-like receptors; however, the fact that these receptors are not blocked by metergoline, a 5-HT_1D ligand, raises questions about their possible correlation with the 5-HT_1D receptor subtype. Since a number of drugs display high affinity for the 5-HT_1D (GR127935) and 5-HT_1F (e.g. methysergide and oxymetazoline) receptor subtypes, in this study we have used these drugs to determine whether the above vasoconstrictor 5-HT₁-like receptors correlate with the 5-HT_1D and/or 5-HT_1F receptor subtypes.One-minute intracarotid infusions of 5-HT (0.3–30 g/min), sumatriptan (1–30 g/min), oxymetazoline (0.03–3 g/min) and noradrenaline (0.3–3 g/min) resulted in dose-dependent decreases in external carotid blood flow without changes in arterial blood pressure or heart rate. These vasoconstrictor responses remained unaltered after i.v. administration of physiological saline (0.015, 0.05 and 0.15 ml/kg; n = 4) or ritanserin (1 mg/kg; n = 5). In contrast, GR127935 (1, 3 and 10 g/kg, n = 6) potently blocked the responses to 5-HT (unmasking a dose-dependent vasodilator component) and sumatriptan without affecting those to oxymetazoline or noradrenaline. Interestingly, methysergide (10, 30 and 100 g/kg, n = 5) also blocked the vasoconstrictor responses to 5-HT and sumatriptan, but unlike GR127935, did not revert the vasoconstrictor response to 5-HT; the responses to oxymetazoline remained unaffected, but those to noradrenaline were apparently attenuated by the highest dose.Taken together, the above findings suggest that the sumatriptan-sensitive 5-HT₁-like receptors mediating canine external carotid vasoconstriction resemble 5-HT_1D receptors, probably of the 5-HT_1D subtype on the basis of the resistance to blockade by ritanserin. The pharmacological profile of these receptors could be similar (bovine and human cerebral arteries, porcine carotid arteriovenous anastomoses and human coronary arteries) to other putative 5-HT_1D receptors mediating vascular responses.     

Effects of 5-HT1A receptor agonists,partial agonists and a silent antagonist on the performance of the conditioned emotional response test in the rat

In the present study, the effects of 5-HT_1A receptor ligands with varying degrees of intrinsic activity at the 5-HT_1A receptor were examined in the conditioned emotional response (CER) test and their effects compared to those of the benzodiazepine receptor agonists, diazepam and chlordiazepoxide. Diazepam (3.0 mg/kg) and chlordiazepoxide (3.0 mg/kg), and the 5-HT_1A receptor partial agonists, ipsapirone (10.0 mg/kg) and gepirone (3.0 mg/kg), alleviated conditioned suppression of lever pressing. The 5-HT_1A receptor partial agonist, buspirone (0.1–1.0 mg/kg), the 5-HT_1A receptor agonist, 8-OH-DPAT (0.01– 0.10 mg/kg), and the 5-HT_1A receptor antagonist, WAY-100635 (0.03–3.0 mg/kg), had no effects on conditioned fear. Neither enhancing the level of food deprivation nor pretreatment with the amnesic agent scopolamine induced anxiolytic-like effects in the present CER test. The anxiolytic-like effects of ipsapirone in this test were completely reversed by WAY-100635. These results indicate that 5-HT_1A agonist, but not antagonist actions, induce an anxiolytic effect in the CER test in rats. Received: 13 March 1996/Final version: 8 July 1996     

5-HT1A receptor antagonists increase the activity of serotonergic cells in the dorsal raphe nucleus in rats treated acutely or chronically with citalopram

In this study we have examined the acute effects of systemic administration of the selective serotonin reuptake inhibitor (SSRI), citalopram, in combination with either of the two selective 5-HT_1A receptor antagonists, (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301] or (+)-N-tertbutyl 3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropionamide dihydrochloride [(+)-WAY100135], on the activity of single 5-HT neurons in the dorsal raphe nucleus (DRN) of anesthetized rats using extracellular recording techniques. Acute administration of citalopram (0.3 mg/kg i.v.) significantly decreased the firing rate of DRN-5-HT cells most likely as a result of indirect stimulation of inhibitory somatodendritic 5-HT_1A autoreceptors located on 5-HT cells in the DRN. This effect of citalopram was completely reversed by (S)-UH-301 (0.5 mg/kg i.v.) and partly by (+)WAY100135 (0.5 mg/kg i.v.). Furthermore, the inhibitory effect of citalopram on the activity of 5-HT neurons was significantly attenuated by pretreatment with (S)-UH-301 (0.25 mg/kg i.v.) or (+)-WAY100135 (0.25 mg/kg i.v.).We have also studied the effects of (S)-UH-301 (0.03–0.50 mg/kg i.v.) on the firing rate of single DRN5-HT cells in rats chronically treated with citalopram (20 mg/kg/day i.p. × 14 days). Administration of (S)UH-301 significantly and dose-dependently increased the activity of 5-HT cells in citalopram-treated rats, but did not affect these neurons in saline-treated (1 m1/kg/day i.p. × 14 days), control rats. Our results thus suggest that 5-HT_1A receptor antagonists can augment both the acute and chronic effects of citalopram on central serotonergic neurotransmission. Since the antidepressant effect of SSRIs is critically linked to the availability of 5-HT, these findings support the notion that 5-HT_1A receptor antagonists may not only shorten the latency of onset of SSRIs in the treatment of depression, but also increase their efficacy.     

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI) exerts an anorexic action that is blocked by 5-HT2 antagonists in rats

Previous literature suggests that the anorexic action of peripherally administered serotonin (5-HT) is mediated by 5-HT₂ receptors. This study, therefore, examined the effect of DOI, a non-indole 5-HT₂ agonist, on deprivation-induced feeding. Rats were first adapted to a schedule in which a milk diet was presented for 6 h daily. Intraperitoneal (IP) administration of DOI (1.0–11.2 mol/kg) inhibited feeding in a dose-related fashion (ID₅₀=2.6 mol/kg). One hour pretreatment with 6.0 mol/kg of the 5-HT₂ antagonists ketanserin and LY53857 completely reversed the anorexic action of an equimolar dose of DOI. Neither ketanserin nor LY53857, alone, altered baseline feeding. Further testing demonstrated the antagonistic effect of LY53857 (0.047–6.0 mol/kg, IP) to be dose related, with an ID₅₀ of 0.14 mol/kg. Ten minute pretreatment with 1-(1-naphthyl)-piperazine (1-NP; 2.0 or 4.0 mol/kg), a mixed-acting agent with 5HT₂ blocking actions, also attenuated the anorexic effect of 6.0 mol/kg DOI. Unlike ketanserin and LY53857, however, 1-NP did reduce food intake by itself. By contrast with ketanserin, LY53857 and 1-NP, the peripherally-acting 5-HT₂ antagonist xylamidine failed to alter the anorexic effect of DOI. Taken together, these results suggest that central 5-HT₂ receptors are important in the control of ingestive behavior.A portion of these results were presented in a preliminary report at the Annual Meeting of the Society for Neuroscience in November 1987.     

Modulation by 5-HT3 and 5-HT4 receptors of the release of 5-hydroxytryptamine from the guinea-pig small intestine

Summary The effects of agonists and antagonists of 5-hydroxytryptamine (5-HT) receptors on the release of endogenous 5-HT from enterochromaffin cells were studied in the vascularly perfused isolated guinea-pig small intestine. The experiments were done in the presence of tetrodotoxin in order to exclude a neuronally mediated influence on 5-HT release.The 5-HT₃ receptor agonist 2-methyl-5-HT increased 5-HT release, and this effect was antagonized by 1 nmol/l tropisetron. Nanomolar concentrations of tropisetron, MDL 72 222 and granisetron decreased 5-HT release. Ondansetron (0.1 and 1 mol/1) did not modify 5-HT release.5-Methoxytryptamine, BIMU8 and cisapride concentration-dependently inhibited 5-HT release. BIMU8 was more potent than 5-methoxytryptamine. Micromolar concentrations of tropisetron (1 and 10 mol/1) enhanced the release, whilst methiothepine (0.1 mol/l) did not affect the release of 5-HT.The results suggest that enterochromaffin cells of the guinea-pig ileum do not contain 5-HT₁ and 5-HT₂ receptors, but are endowed with 5-HT₃ and 5-HT₄ autoreceptors. Activation of the 5-HT₃ receptors triggers a positive feedback mechanism leading to an increase of 5-HT release. The 5-HT₃ receptors on the enterochromaffin cell differ from neuronal 5-HT3 receptors on guinea-pig myenteric plexus by their high affinity for tropisetron and MDL 72 222, and their very low affinity for ondansetron. Stimulation of 5-HT₄ receptors causes inhibition of release; the inhibitory 5-HT₄ receptor mechanism appears to predominate.Correspondence to H. Kilbinger at the above address     

5-HT(1A) receptor activation improves anti-cataleptic effects of levodopa in 6-hydroxydopamine-lesioned rats

Background and the purpose of the study

In Parkinson›s disease (PD) prolong use of L-DOPA causes some motor disorders such as wearing-off and L-DOPA induced dyskinesia (LID). In this investigation the effect of 8-OHDAPT, as a 5-HT_1A agonist on anti-cataleptic effect of L-DOPA in 6-hydroxydopamine (6-OHDA) lesioned male Wistar rats was investigated.

Methods

Catalepsy was induced by unilateral injection of 6-OHDA (8 µg/2µl/rat) into the central region of the SNc. After 3 weeks as a recovery period, animals received intraperitoneally (i.p.) L-DOPA (15 mg/kg) twice daily for 20 days, and anti-cataleptic effect of L-DOPA was assessed by bar-test at days of 5, 10, 15 and 20.

Results and major conclusion

The results showed that L-DOPA had anti-cataleptic effect only until the day of 15, and its effect was decreased on the day of 20. On the day of 21, rats were co-injected with three different doses of 8-OHDAPT (0.1, 0.5 and 2.5 mg/kg, i.p.) and L-DOPA (15 mg/kg, ip). 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OHDAPT) improved anti-cataleptic effect of L-DOPA at the dose of 0.5 mg/kg. Moreover the effect of 8-OHDAPT on anti-cataleptic effect of L-DOPA (15 mg/kg, ip) was abolished by 1-(2-methyoxyphenyl)-4-[4-(2-phthalamido) butyl] piperazine hydrobromide (NAN-190; 0.5 mg/kg, i.p.) as a 5-HT_1A receptor antagonist. According to the obtained results, it may be concluded that activation of 5-HT_1A receptors by 8-OHDAPT may improve anti-cataleptic effect of L-DOPA in a 6-OHDA- induced rat model of PD. Further studies are required to clarify the exact mechanism of interaction between 5-HT_1A and dopaminergic neurons.     

Chronic lithium treatment enhances the postsynaptic 5-HT1A receptor-mediated 5-HT behavioral syndrome induced by 8-OH-DPAT in rats via catecholaminergic systems

The effects of antimanic agents, including lithium, carbamazepine, clonazepam and zotepine, on the postsynaptic 5-HT_1A receptor-mediated behavioral and hypothermic responses induced by 8-OH-DPAT in rats, and on [³H]8-OH-DPAT binding to 5-HT_1A receptors in the rat hippocampus were examined. Treatment with lithium (3 mEq/kg, IP) for 14 days enhanced forepaw treading, one component of the 5-HT behavioral syndrome induced by 8-OH-DPAT, and this enhancement by lithium was abolished by catecholamine depletion with reserpine or -methyl-p-tyrosine, but not by 5-HT depletion withp-chlorophenylalanine. These data suggest that lithium enhances 5-HT_1A-mediated behavior via catecholaminergic systems. In contrast, chronic lithium treatment did not alter the hypothermic response to 8-OH-DPAT in untreated rats, as well as in rats treated with reserpine. These findings strengthen the suggestion that lithium has no direct influence on the postsynaptic 5-HT_1A-mediated response. Other antimanic agents had no effect on either forepaw treading or hypothermia induced by 8-OH-DPAT. Radioligand binding studies using [³H]-8-OH-DPAT demonstrated that chronic lithium treatment, but not other antimanic agents, caused 5-HT_1A receptor down-regulation in rat hippocampus. A discrepancy therefore exists between 5-HT_1A receptor down-regulation and unaltered 5-HT_1A-mediated behavioral and hypothermic responses in catecholamine-depleted rats after chronic lithium treatment.     

The 5-HT1A receptor selective ligands, (R)-8-OH-DPAT and (S)-UH-301, differentially affect the activity of midbrain dopamine neurons

Summary The effects of the selective 5-HT_1A receptor agonist (R)-8-hydroxy-2(di-n-propylamino)tetralin [(R)-8-OH-DPAT] and the novel 5-HT_1A antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301] were studied with regard to the firing pattern of single mesencephalic dopamine (DA) neurons with extracellular recording techniques in chloral hydrate anesthetized male rats. Neuronal activity was studied with respect to firing rate, burst firing and regularity of firing. In the ventral tegmental area (VTA) low doses of (R)-8-OH-DPAT (2–32 g/kg i.v.) caused an increase in all three parameters. The effect on firing rate of DA neurons was more pronounced in the parabrachial pigmentosus nucleus than in the paranigral nucleus, the two major subdivisions of VTA. In the substantia nigra zona compacta (SN-ZC), (R)-8-OH-DPAT (2–256 g/kg i.v.) had no effect on firing rate and regularity of firing and only slightly increased burst firing. High doses of (R)-8-OH-DPAT (512–1024 g/kg i.v.) decreased the activity of DA cells in both areas, an effect that was prevented by pretreatment with the selective DA D₂ receptor antagonist raclopride. (S)-UH-301 (100–800 g/kg i.v.) decreased both firing rate and burst firing without affecting regularity of DA neurons in the VTA. In the SN-ZC, (S)-UH-301 decreased the firing rate but failed to affect burst firing and regularity of firing. These effects of (S)-UH-301 were blocked by raclopride pretreatment. Local application by pneumatic ejection of 8-OH-DPAT excited the DA cells in both the VTA and the SN-ZC, whereas (S)-UH-301 inhibited these cells when given locally. These results show that 5-HT_1A receptor related compounds differentially affect the electrophysiological activity of central DA neurons. The DA receptor agonistic properties of these compound appear to contribute to the inhibitory effects of high doses of (R)-8-OH-DPAT and (S)-UH-301 on DA neuronal activity. Given the potential use of 5-HT_1A receptor selective compounds in the treatment of anxiety and depression their effects on central DA systems involved in mood regulation and reward related processes are of considerable importance.Correspondence to T. H. Svensson at the above address     

Modification of the behavioral effects of morphine in rats by serotonin (5-HT)1A and 5-HT2A receptor agonists: antinociception, drug discrimination, and locomotor activity

Rationale

Indirect-acting serotonin (5-HT) receptor agonists can enhance the antinociceptive effects of morphine; however, the specific 5-HT receptor subtype(s) mediating this enhancement is not established.

Objective

This study examined interactions between morphine and both 5-HT_1A and 5-HT_2A receptor agonists in rats using measures of antinociception (radiant heat tail flick and warm water tail withdrawal), drug discrimination (3.2 mg/kg morphine versus saline), and locomotion.

Methods

Male Sprague–Dawley rats (n?=?7-8 per group) were used to examine the effects of morphine alone and in combination with DOM (5-HT_2A agonist) and 8-OH-DPAT (5-HT_1A agonist).

Results

DOM did not modify antinociceptive or discriminative stimulus effects while modestly attenuating locomotor-stimulating effects of morphine; the effect of DOM (0.32 mg/kg) on morphine-induced locomotion was prevented by the 5-HT_2A receptor-selective antagonist MDL 100907. In contrast, 8-OH-DPAT (0.032–0.32 mg/kg) fully attenuated the antinociceptive effects (both procedures), did not modify the discriminative stimulus effects, and enhanced (0.32 mg/kg) the locomotor-stimulating effects of morphine. These effects of 8-OH-DPAT were prevented by the 5-HT_1A receptor-selective antagonist WAY100635.

Conclusion

Agonists acting at 5-HT_1A or 5-HT_2A receptors do not modify all effects of mu opioid receptor agonists in a similar manner. Moreover, interactions between 5-HT and opioid receptor agonists vary significantly between rats and nonhuman primates, underscoring the value of comparing drug interactions across a broad range of conditions and in multiple species.