The effects of quipazine,fenfluramine and apomorphine on the morphine potentiation of tonic immobility

Acute administration of morphine (2 mg/kg, IM) enhanced tonic immobility (TI) durations in three-week old chickens. This effect could be reversed with the 5-HT receptor agonist quipazine. Similarly, promoting 5-HT release by fenfluramine antagonized the morphine potentiation of the response. Both 5-HT agonists reduced TI durations. Finally, the DA receptor agonist apomorphine produced decrements in TI duration and blocked the effect of morphine. The results suggest the involvement of serotonergic and dopaminergic mechanisms in the morphine potentiation of the response. The findings are also discussed in terms of a revised serotonergic model of tonic immobility.     

The effects of tryptophan and manipulations of serotonergic receptors on tonic immobility in chickens

The effects of serotonergic manipulations on tonic immobility (TI) were examined. Systemic injections of tryptophan enhanced TI duration. This effect was reversed by quipazine, a 5-HT receptor agonist, and p-chloroamphetamine, a 5-HT releaser. Separately, these drugs caused marked reductions in TI duration. Fenfluramine, which promotes 5-HT release, also reduced TI duration. The quipazine attenuation of TI was prevented by pretreatment with the 5-HT receptor blocker cinanserin. The results are discussed in terms of 5-HT receptor mechanisms and the raphe model of tonic immobility.     

Tonic immobility in domestic fowl: Anticataleptic effects of quipazine

Quipazine, a putative serotonergic agonist, produced marked decreases in tonic immobility (TI) duration in doses of 5–25 mg/kg. Quipazine-treated animals required more elicitation attempts before displaying TI. Quipazine also blocked the haloperidol enhancement of tonic immobility. In a third experiment, quipazine produced stereotyped responses in chickens which yielded increases in activity on a stabilimeter platform. The results are discussed in terms of catalepsy and serotonergic and dopaminergic mechanisms.     

Role of 5-HT(2C) receptors in the control of central dopamine function

Substantial evidence suggests that the functional status of the mesocorticolimbic dopamine (DA) system originating in the ventral tegmental area is under a phasic and tonic inhibitory control by the 5-HT system that acts by stimulating 5-HT(2C) receptor subtypes. Indeed, electrophysiological and biochemical data demonstrate that 5-HT(2C) receptor agonists decrease, whereas 5-HT(2C) receptor antagonists enhance, mesocorticolimbic DA function. However, 5-HT(2C) receptors do not appear to play a relevant role in the control of the nigrostriatal DA system originating in the substantia nigra pars compacta. In this article, the role of 5-HT(2C) receptors in the control of brain DA function will be reviewed, and the search for new therapies for neuropsychiatric disorders, such as depression, schizophrenia and drug addiction, based on these findings will be discussed.     

Tonic immobility in guinea pigs: a behavioural response for detecting an anxiolytic-like effect?

Tonic immobility (TI) is considered to be an innate fear response characterized by a temporary state of profound and reversible motor inhibition. TI occurs in a wide range of species in a predator-prey confrontation and is hypothesized to be a terminal defence response occurring when there is physical contact between prey and predator. The objective of the present study was to investigate the validity of the TI model in guinea pigs for detection of anxiolytic and/or antidepressant drug activity. Compounds that reduced TI include the serotonin (5-HT) releaser fenfluramine, the 5-HT(1A) receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone, the 5-HT(2C/2B) receptor antagonist SB206553, the 5-HT(2A) receptor antagonist MDL 100.151 -- but only at doses thought also to inhibit 5-HT(2C) receptors--the noradrenaline (NA) reuptake inhibitor desipramine, the benzodiazepine inverse agonist FG-7142, the alpha(2)-adrenergic receptor antagonist yohimbine, the neurokinin (NK)(1) receptor antagonist L-733.060, and the NK(2) receptor antagonist SR-48968. Compounds that increased TI include the benzodiazepine agonists diazepam and alprazolam, and the alpha(2)-adrenergic receptor agonist clonidine. The selective 5-HT reuptake inhibitors citalopram, paroxetine and fluoxetine, the 5-HT(1A) receptor antagonist WAY100.635, the 5-HT(2C) receptor agonist MK-212, the 5-HT/NA reuptake inhibitor imipramine, the NA reuptake inhibitor talopram, the benzodiazepine antagonist flumazenil, the alpha(2)-adrenergic receptor antagonist idazoxan and the psychostimulant amphetamine did not have any effect. These findings indicate that the serotonergic, noradrenergic and neurokinin systems are involved in mediating or modulating TI behaviour in guinea pigs. The potential of TI as a behaviour for detecting anxiolytic-like effect may be questioned due to the contradictory effect of the benzodiazepine ligands, which may be attributed to the sedative and/or ataxic effects of the compounds. Nevertheless, there is preclinical evidence suggesting that 5-HT(1A) receptor agonists, 5-HT(2C) receptor antagonists and NK(1) and NK(2) receptor antagonists possess anxiolytic potential. Only when results of clinical investigations of the anxiolytic potential of non-benzodiazepine ligands (for example the NK receptor antagonists) are available, will it be possible to determine fully the predictive validity of the TI model.     

Morphine and naloxone effects on tonic immobility and the dorsal immobility response in the rat

Adult male Wistar rats treated with morphine sulfate (0.5, 5.0, and 10.0 mg/kg, SC) showed a dose-dependent potentiation of tonic immobility (TI) and dorsal immobility response (DIR) durations. Naloxone (4.0 mg/kg, SC) did not affect the DIR durations but reversed the potentiated morphine effects on both TI and DIR. These results suggest that although opiate receptors may be involved, mu-opiate receptor function is not essential for modulating various complex immobility responses.     

Role of serotonin(2C) receptors in the control of brain dopaminergic function

There is substantial evidence that the functional status of mesocorticolimbic dopaminergic (DA) system originating in the ventral tegmental area (VTA) is under a phasic and tonic inhibitory control by the serotonergic system, which acts by stimulating serotonin(2C) (5-HT(2C)) receptor subtypes. This assertion is based upon a number of electrophysiological and biochemical data showing that 5-HT(2C) receptor agonists decrease, while 5-HT(2C) receptor antagonists enhance mesocorticolimbic DA function. On the other hand, it does not seem that 5-HT(2C) receptors play a relevant role in the control of nigrostriatal DA system originating in the substantia nigra pars compacta (SNc). The authors of this article review the most relevant data regarding the role of 5-HT(2C) receptors in the control of brain DA function and underline the importance of this subject in the search of new therapies for neuropsychiatric disorders such as depression, schizophrenia, drug addiction, and Parkinson's disease.     

Serotonin (5-HT)2A receptor activation enhances dialysate levels of dopamine and noradrenaline, but not 5-HT, in the frontal cortex of freely-moving rats

The 5-HT2 receptor agonist, DOI, dose-dependently (0.16-10.0 mg/kg, s.c.) increased dialysate levels of dopamine (DA) and noradrenaline (NA), but not 5-HT, in the frontal cortex (FCX) of freely-moving rats. This action was abolished by the selective 5-HT2A antagonist, MDL100,907 (0.04), which did not, itself, modify levels of DA and NA. In contrast, the selective 5-HT2B/2C antagonist, SB206,553 (0.63), increased levels of DA and NA additively with DOI. Thus, in contrast to a tonic, inhibitory influence of 5-HT2C receptors (see Millan, M.J., Dekeyne, A., Gobert, A., 1998. Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NAD), but not 5-HT, release in the FCX in vivo. Neuropharmacology 37, 953-955), 5-HT2A receptors exert a phasic, facilitatory influence upon FCX levels of DA and NA.     

Differential cholinergic influences on the immobility response in various strains of domestic fowl

A series of five experiments examined the effects of two anticholinergic drugs, atropine and scopolamine, on the duration of tonic immobility (TI) and susceptibility to the TI response in both Production Red and White Leghorn chickens (Gallus gallus), in an attempt to resolve previous contradictory findings about the effects of cholinergic manipulations on tonic immobility. These two anticholinergic drugs significantly reduced the duration of TI and, therefore, supported the conclusion that cholinergic systems are involved with the immobility response. However, the effects of these drugs on TI differed depending on the age, strain, local population, and handling experience of the individual birds.     

Role of 5-HT and NA in spinal dopaminergic analgesia

Spinal rats and rats with an intact neuraxis given the dopamine (DA) agonist R-apomorphine (0.31-1.75 mumol/kg) in the lumbar subarachnoid space by intrathecal injection were tested 5 and 10 min later for spinal analgesia (increased tail-flick response latency). Apomorphine produced analgesia in spinal rats but not in rats with an intact neuraxis. However, pretreatment of intact rats with the serotonergic (5-HT) receptor antagonist methysergide, the noradrenergic (NA) receptor antagonist phentolamine or the two antagonists together led to a dose-dependent analgesia following apomorphine. Intact rats pretreated with the monoamine depleting drug reserpine, the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) or the NA synthesis inhibitor FLA 63 also showed analgesia to apomorphine. On the other hand, pretreatment with the catecholamine depleting agent alpha-methyl-p-tyrosine (AMPT), the beta-adrenergic receptor blocker propranolol or the opioid receptor antagonist naloxone failed to produce DA analgesia. The present findings suggest that both 5-HT and NA descending fiber systems exert tonic inhibitory effects on spinal DA nociceptive processes.     

Sex differences in the regulation of serotonergic transmission and behavior in 5-HT receptor knockout mice.

Few studies have examined the relationship between genetics, stress, and sex-linked differences in neurotransmitter systems. Examining serotonin (5-HT) receptor knockout mice on stress-induced behavioral depression, female 5-HT1B receptor knockout mice demonstrated significantly reduced immobility than either male 5-HT1B receptor knockout mice or male and female wild-type mice on the tail suspension test (TST) and forced swimming test. The behavioral phenotype was identified as likely due to a disinhibition of 5-HT release, because depletion of 5-HT with parachlorophenylalanine selectively reduced immobility of female 5-HT1B receptor knockout mice in the TST. In contrast, male and female 5-HT1A receptor knockout mice demonstrated reduced immobility compared with control mice, but the depletion of 5-HT with PCPA did not reverse the antidepressant-like phenotype. Microdialysis studies confirmed significantly higher baseline levels of hippocampal 5-HT in female, but not male, 5-HT1B receptor knockout mice. Both male and female 5-HT1B receptor knockout mice demonstrated augmented dialysate responses to fluoxetine. Also, both male and female 5-HT1B receptor knockout mice demonstrated reductions of immobility in the TST after treatment with fluoxetine. Therefore, female 5-HT1B receptor knockout mice demonstrate a sex-linked disinhibition of 5-HT release that sustained higher baseline levels of hippocampal 5-HT and behavioral vulnerability to 5-HT depletion.     

Influence of serotonin 5-HT(7) receptor blockade on the behavioral and neurochemical effects of imipramine in rats

The aim of the present study was to examine the effect of the selective 5-HT(7) receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine (SB-269970), administered alone or in combination with imipramine, on the immobility time of rats in the forced swim test as well as on the extracellular levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and their metabolites in the prefrontal cortex of freely moving rats. Both compounds were administered intraperitoneally (ip). Like imipramine (30 mg/kg, but not 20 mg/kg), SB-269970 (1.25 and 2.5 mg/kg, but not 0.625 mg/kg) significantly shortened the immobility time of rats without affecting their exploratory locomotor activity measured in the open field test. SB-269970 (0.625 and 1.25 mg/kg) raised the extracellular levels of DA, NA, 5-HT and their metabolites in rat prefrontal cortex. In that structure, imipramine (20 mg/kg) produced an increase in all the neurotransmitters measured, but failed to affect the levels of their metabolites. A combination of the inactive doses of SB-269970 (0.625 mg/kg) and imipramine (20 mg/kg) found in the forced swim test produced antidepressant-like effect, which did not stem from the increased exploratory locomotor activity. At the same time, that combination voked a vast increase in the output of NA - but not DA and 5-HT - compared to the effects of both those drugs given alone. These results open up a possibility that the stimulating effect of SB-269970 on DA, NA and 5-HT transmission in the prefrontal cortex plays some role in the antidepressant-like activity of this compound. Moreover, these findings suggest that the increase in cortical NA level seems to account for the anti-immobility action observed after joint administration of the selective 5-HT(7) receptor antagonist and imipramine in rats.     

Depletion of serotonin and catecholamines block the acute behavioral response to different classes of antidepressant drugs in the mouse tail suspension test

RATIONALE: Few studies have investigated whether the behavioral effects elicited by different types of antidepressant drugs are mediated by either serotonin (5-HT) or the catecholamines norepinephrine (NE) and dopamine (DA). OBJECTIVES: By depleting 5-HT, or NE and DA, the present study investigated the contributions of these monoamines to the acute behavioral effects of selective serotonin reuptake inhibitors (SSRIs; fluoxetine and citalopram) and norepinephrine reuptake inhibitors (NRIs; desipramine and reboxetine) in the mouse tail suspension test (TST). RESULTS: Depletion of 5-HT tissue content by para-chlorophenylalanine (PCPA), an inhibitor of tryptophan hydroxylase, completely blocked reductions of immobility by the SSRIs in the TST. In contrast, PCPA did not alter the behavioral effects of the NRIs. Inhibition of catecholamine synthesis by alpha-methyl-para-tyrosine (AMPT) reduced brain NE and DA tissue content, whereas disruption of vesicular storage with reserpine decreased brain NE, DA and 5-HT tissue content. However, neither treatment completely prevented responses to desipramine, fluoxetine, or citalopram in the TST. Depleting both newly synthesized and vesicular components of NE and DA transmission with a combination of reserpine and AMPT completely prevented the behavioral effects of desipramine, reboxetine, and fluoxetine and attenuated those of citalopram. Although PCPA did not alter baseline immobility, AMPT and reserpine increased baseline values in the TST. CONCLUSIONS: These studies demonstrated that endogenous 5-HT synthesis mediates the behavioral effects of SSRIs, but not NRIs, in the TST. In contrast, disruption of the behavioral effects of NRI and SSRI antidepressants required disruption of both catecholamine synthesis and vesicular storage and release mechanisms.     

Possible serotonergic mediation of tonic immobility: Effects of morphine and serotonin blockade

Small doses of morphine, within the range of 0.02 mg/kg to 10.15 mg/kg were administered to chickens (Gallus gallus) and the effect on the fear-based tonic immobility (TI) response determined. All doses at and above 0.13 mg/kg enhanced the TI response significantly above the levels produced for the 0.02 mg/kg dose and the distilled water control group. Administration of a single large dose of p-chlorophenylalanine prevented the morphine-induced enhancement of TI. It was suggested that serotonin systems mediate morphine effects on tonic immobility in chickens.The research reported here is in compliance with the Controlled Substances Act of 1970. The second author possesses BNDD registration number PM0096366.     

5-HT1B receptors modulate release of [3H]dopamine from rat striatal synaptosomes: further evidence using 5-HT moduline, polyclonal 5-HT1B receptor antibodies and 5-HT1B receptor knock-out mice

In previous paper based on classical pharmacological tools, we identified a Gi protein-coupled presynaptic 5-hydroxytryptamine (5-HT) 1B receptor causing inhibition of dopamine (DA) release in rat striatal synaptosomes. It was the aim of the present study to further explore this receptor, using 5-HT moduline, a polyclonal antibody directed against 5-HT1B receptors and 5-HT1B receptor knock-out mice. Preincubation of rat striatal synaptosomes with 5-HT moduline (0.1, 1, or 10 microM) significantly reduced the inhibitory effect of CP93,129, a selective rat 5-HT1B receptor agonist, on K+-evoked overflow of [3H]DA in a non-competitive manner: 5-HT moduline did not modify the IC50 of CP93,129, but concentration-dependently reduced the maximal inhibitory effect. Preincubation of rat striatal synaptosomes with a specific polyclonal 5-HT1B receptor antibody also resulted in a significant attenuation of the inhibitory effect of CP93,129 on K+-evoked overflow of [3H]DA. In female 129/Sv wild-type mice, CP93,129 and 5-carboxyamidotryptamine maleate (5-CT), a non-selective 5-HT1B receptor agonist, inhibited the K+-evoked [3H]DA overflow in a concentration-dependent manner. Sumatriptan, a selective rat 5-HT1D receptor agonist, did not modify the overflow of [3H]DA. SB224289, a selective 5-HT1B receptor antagonist, abolished the inhibitory effects of CP93,129 and 5-CT. The inhibitory effects of CP93,129 and 5-CT were absent in synaptosomes from 5-HT1B receptor knockout mice. No compensatory inhibition effect in mutant mice was observed using sumatriptan. In conclusion, the results show that a non-competitive antagonist of the 5-HT1B receptor concentration-dependently decreases the maximal inhibitory effect of a 5-HT1B receptor agonist on the synaptosomal K+-evoked release of [3H]DA in striatum. Moreover, a specific antibody raised against the receptor and particularly directed against a region of the receptor protein involved in signal transduction, namely the coupling with the G-protein, also antagonizes the inhibitory effect of the stimulation of 5-HT1B receptor on the release of [3H]DA. Ultimately the disruption of 5-HT1B receptor gene in 5-HT1B knock-out mice leads to a total suppression of the effect of 5-HT1B receptor agonists on [3H]DA release. These observations further support our previous observations using selective agonists/antagonists, indicating that 5-HT1B receptors control the release of neuronal DA as presynaptic heteroreceptors.     

DA1 receptor activity opposes anorectic responses to amino acid-imbalanced diets

The serotonin3 (5-HT3) receptor plays an important role in the aminoprivic feeding model. Other neurochemical systems, including cholecystokinin (CCK) and dopamine (DA), are known to affect food intake. We pretreated rats systemically with tropisetron, a 5-HT3 receptor antagonist, alone and combined with antagonists of DA1 and DA2 receptors, and measured intake of an amino acid-imbalanced diet (IMB). As expected, tropisetron significantly increased intake of IMB. SCH-23390, a DA1 antagonist, increased IMB anorexia. When combined with tropisetron, DA2 antagonism with eticlopride reduced short-term intake of both the basal diet (BAS) and IMB. In the IMB model, specificity of 5-HT3-DA2 interactions, and of 5-HT3-CCK(A) interactions from previous studies, prompted investigation of CCK(A)-DA2 interactions; there appeared to be none. SKF-38393, a DA1 agonist, combined with the CCK(A) receptor antagonist, devazepide, increased BAS and tended to increase IMB intake. Thus, CCK(A)-DA1 interactions were not specific for IMB. These data suggest that DA1 receptor activity opposes IMB anorexia, possibly via an interaction with the 5-HT3 receptor.     

Short-term effects of melatonin and pinealectomy on serotonergic neuronal activity across the light-dark cycle

Melatonin (MLT) and serotonin (5-HT) are two biosynthetically related compounds implicated in several common physiological functions and the etiology of mood disorders. How they interact, though, is not yet fully understood. In this study, single-unit extracellular recordings were used to monitor dorsal raphe nucleus (DR) 5-HT neuronal activity in anesthetized rats, under basal conditions (CTRL), in response to MLT administration, and after pinealectomy (PX) across the light-dark cycle. Under basal conditions, the number of spontaneously active 5-HT neurons and their firing rate were both significantly lower in the dark phase. In the light phase, administration of MLT at low doses (0.5-1?mg/kg, i.v.) decreased 5-HT firing activity. This inhibitory effect of MLT was completely blocked by the MT?/MT? receptor antagonist luzindole, but not by the selective MT(2) receptor antagonist 4P-PDOT, the selective 5-HT(1A) receptor antagonist WAY100635, or by the α? adrenoceptor antagonist idazoxan. In the opposite experiment, PX increased 5-HT firing activity in the dark phase, and this was reversed by MLT administration (1?mg/kg, i.v.). Finally, in a forced swim test, MLT (1?mg/kg, i.p.) increased immobility time and decreased swimming behavior. Together, these results suggest that nocturnal MLT secretion imposes tonic inhibitory control over a sub-population of DR 5-HT neurons. This MLT-induced decrease in 5-HT neurotransmission may represent a biological mechanism underlying mood disorders characterized by increased MLT secretion, such as seasonal affective disorder.     

Central and peripheral effects of serotonin on the immobility response in chickens

The effects of low and high doses of serotonin on tonic immobility (TI) duration and susceptibility in 10- and 45-day-old chickens were examined. High doses of serotonin reduced the number of inductions required to produce TI, regardless of the subject's age. In contrast, low and high doses of serotonin produced biphasic increases and decreases in TI duration in 10-day-old birds, but there were no apparent effects on immobility duration by either dose of this drug in older chickens. These results are discussed in terms of the formation of the blood-brain barrier in domestic fowl and the differential peripheral versus central actions by serotonin on TI susceptibility and response duration.     

Effects of WAY 100635 on antipsychotic-induced catalepsy in 5-HT depleted animals: a role for tonic activation of 5-HT(1A) receptors

We recently observed that the 5-hydroxytryptamine (5-HT)(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)-cycloh exanecarboxamide (WAY 100635) enhanced antipsychotic-induced catalepsy, which we hypothesized to be due to a blockade of tonic 5-HT(1A) receptor activation. Here, we examined this hypothesis by studying the effects of WAY 100635 in animals that were depleted of 5-HT by repeated treatment with the 5-HT synthesis inhibitor p-chlorophenylalanine methyl ester. Depletion of 5-HT abolished the enhancement by WAY 100635 of catalepsy induced by low doses of the antipsychotics nemonapride and raclopride, in agreement with the hypothesis that WAY 100635 enhances catalepsy by blocking tonic 5-HT(1A) receptor activation. Given the predictive validity of catalepsy, these findings indicate that 5-HT(1A) receptor blockade may enhance the extrapyramidal side-effects of antipsychotics in humans.     

The absence of 5-HT<Subscript>1A</Subscript> receptors has minor effects on dopamine but not serotonin release evoked by MK-801 in mice prefrontal cortex

RATIONALE: Non-competitive NMDA receptor antagonists markedly increase neuronal activity in medial prefrontal cortex (mPFC), an effect which partly underlies their schizomimetic actions. Projection pyramidal neurons and local GABAergic interneurons in mPFC express 5-HT(1A) receptors, whose activation modulates dopaminergic (DA) and serotonergic (5-HT) activity in midbrain and the cortical release of both monoamines. OBJECTIVE: To examine whether the presence of 5-HT(1A) receptors can modulate the effect of NMDA receptor blockade with MK-801 (dizocilpine) on DA and 5-HT release in mouse mPFC. MATERIALS AND METHODS: Brain microdialysis and locomotor activity measures in wild-type and 5-HT(1A) receptor knockout mice. RESULTS: Systemic MK-801 administration (0.125, 0.25, 0.50, and 1 mg/kg i.p.) induced a dose-dependent increase in mPFC 5-HT output, which was independent of the genotype. MK-801 increased DA output in a dose-dependent manner with a significant effect of genotype on low doses (0.125, 0.25 mg/kg). These differences were not paralleled by differences in gross locomotor activity. Overall, MK-801 increased more markedly DA than 5-HT output in both genotypes. Finally, the local perfusion of MK-801 in mPFC (30, 100, 300 muM) by reverse dialysis did not elevate dialysate DA or 5-HT concentrations in mPFC. CONCLUSION: 5-HT(1A) receptors partly modulate the increase in mPFC DA (but not 5-HT) release produced by NMDA receptor blockade. The lack of effect observed after the local MK-801 application suggests that the change in cortical monoamines is mainly driven by subcortical NMDA receptor blockade, without a significant involvement of PFC 5-HT(1A) receptors.