Effects Of Serotonergic Drugs Research Articles

A unified hypothesis of SUDEP: Seizure-induced respiratory depression induced by adenosine may lead to SUDEP but can be prevented by autoresuscitation and other restorative respiratory response mechanisms mediated by the action of serotonin on the periaqueductal gray.

Sudden unexpected death in epilepsy (SUDEP) is a major cause of death in people with epilepsy (PWE). Postictal apnea leading to cardiac arrest is the most common sequence of terminal events in witnessed cases of SUDEP, and postconvulsive central apnea has been proposed as a potential biomarker of SUDEP susceptibility. Research in SUDEP animal models has led to the serotonin and adenosine hypotheses of SUDEP. These neurotransmitters influence respiration, seizures, and lethality in animal models of SUDEP, and are implicated in human SUDEP cases. Adenosine released during seizures is proposed to be an important seizure termination mechanism. However, adenosine also depresses respiration, and this effect is mediated, in part, by inhibition of neuronal activity in subcortical structures that modulate respiration, including the periaqueductal gray (PAG). Drugs that enhance the action of adenosine increase postictal death in SUDEP models. Serotonin is also released during seizures, but enhances respiration in response to an elevated carbon dioxide level, which often occurs postictally. This effect of serotonin can potentially compensate, in part, for the adenosine-mediated respiratory depression, acting to facilitate autoresuscitation and other restorative respiratory response mechanisms. A number of drugs that enhance the action of serotonin prevent postictal death in several SUDEP models and reduce postictal respiratory depression in PWE. This effect of serotonergic drugs may be mediated, in part, by actions on brainstem sites that modulate respiration, including the PAG. Enhanced activity in the PAG increases respiration in response to hypoxia and other exigent conditions and can be activated by electrical stimulation. Thus, we propose the unifying hypothesis that seizure-induced adenosine release leads to respiratory depression. This can be reversed by serotonergic action on autoresuscitation and other restorative respiratory responses acting, in part, via the PAG. Therefore, we hypothesize that serotonergic or direct activation of this brainstem site may be a useful approach for SUDEP prevention.

Effect of single doses of citalopram and reboxetine on urethral pressure: A randomized, double-blind, placebo- and active-controlled three-period crossover study in healthy women.

AimsUrethral closure function is essential for urinary continence in women and decreased urethral pressure is associated with stress urinary incontinence (SUI). For decades, the effects of serotonergic drugs on central neural control of urethral closure have been investigated and discussed. Epidemiological studies suggest that the use of selective serotonin reuptake inhibitors (SSRIs), such as citalopram, is associated with SUI. However, the literature findings are conflicting. This study aimed to evaluate citalopram's effect on opening urethral pressure (OUP) in healthy women.MethodsWe conducted a randomized, double‐blind, placebo‐ and active‐controlled crossover study in 24 healthy women. On three study days, which were separated by 8 days of washout, the subjects received single doses of either 40 mg citalopram (and placeboreboxetine), 8 mg reboxetine (and placebocitalopram), or two placebos. Study drugs were administered at a 1‐h interval due to a difference in estimated time to peak plasma concentration (t max). We measured OUP with urethral pressure reflectometry under both resting and squeezing conditions of the pelvic floor at estimated t max for both study drugs (one timepoint).ResultsCompared to placebo, citalopram increased OUP by 6.6 cmH20 (95% confidence interval [CI] 0.04–13.1, p = 0.048) in resting condition. In squeezing condition, OUP increased by 7.1 cmH20 (95% CI: 1.3–12.9, p = 0.01). Reboxetine increased OUP by 30.0 cmH20 in resting condition compared to placebo (95% CI: 23.5–36.5, p < 0.001), and 27.0 cmH20 (95% CI: 21.2–32.8, p < 0.001) in squeezing condition.ConclusionCitalopram increased OUP slightly compared to placebo suggesting that SSRI treatment does not induce or aggravate SUI.

Effect of serotonergic drugs on motor function in a hemiparkinsonian rat model

Effect of serotonergic drugs on motor function in a hemiparkinsonian rat model

Effects of serotonergic drugs on locomotor activity and vigilance states in ring doves

Serotonergic system is implicated on sleep-waking states in mammals. Since studies on serotonin regulation of sleep in birds are scarce, ring dove was chosen as experimental subject in the present work. The role of the neurotransmitter serotonin on vigilance states was studied in ring doves intraperitoneally treated with the 5-HT 1A agonist 8-OH-DPAT, the 5-HT 1A antagonist WAY100635 and the inhibitor of serotonin synthesis para-chlorophenylalanine (PCPA) by means of behavioural, electrophysiological and infrared actimetry criteria. 8-OH-DPAT (1 mg/kg) treatment increased locomotor activity, active waking and grooming states and reduced SWS and REM sleep. Pre-treatment with WAY100635 (0.5 mg/kg) prevented the effects induced by 8-OH-DPAT. Serotonin depletion induced by PCPA treatment (two consecutive injections of 300 mg/kg over two consecutive days) reduced locomotor activity, waking and grooming activity while increased both SWS and REM sleep. Moreover, 8-OH-DPAT (0.5 mg/kg) in PCPA treated ring doves produced a notable rise in the locomotor activity, active waking and grooming states, while it decreased sleep. Altogether, the results support the idea that serotonin plays an active role in wakefulness, probably through the activation of 5-HT 1A receptors that increases wake activities and reduces sleep in ring doves.

The effects of tianeptine or paroxetine on 35% CO2 provoked panic in panic disorder

Antidepressants that inhibit the reuptake of serotonin (5-HT) are particularly effective in the treatment of panic disorder. Evidence suggests that increased 5-HT availability is important for the anti-panic effect of serotonergic drugs and in maintaining the response to selective serotonin reuptake inhibitors (SSRIs). Tianeptine is an antidepressant with 5-HT reuptake enhancing properties (i.e. the opposite pharmacological profile to that of SSRIs). Therefore, no effect would be expected in panic disorder. The aim of the present study was to compare the effect of tianeptine with that of paroxetine, a selective 5-HT reuptake inhibitor with demonstrated efficacy in panic disorder, on the vulnerability to a laboratory panic challenge in panic disorder patients. Twenty panic disorder patients were treated with either tianeptine or paroxetine for a period of 6 weeks, in a randomized, double-blind, separate group design. The reaction to a 35% CO2 panic challenge was assessed at baseline and after treatment. Improvement on several clinical scales was also monitored. Tianeptine, as well as paroxetine, showed a significant reduction in vulnerability to the 35% CO2 panic challenge. In spite of their opposite influence on 5-HT uptake, both tianeptine and paroxetine appeared to reduce the reaction to the panic challenge. These results raise questions about the necessity of 5-HT uptake for the therapeutic efficacy of anti-panic drugs.

Influence of Housing Conditions on the Effects of Serotonergic Drugs on Feeding Behavior in Non-Deprived Rats

Serotonin plays an important role in the regulation of food and water intake, and drugs that inhibit the uptake of this neurotransmitter have been used as appetite suppressors. As the clinical usage of anorectics necessarily involves chronic drug administration, the effects of chronic treatment in animals are likely to be of greater clinical relevance than acute drug effects. Besides, little effort has been made to examine whether these effects interact with stressful situations, such as isolation. We have therefore examined the effects of fluoxetine, a selective 5-HT reuptake inhibitor, and gepirone, a 5-HT1A agonist, on body weight in isolated and in group-housed rats during 3 weeks of daily treatment. Gepirone caused an increase in body weight only in isolated rats. On the other hand, fluoxetine caused a significant reduction in body weight in both singly- and group-housed animals. The effects of these serotonergic agents were more prominent during the first week of treatment. From the data obtained in this study, it is suggested that increased 5-HT transmission produced by fluoxetine during chronic administration seems to be crucial for the appetite-regulating action of 5-HT, and this hypophagic effect does not seem to be dependent on the activation of 5-HT1A receptors since it was not shared by gepirone. Moreover, a concomitant stressful situation, such as isolation, interferes with the action of gepirone on feeding behavior. The hyperphagic effects of chronic regimen with gepirone in isolated animals are probably due to the concurrent reduction of the 5-HT transmission caused by this anxiogenic condition at the earlier stages of treatment. On the other hand, the anorectic effects of fluoxetine do not seem to interact with the stressful situations caused by isolation.

Influence of central serotonergic mechanisms on lower urinary tract function

The effects of serotonergic drugs on the central nervous system control of the lower urinary tract have revealed possible approaches for the treatment of detrusor overactivity and urinary incontinence. Studies in animals of the distribution of serotonergic nerves and receptors and the changes in voiding function induced by serotonin (5-hydroxytryptamine [5-HT]) receptor agonists and antagonists, as well as 5-HT reuptake inhibitors, form a basis for the development of such treatments. In rats and cats, spinal reflex circuits involved in voiding function exhibit a dense serotonergic innervation, multiple 5-HT receptors, and sensitivity to various drugs that affect serotonergic transmission. Although there is some evidence in the rat for serotonergic facilitation of voiding, most experiments in rats and cats indicate that activation of the central serotonergic system by 5-HT reuptake inhibitors, as well as by 5-HT 1A and 5-HT 2 receptor agonists, depresses reflex bladder contractions and increases the bladder volume threshold for inducing micturition. These data indicate that activation of the central serotonergic system can suppress voiding by enhancing efferent control of the urethral outlet and inhibiting the parasympathetic excitatory input to the urinary bladder. The 5-HT receptors and reuptake mechanisms, therefore, represent targets for the development of new treatments of detrusor overactivity and urinary incontinence.

Effects of strain and serotonergic agents on prepulse inhibition and habituation in mice

Neural sensorimotor gating mechanisms prevent the interruption of ongoing information processing routines by ensuing stimuli to permit mental integration and adaptive behavior. Prepulse inhibition (PPI), an operational measure of sensorimotor gating, is now being investigated using murine models to exploit transgenic and “knockout” technology. The present studies were undertaken to evaluate potential murine strain differences in the effects of serotonergic drugs on PPI and habituation. Two strains used most often as a genetic background for transgenic or knockout manipulations, C57BL/6 and 129Sv, and the outbred ICR strain were used. We assessed the effects of the 5-HT 1A/1B agonist 5-methoxy-3(1,2,3,6)tetrahydropyridin-4-yl-1H-indole (RU24969), the 5-HT 1A agonist 8-hydroxy-2(di- n-propylamino)tetralin (8-OH-DPAT), the 5-HT 2A/2C agonist (±)2,5-dimethoxy-4-methylamphetamine (DOM), and the serotonin releaser (+)3,4-methylenedioxy-N-methylamphetamine (MDMA) on PPI and habituation of acoustic startle in the three strains. C57BL/6 mice exhibited lower baseline PPI levels than 129Sv and ICR mice, and 129Sv mice habituated less than C57BL/6 and ICR mice. MDMA decreased PPI in C57BL/6 and ICR, but not 129Sv mice, and RU24969 disrupted habituation in C57BL/6 and 129Sv, but not ICR mice. Lastly, RU24969 decreased and 8-OH-DPAT increased PPI across all strains, although qualitative differences were observed. Thus, both baseline and serotonergic drug-induced effects on murine PPI and habituation are strain-dependent.

Serotonin and sexual behavior in the male rabbit.

Sexual behavior was evaluated in sexually experienced male rabbits after the administration of different serotonergic drugs. The serotonin1A receptor agonist 8-OH-DPAT, 1 mg/kg, inhibited male rabbit sexual behavior when animals were tested 15 min after subcutaneous (SC) administration of this compound. Lower doses, 0.25 and 0.5mg/kg, were ineffective at a test 30 min after drug injection. Furthermore, 8-OH-DPAT, 0.25mg/kg, failed to revert the inhibitory effects upon sexual behavior produced by lidocaine application to the rabbit penis. Stimulation of 5-HT1B/2C receptors by TFMPP, at doses between 0.625 and 2.5 mg/kg, produced a drastic inhibition of sexual behavior when the drug was administered SC 30 min before behavioral observation. Doses below 5mg/kg were ineffective when given intraperitoneally 15 min before test. When the 5-HT1D/2C receptors were stimulated by the agonist mCPP a reduced number of mounts and ejaculations was observed after the SC administration of 1.25 and 2.5 mg/kg. Similarly, the mixed 5-HT agonist/antagonist lisuride reduced the percentage of rabbits displaying mounting behavior at doses of 0.25 and 0.5 mg/kg SC. All compounds tested produced a clear inhibition of male rabbit sexual behavior independently of the receptor subtype activated. These results are at variance with previous observations in rats where 8-OH-DPAT and lisuride produced a drastic facilitation of masculine coital behavior. Moreover, while the inhibition of male sexual behavior in rats produced by TFMPP and mCPP is associated with a disruption of the execution of this behavior, in rabbits these compounds reduced sexual motivation. These results indicate that the effects of serotonergic drugs on sexual behavior are species specific.

S-100beta protects cultured neurons against glutamate- and staurosporine-induced damage and is involved in the antiapoptotic action of the 5 HT(1A)-receptor agonist, Bay x 3702.

The serotonin (5-HT)(1A) receptor agonists have already been shown to protect cultured neurons from excitotoxic as well as from apoptotic damage [B. Ahlemeyer, J. Krieglstein, Stimulation of 5-HT(1A) receptors inhibits apoptosis induced by serum deprivation in cultured neurons from chick embryo, Brain Res. 777 (1997) 179-186. ; B. Ahlemeyer, A. Glaser, C. Schaper, I. Semkova, J. Krieglstein, The 5-HT(1A) receptor agonist, Bay x 3702, inhibited apoptosis induced by serum deprivation in cultured neurons, Eur. J. Pharmacol. 370 (1999) 211-216.; J.H.M. Prehn, M. Welsch, C. Backhauss, J. Nuglisch, F. Ausmeier, C. Karkoutly, J. Krieglstein, Effects of serotonergic drugs in experimental brain ischemia: evidence for a protective role of serotonin in cerebral ischemia, Brain Res. 630 (1993) 110-120.; I. Semkova, P. Wolz, J. Krieglstein, Neuroprotective effect of 5-HT(1A) receptor agonist, Bay x 3702, demonstrated in vitro and in vivo, Eur. J. Pharmacol. 359 (1998) 251-260.; B. Suchanek, H. Struppeck, T. Fahrig, The 5-HT(1A) receptor agonist, Bay x 3702, prevents staurosporine-induced apoptosis, Eur. J. Pharmacol. 355 (1998) 95-101.] and to increase the release of the neurotrophic protein, S-100beta [P.M. Whitaker-Azmitia, R. Murphy, E.C. Azmitia, Stimulation of astroglial 5-HT(1A) receptors releases the serotonergic growth factor, protein S-100, and alters astroglial morphology, Brain Res. 497 (1989) 80-86. ; P.M. Whitaker-Azmitia, R. Murphy, E.C. Azmitia, S-100 protein is released from astroglial cells by stimulation of 5-HT(1A) receptors, Brain Res. 528 (1990) 155-158.]. In this study, we tried to find out whether S-100beta can protect cultured neurons from glutamate- and staurosporine-induced damage and whether the neuroprotective activity of the highly selective 5-HT(1A) receptor agonist, Bay x 3702, is mediated by an induction of S-100beta. Extracellularly added S-100beta (1-10 ng/ml) reduced staurosporine-induced damage in pure neuronal cultures from chick embryo telencephalon as well as in mixed neuronal/glial cultures from neonatal rat hippocampus. In addition, S-100beta (1 ng/ml) reduced neuronal death induced by exposure to glutamate (0.25 mM, 30 min) in mixed neuronal/glial cultures from neonatal rat hippocampus. In cultured rat cortical astrocytes, a 24 h-treatment with Bay x 3702 (1 nM) increased the S-100beta content in the culture medium from 2.2+/-0.3 (controls) to 6.2+/-0.7 ng/ml. In the adult rat, a 4 h-infusion of 4 microg/kg Bay x 3702 (i.v.) was found to increase the S-100beta content in the striatum 6 h after the beginning of the infusion to 153+/-37 microg/g compared with 60+/-20 microg/g in vehicle-treated rats. Bay x 3702 had no effect on the S-100beta content in the rat hippocampus. Finally, we tried to block the protective effect of Bay x 3702 against staurosporine-induced damage in mixed neuronal/glial cultures from rat neonatal hippocampus by anti-S-100beta antibodies. We found only a partial blockade, although the antibodies fully blocked the antiapoptotic effect of S-100beta itself demonstrating that the antibody was effective in blocking neuroprotection by S-100beta. Thus, we conclude that S-100beta was able to protect cultured neurons against glutamate- and staurosporine-induced damage. Furthermore, S-100beta mediated partially the protective effect of the 5-HT(1A) receptor agonist, Bay x 3702, against staurosporine-induced apoptosis in mixed neuronal/glial cultures from neonatal rat hippocampus.

P–617 - Effect of serotonergic drugs on propranolol-induced rat’s uterine contraction under ether anesthesia.

P–617 - Effect of serotonergic drugs on propranolol-induced rat’s uterine contraction under ether anesthesia.

Effects of serotonergic drugs on lateralized aggression and aggressive displays in Anolis carolinensis

Previous work demonstrated that the brains of many reptiles, including the American chameleon Anolis carolinensis ( A. carolinensis), are functionally `split'. Because the left eye in this species projects predominantly to the right hemisphere, and vice versa, inferences about lateralized brain functioning can be made in A. carolinensis by observation of eye use during behavioral encounters. Using this model, past work suggested that territorial aggression in Anolis is under the preferential control of the right hemisphere, and that acute stress or chronic alcohol exposure selectively reduces right hemisphere mediated territorial aggression. In addition, drugs which increase serotonin (5-HT) in the synaptic cleft inhibit aggressive responding in anoles in both hemispheres. The current experiment examined whether or not the administration of the serotonin agonists 8-hydroxy-2-(di-n-propylamine) tetralin (8-OHDPAT), quipazine, or meta-chlorophenylbiguanide (mCPBG) alter territorial aggression in Anolis. Nine adult socially isolated male A. carolinensis underwent a series of behavioral trials during which an antagonistic male was introduced into the cage. Once stable responding was initiated, all subjects were injected in a semi-randomized crossover manner with the following agents, (1) lactated Ringer's, (2) the 5-HT2 agonist quipazine (1.5 mg/kg and 3.0 mg/kg), (3) the 5-HT1 agonist 8-OHDPAT (83 mg/kg), and (4) the 5-HT3 agonist mCPBG (3.0 mg/kg and 9 mg/kg). Twenty minutes post injections, the male intruder was reintroduced into the subject's cage. Several behaviors were recorded, including: (1) the time to the first aggressive response, (2) the number of aggressive episodes mediated by the left eye or right eye, and (3) changes in skin color and posture. Aggressive responding was virtually eliminated in all subjects injected with 8-OHDPAT. On the other hand, one-way ANOVA found that both the 9 mg/kg dose of mCPBG ( P=0.007), and the 3.0 mg/kg dose of quipazine ( P=0.035), selectively decreased territorial aggression mediated by the left eye/right hemisphere compared to lactated Ringer's controls, but had no effect on aggression mediated by the right eye/left hemisphere. Although 8-OHDPAT inhibited aggression, injected subjects developed phenotypic displays of aggressive coloring/posturing, such as blackening of the eye spot and a raising of the neck crest. These results suggest that aggressive action can be differentiated from phenotypic displays that accompany aggression by a 5-HT1 agonist. They also indicate that there is an asymmetrical effect of 5-HT2/5-HT3 serotonin agonists on hemispheric mediation of aggression in this species.

The effects of serotonergic drugs on short-term spatial memory in rats

The effects of modulating the serotonergic system on short-term spatial memory were investigated using delayed matching to position and delayed non-matching to position procedures. Rats were trained on one of the two tasks until stability and then administered the drugs 30 min before a session. Fluoxetine (0.625-10 mg/kg), a serotonin uptake inhibitor, fenfluramine (0.313-5 mg/kg), a serotonin release enhancer, and ipsapirone (2.5-10 mg/kg), a serotonin 1A partial agonist, were all injected subcutaneously in saline solution. Apart from fenfluramine, none of the compounds affected accuracy in either procedure, but some effects on other non- mnemonic measures were seen. At 5 mg/kg, fenfluramine significantly affected latency to respond, total responses on the levers and nosepokes in the foodtray as well as accuracy, indicating a non-specific disruption of behaviour rather than a selective effect on memory processes. These data suggest that cognitive effects of serotonergic drugs are difficult to identify in normal animals, irrespective of the mechanism of action of the drug. These data conflict with recent reports indicating memory-enhancing effects of serotonin uptake inhibitors.

Effect of serotonergic drugs on footshock-induced ultrasonic vocalization in adult male rats

Modulation of ultrasonic vocalization (20-30kHz) emitted by adult rats under stressful conditions such as unavoidable foot-shock has been evaluated as a model of anxiety. The effects of 5-HT(1A) receptor agonists with different intrinsic activities and the role of other 5-HT(1) receptor subtypes, and of 5-HT(2) and 5-HT(3) receptors, in mediation of ultrasonic vocalization were studied, as were the effects of increasing serotonergic activity by administration of the 5-HT releaser fenfluramine or the 5-HT precursor 1-5 HTP. The time spent vocalizing 1-6min after four increascapable (1.0mA) footshocks was recorded. Drugs with affinity for 5-HT(1A) receptors (i.e. 8-OHDPAT, flesinoxan, ipsapirone, buspirone, gepirone, NAN-190) abolished the vocalization irrespective of their efficacy. The mixed 5-HT(1) receptor and beta-adrenoceptor antagonists (-)-alprenolol and pindolol inhibited foot-shock-induced ultrasonic vocalization, whereas (-) penbutolol was ineffective. The beta(1)-adrenoceptor antagonist metoprolol and the beta(2)-adrenoceptor antagonist ICI 118.551 were without effect. This suggests that (-)-alprenolol and pindolol act as partial 5-HT(1) agonists in the test model. The non-selective 5-HT(1) receptor agonists eltoprazine, m-CPP and 5-MeODMT and the 5-HT(2) receptor agonists DO1 and d-LSD also abolished the vocalization, whereas the 5-HT(2) receptor antagonist ritanserin and the 5-HT(3) receptor antagonists ondansetron, ICS 205-930 and zacopride were without effect. (-)-Penbutolol reversed 8-OHDPAT-induced inhibition. Ritanserin reversed DOI-induced inhibition of ultrasonic vocalization, but not 8-OHDPAT-induced inhibition. This suggests that there is no functional interaction between 5-HT(1A) and 5-HT(2) receptors in this model. Fenfluramine and 1-5-HTP dose-dependently inhibited footshock-induced ultrasonic vocalization. These findings indicate that the effect most likely is mediated by postsynaptic 5-HT receptors, although contribution by presynaptic 5-HT receptors cannot be excluded. In conclusion, this study indicates that 5-HT(1A) receptors and 5-HT(2) receptors are involved in mediation of ultrasonic vocalization.

Effects of serotonergic drugs in rats trained to discriminate clozapine from haloperidol

Because of the low discriminability of most neuroleptics, their use as stimuli in two-lever drug discrimination procedures has not been widespread. Several recent reports have demonstrated that the atypical neuroleptic clozapine (CLZ) has stronger cue properties than typical neuroleptics such as haloperidol (HAL). Most of these studies have tested animals trained to discriminate CLZ from vehicle. The present study examined the effects of CLZ, HAL, and three centrally acting serotonergic drugs (ritanserin, MDL 72222, and buspirone) in a drug-drug discrimination procedure with rats trained to discriminate CLZ (5.0 mg/kg) from HAL (0.03 mg/kg). Rats responded predominantly on the CLZ lever during substitution tests with CLZ. Substitution tests with the other four drugs produced 50% or less responding on the CLZ lever. These results are consistent with those of a previous study in which rats were trained to discriminate CLZ from vehicle (Wiley & Porter, 1992) and suggest that the CLZ cue is not mediated by blockade of dopamine D2 receptors, antagonism at 5-HT2 or 5-HT3 receptors, or agonistic activity at 5-HT1A receptors. Potential clinical implications of these results are discussed.

Effect of serotonergic drugs on negative contrast in consummatory behavior

The effect of acute and chronic administration of the 5-HT 1A agonist buspirone on successive negative contrast was investigated in Experiments 1–6. Contrast in consummatory behavior was induced by shifting rats from a 32% to a 4% sucrose solution. Experiments 1–5 showed that buspirone (0.125, 0.25, 0.5, 1.0, 2.0, 15.0 mg/kg) was ineffective in alleviating contrast or in facilitating recovery from contrast. The 15 mg/kg dose substantially decreased consummatory responding. Experiment 6 showed that the chronic (24 days) administration of buspirone (0.5, 2.0 mg/kg) also did not alleviate contrast. The chronic, but not the acute administration of the 2.0 mg/kg dose decreased consummatory behavior. In Experiment 7 the 5-HT 1A agonist gepirone (2.5, 5.0 and 10.0 mg/kg) was also found to be ineffective in reducing contrast but, at the higher doses, decreased overall sucrose intake. Experiments 8 and 9 found that the 5-HT 2 antagonists ketanserin (2.0 and 8.0 mg/kg) and ritanserin (0.63 and 2.5 mg/kg) also did not alleviate contrast. Midazolam (1.0 mg/kg), included as a positive control, eliminated contrast. These data suggest that serotonergic mechanisms are not involved in negative contrast.

The behavioural despair models as a predictor of antidepressant activity: effects of serotonergic drugs

The forced swimming test in rats can discriminate clinically effective antidepressants from other psychoactive drugs under the conditions described here (preexposure to stress and repeated drug administration). Drugs stimulating central s-adrenoceptors also reduced immobility. Drugs stimulating the 5-HT1A receptor also showed a clearcut antidepressant-like effect in this model. Of the various 5-HT antagonists tested, only those sharing a high affinity for the 5-HT1C receptor were active in the forced swim model.

The effects of serotonergic drugs on the locomotor pattern and on cutaneous reflexes of the adult chronic spinal cat

The effects of serotonergic substances on the locomotor pattern and cutaneous reflexes were studied in 3 adult chronic spinal cats trained for 1–3 months to walk with their hindlimbs on a treadmill. The 5-hydroxytryptamine (5-HT) precursor, 5-hydroxytryptophan (5-HTP), and two 5-HT agonists, 5-methoxy- N, N-dimethyltryptamine and quipazine, were found to generally increase the step length and augment the amplitude of hindlimb extensors and flexors as well as axial muscles. Correspondingly, the excursion of the hip, the knee and the ankle joints was increased, mainly in the flexion direction. Cyproheptadine, a 5-HT antagonist, partially or completely antagonised these effects. The threshold current needed to elicit a flexion reflex by stimulating the dorsum of the paw through implanted wires, was lower after the injection of 5-HT agonists than in the immediately preceding control period. Fast paw shaking initiated by dipping the paw in water was unchanged after quipazine and was not abolished by cyproheptadine. In accordance with others, our results suggest that serotonergic drugs may increase the excitability of several types of spinal neurones, including motoneurones, and consequently influence the locomotor pattern as well as the reflex responsiveness. The changes observed with serotonergic agonists were different in many respects from those obtained with noradrenergic agonists and these differences are discussed. This may indicate specific roles for these classes of substances on locomotor function and reflex activity and also provide a basis for further clinical investigations.

Behavioural Pharmacology of 5-HT

Contents: Section I: A.R. Cools, Introduction. A.R. Green, Behavioural Pharmacology of 5-HT: An Introduction. T.P. Blackburn, D.A. Martin, P. Slater, Is Rotational Behaviour in the Rat a 5-HT1A or 5-HT1B Mediated Response? A.J. Stoessl, C.T. Dourish, S.D. Iversen, Serotonic Mediated Behaviour Following Central or Peripheral Administration of the Selective NK-3 Tachykinin Agonist Senktide. Section II: P. Bevan, 5-HT and Sexual Behavior. S. Ahlenius, K. Larsson, New Aspects on the Serotonergic Modulation of Male Rat Sexual Behaviour. S.D. Mendelson, B.B. Gorzalka, Differential Roles of 5-HT Receptor Subtypes in Female Sexual Behaviour. M.D. James, S.M. Lane, D.R. Hole, C.A. Wilson, Hypothalamic Sites of Action of the Dual Effect of 5-HT on Female Sexual Behaviour in the Rat. L. R nyi, T. Lewander, 5-HT1A and 5-HT1B Agonists Produce Opposite Effects on the Ejaculatory Response Induced by Amphetamine in Rats. H.H.G. Berendsen, R.J.M. Smets, C.L.E. Broekkamp, Functional Interplay of Serotonin(5-HT)-Receptor Subtypes. Section III: P. Bevan, 5-HT and Aggression. B. Olivier, J. Mos, M. Tulp, J. Schipper, P. Bevan, Modulatory Action of Serotonin in Aggressive Behaviour. K.A. Miczek, P. Donat, Brain 5-HT System and Inhibition of Aggressive Behaviour. D.C. Blanchard, K. Hori, R.J. Rodgers, C.A. Hendrie, R.J. Blanchard, Differential Effects of Benzodiazepines and 5-HT1A Agonists on Defensive Patterns in Wild Rattus. C. Gentsch, M. Lichtsteiner, H. Feer, Competition for Sucrose-Pellets in Triads of Male, Wistar Rats, the Effects of Eight 5-HT- Agonists. Section IV: A.R. Cools, Depression and Psychosis. P. Willner, Towards a Theory of Serotonergic Dysfunction in Depression. J.F.W. Deakin, 5-HT Receptor Subtypes in Depression. J.A.M. van der Heyden, Modulation of the 5-HT System and Antipsychotic Activity. G.A. Kennet, G. Curzon, Mechanism of Action of 8-OH-DPAT on a Rat Model for Human Depression. P. Martin, A.M. Laporte, P. Soubrie, E. El Mestikawy, M. Hamon, Reversal of Helpless Behaviour in Rats by Serotonin Uptake Inhibitors. T.F. Meert, C.J.E. Niemegeers, Y.G. Gelders, P.A.J. Janssen, Ritanserin (R 55 667), an Original Thymosthenic. N.M. Barnes, B. Costall, A.M. Domeney, M.E. Kelly, R.J. Naylor, M.B. Tyers, The Abilities of 5-HT3 Antagonists to Inhibit the Hyperreactivity Caused by Dopamine Infusion into the Nucleus Accumbens of the Rat. M.A. Geyer, 5-HT2 Antagonists Increase Tactile Startle Habituation in an Animal Model of a Habituation Deficit in Schizophrenia. Section V: A.R. Cools, Feeding Behaviour. E. Goodall, T. Silverstone, Pharmacological Evidence for the Involvement of Serotonergic Mechanisms in Human Feeding. R. Samanin, Serotonin and Feeding. P.H. Hutson, G.A. Kennett, T.P. Donohoe, C.T. Dourish, G. Curzon, Opposite Effects of 5-HT1A and 5-HT1B/1C agonists on Food Intake. J.D. Leander, Effects of Selective Serotonergic Agonists on Palatability-Induced Ingestion. A.M.J. Montgomery, P. Willner, R. Muscat, 8-OH-DPAT Reliably Increases Ingestion of Solid but not Liquid Diets. C.L. Lawton, J.E. Blundell, Pharmacological Manipulation of 5-HT: Effect on Intake of Diets Supplemented with Either Sweet or Bland Carbohydrates. Section VI: T. Archer, 5-HT, Pain and Anxiety. O-G. Berge, C. Post, T. Archer, The Behavioural Pharmacology of Serotonin in Pain Processes. C.L. Broekkamp, F. Jenck, The Relationship Between Various Animal Models of Anxiety, Fear-Related Psychiatric Symptoms and Response to Serotonergic Drugs. P. Soubrie, 5-HT1A Receptors: A Bridge Between Anxiety and Depression? M.B. Tyers, A Review of the Evidence Supporting the Anxiolytic Potential of 5-HT3 Receptor Antagonists. J. Mos, B. Olivier, Ultrasonic Vocalizations by Rat Pups as an Animal Model for Anxiolytic Activity: Effects of Serotonergic Drugs. S.A. Lorens, H. Mitsushio, L.D. Van der Kar, Effects of the 5-HT1A Agonist Ipsapirone on the Behavioural, Endocrine and Neurochemical Responses to Conditioned Fear. P. Moser, Buspirone, Ipsapirone and 5-HT1A-Receptor Agonists Show an Anxiogenic-Like Profile in the Elevated Plus-Maze. A. Fernandez-Guasti, E. Hong, Antianxiety Effect of Various Putative 5-HT1 Receptor Agonists on the Conditioned Defensive Burying Paradigm. B.Costall, A.M. Domeney, P.A. Gerrard, B.J. Jones, M.E. Kelly, N.R. Oakley, M.B. Tyers, The Anxiolytic Activities of the 5-HT3 Receptor Antagonists GR38032F, ICS 205-930 and BRL 43694. J. Mos, J.A.M. van der Heyden, B. Olivier, Behavioural Effects of 5-HT3 Antagonists in Animal Models for Aggression, Anxiety and Psychosis. Section VII: T.U.C. Jarbe, T.Archer, 5-HT: Drug Discrimination and Aversion. W. Koek, F.C. Colpaert, Receptor Mechanisms of the Discriminative Stimulus Properties of Putative Serotonin Agonists. F.G. Graeff, Serotonin and Aversion. R.A. Glennon, R. Young, M.E. Pierson, Stimulus Properties of Arylpiperazine Second Generation Anxiolytics. J.E. Barrett, S.N. Olmstead, Z. Lei, C. Harrod, S.M. Hoffmann, K. Glover, M.A. Nader, B.A. Weissman, Behavioural, Neurochemical and Discriminative Stimulus Effects of Spiroxatrine, a Putative 5-HT1A Receptor Antagonist. I. Lucki, J.A. South, Rapid Training of the Stimulus Properties of Selective 5-Hydroxtryptamine1A Agonists. Section VIII: P. Bevan, S. Lorens, T. Archer, Behavioural Pharmacology of 5-HT: Possible Progress in the Laterality of Concepts.

Effect of some serotoninergic agents on the rectal temperature of the domestic fowl ( gallus domesticus)

The information currently available in the literature on the effects of serotonergic drugs on thermoregulation in the avian species is very scanty. Therefore, it was the objective in this project to study the influence of 5-hydroxytryptamine (5-HT), 5-hydroxytryptophan (5-HTP), benserazide, carbidopa (Mk 486), citalopram, cyproheptadine, methysergide, xylamidine, p-chlorophenylalanine (PCPA) and lysergic acid diethylamide (LSD-25) on the rectal temperature of young chicks. 5-hydroxytryptamine (0.8 mg/kg), produced significant dose-dependent hypothermia in young chicks. Similarly, 5-HTP (16 mg/kg) profoundly lowered the rectal temperature of young chicks. The hypothermie effect of 5-HTP was potentiated by benserazide (1.25–2.5 /kg). Pretreatment with carbidopa (50 mg/kg) potentiated 5-HTP induced hypothermia. Citalopram (5 mg/kg) significantly potentiated hypothermia induced by 5-HT. Pretreatment with PCPA (200 mg/kg, 24 hr previously) alone resulted in hyperthermia while the hypothermie effect of 5-HTP (16 mg/kg) was antagonised by pretreatment with PCPA. Cyproheptadine (1.25 mg/kg) antagonised the hypothermie effect of 5-HT (0.1 and 0.8 mg/kg). The antagonistic effect was weak when the chicks were pretreated with larger doses of cyproheptadine (i.e. 2.5–10 mg/kg). The hypothermia induced by 5-HT (0.8 mg/kg) was antagonised by smaller doses of methysergide (0.125–1.0 mg/kg) but potentiated by larger doses of methysergide (2.0 and 4.0 mg/kg). Xylamidine (1–2 mg/kg) alone induced hyperthermia and effectively antagonised hypothermia induced by 5-HT (0.8 mg/kg). d-Lysergic acid diethylamide (2.5–10 μg/kg) alone induced hypothermia. The interaction between LSD and 5-HT was dose-dependent and biphasic. Thus, small doses (2.5 μg/kg) potentiated while large doses (5 and 10 μg/kg) of LSD antagonised the 5-HT-induced hypothermia. Antagonism to hypothermia induced by 5-HTP (16 mg/kg) was also observed in chicks pretreated with LSD (5 μg/kg). In chicks pretreated with PCPA (200 mg/kg), LSD (5 μg/kg) reversed the hyperthermia. In conclusion, it appears that in the avian species, 5-HT acts as an excitatory transmitter in the heat loss effector pathways producing hypothermia, which is influenced by drugs acting on serotonergic mechanisms.