MCL0042: a nonpeptidic MC4 receptor antagonist and serotonin reuptake inhibitor with anxiolytic- and antidepressant-like activity

In the present study, we examined the anxiolytic and antidepressant effects of MCL0042, a novel compound showing activity in both MC4 receptor antagonism and serotonin transporter inhibition. MCL0042 showed relatively high affinity for the MC4 receptor and serotonin reuptake site, as determined by receptor binding assays. MCL0042 attenuated [Nle(4),d-Phe(7)]alpha-MSH-increased cAMP formation in MC4 receptor expressing cells, and it inhibited [(3)H]serotonin uptake by rat brain synaptosomes; thus, MCL0042 is an MC4 receptor antagonist and serotonin transporter inhibitor. Subcutaneous administration of MCL0042 significantly increased the number of licks in a Vogel punished drinking test in rats, and it also significantly attenuated swim stress-induced reduction in time spent in open arms in an elevated plus-maze task in rats, showing the anxiolytic-like potential of MCL0042. Moreover, repeated administration of MCL0042 for 14 days attenuated olfactory bulbectomy-induced locomotor hyperactivity in rats, indicating antidepressant-like potential. These data show that MCL0042 has unique properties of both the MC4 receptor antagonist and serotonin transporter inhibitor, and produces anxiolytic and antidepressant activity in rats. Moreover, blockade of both the MC4 receptor and serotonin reuptake sites might represent a useful approach in the treatment of anxiety and depression.     

Serotonergic mechanisms in the behavioral effects of buspirone and gepirone

The literature describing the role of serotonin (5-HT) in the mediation of anxiety is a controversial one. Serotonergic involvement in the mechanism of action of two nonbenzodiazepine anxiolytics, buspirone and gepirone, supports a role for serotonin in anxiety. The anticonflict effect of both drugs is blocked by serotonin lesions, and gepirone induces the serotonin syndrome. A shift in the gepirone dose-response curve to the left in serotonin lesioned rats suggests that this may be 5-HT-receptor mediated. Both buspirone and gepirone enhance the acoustic startle response and gepirone's effect is attenuated in serotonin lesioned animals. While other components of buspirone's mechanism of action may suppress the behavioral expression of its serotonergic interactions, results from these studies suggest that serotonin agonist-like activity may be an important mechanism in the actions of a clinically proven nonbenzodiazepine anxiolytic (buspirone), and anxiolytic candidate (gepirone).     

Investigation into the age-dependence of release of serotonin and noradrenaline in the rat brain cortex and of autoreceptor-mediated modulation of release

Slices of cerebral cortex from young adult and aged rats, preincubated with [3H]serotonin or [3H]noradrenaline were superfused and the electrically (3 Hz) evoked overflow of tritium and its modulation by the respective agonists and antagonists were studied. The electrically evoked overflow in slices preincubated with [3H]serotonin from 2.5-year-old rats was smaller (by about 35%) than in slices from 3-month-old animals. No difference was found for the inhibition by serotonin and the facilitation by metitepine of the evoked overflow and for the metitepine-induced shift of the concentration-response curve for serotonin to the right. There was no difference between slices preincubated with [3H]noradrenaline from 3 months, 1, 2 and 2.5-year-old rats, with respect to the electrically evoked overflow, its inhibition and facilitation by noradrenaline and phentolamine, respectively, and the phentolamine-induced shift of the concentration-response curve for noradrenaline to the right. The present results suggest that the release of serotonin is reduced in the cerebral cortex of aged rats whereas the release of noradrenaline and the autoreceptor-mediated modulation of the release of either monoamine is not altered.     

安定对大鼠开场行为活动和高钾诱发单胺递质释放的影响

急性ip安定3mg/kg显著抑制大鼠开场(OF)行为活动。慢性ip同一剂量安定15d,对OF抑制产生耐受。完成OF观察后,断头取脑,观察高K⁺诱发不同脑区单胺递质释放变化。整体急性ip安定3mg/kg产生与离体条件下9μmol/L安定相似的抑制高K⁺诱发单胺递质释放作用。慢性ip安定,对海马和杏仁核区高K~+诱发儿茶酚胺释放抑制作用产生显著耐受;未观察到对高K⁺诱发5-羟色胺抑制作用的耐受现象。     

Possible involvement of presynaptic 5-HT autoreceptors in effect of lithium on 5-HT release in hippocampus of rat

The effects of subacute treatment with lithium on the stimulation-induced release of serotonin (5-HT) and the function of 5-HT autoreceptors in the hippocampus and frontal cortex of the rat were studied. In the rats treated with lithium for 3 days, the high K+-evoked release of endogenous 5-HT from the slices of hippocampus, but not the slices of frontal cortex, was significantly increased. High K+-induced release of [3H]5-HT from the slices of hippocampus of control rats preloaded with [3H]5-HT was decreased when the slices were exposed to 5-HT, while it was increased when they were exposed to methiothepin. In the slices of hippocampus from the lithium-treated rats, this inhibitory effect of 5-HT on the release of [3H]5-HT, evoked by either high K+ or electrical stimulation was significantly attenuated. On the other hand, it was not modified in the slices of frontal cortex. The results suggest that lithium may inhibit the function of 5-HT autoreceptors to regulate the release of 5-HT. This action may, in part, trigger the development of the down-regulation of 5-HT1 receptors occurring in the hippocampus but not in the frontal cortex after chronic treatment with lithium.     

The influence of cypramil on depressive disorders of behavior in young thyroidectomized male rats

The activity of selective serotonin re-uptake inhibitor cypramil (cipramil, citalopram) has been studied in young male rats with thyroid hormone dysbalance induced by thyroidectomy. Thyroidectomy increased the level of depressed behavior in the Porsolt forced swim test and enhanced the expression of emotional behavior in the open-field test. The replacement treatment of thyroidectomized rats with triiodothyronine (T3) produced an antidepressant and anxiolytic effects. The chronic administration of cypramil also produced an antidepressant action in the Porsolt test, the drug effect being more pronounced in the case of a combined treatment with cypramil and T3 (synergism). Cypramil reduced the horizontal motor activity and the oprientation-research activity in the open-field test, but these drug effects were less pronounced in the case of joint administration with T3.     

Pharmacological profile of a potential anxiolytic: AP159, a new benzothieno-pyridine derivative

AP159 ([N-cyclohexyl-1,2,3,4-tetrahydrobenzo(b)thieno(2,3c)pyridine]-3-carboamide,hydrochloride) showed clear anti-conflict activity in rats in the absence of effects on muscle relaxation, potentiation of anesthesia (in mice) or anticonvulsant activity (in mice). This anticonflict effect was antagonized by treatment with Ro15-1788. By contrast with the deficits produced by diazepam, AP159 did not impair passive avoidance. The latter drug also improved scopolamine-induced amnesia in the same task. AP159 did not inhibit³H-flunitrazepam binding, but potently inhibited³H-8OH-DPAT binding. This compound increased serotonin and 5HIAA content of the midbrain raphe nuclei and of the amygdala centralis. AP159 has been shown to be a novel non-BZP anxiolytic agent with no side effects in laboratory animals; it could be a clinically effective anxiolytic agent.     

The effect of venlafaxine on behaviour, body weight and striatal monoamine levels on sleep-deprived female rats

Partial sleep deprivation is clinically associated with fatigue, depressive symptoms and reduced memory. Previously, it has been demonstrated that venlafaxine, an atypical antidepressant, increases the levels of noradrenaline and serotonin in rat hippocampus. The aim of this study was to evaluate the effects of venlafaxine on depression, anxiety, locomotor activity and memory in a model of REM sleep (REMs) deprivation in rats. We have also studied the influence of venlafaxine on monoamine levels in the striatum. Six groups of animals (N=20 each) were treated with saline or venlafaxine (1 or 10 mg/kg) during 10 days, submitted or not to REMs deprivation and studied with the forced swimming test of Porsolt (STP), plus-maze, passive avoidance and open-field tests right after sleep deprivation. Animals were also studied for passive avoidance 24 h later (rebound period). Brain samples for monoamine measurements were collected either immediately after REMs deprivation or after 24 h. Both REMs deprivation and venlafaxine showed an antidepressant effect. An anxiolytic effect was also observed after REMs deprivation. Previous treatment with venlafaxine blocked the antidepressant and anxiolytic effects of REMs deprivation. REMs deprivation alone and treatment with venlafaxine 10 mg/kg increased locomotor activity, and this effect was inhibited by venlafaxine in REMs deprived rats. Both venlafaxine treatment and REMs deprivation induced weight loss. Venlafaxine treatment, but not REMs deprivation, induced an increase in striatal dopamine (DA) levels. The combination of REMs deprivation and venlafaxine treatment was associated with an increase in serotonin turnover 24 h after rebound sleep. In this study, venlafaxine treatment hindered most behavioral effects of REMs deprivation and was associated with an interference on dopamine and serotonin systems in the striatum.     

Central serotonergic activity after neurogenic hypertension

Sinoaortic denervated rats, 24 h after operation, showed a 25% increase in the central (hypothalamus, frontal cortex, midbrain, pons and medulla oblongata) tryptophan content and about a 70% rise in plasma free fatty acid (NEFA) concentration. The synaptosomal serotonin (5-HT) uptake and tryptophan hydroxylase activity of slices from these central areas were not significantly different when compared to those from sham-operated rats. There was also an increase in tryptophan and NEFA concentration at 24 h in fasted sham-operated rats. Seven days after neurogenic hypertension, the central tryptophan content had returned to control values. However, a 50% increase in the tryptophan hydroxylase activity of slices from the midbrain area together with a higher turnover rate of serotonin was found in the denervated group of rats. The synaptosomal 5-HT uptake remained unchanged. These results suggest that sinoaortic denervation could induce changes in the serotonergic neurons localized in central nervous system areas during the first week after operation.     

Anxiolytic-like action of MTEP expressed in the conflict drinking Vogel test in rats is serotonin dependent

The purpose of the present study was to investigate whether the anxiolytic-like action of a selective and brain penetrable group I metabotropic glutamate (mGlu5) receptor antagonist 3-[(2-methyl-1,3-tiazol-4-yl)ethynyl]-pyridine (MTEP) is dependent upon the serotonergic system. Experiments were performed on male Wistar rats. The Vogel conflict drinking test was used to detect anxiolytic-like activity. MTEP administered intraperitoneally at doses of 1, 3 and 6 mg/kg induced anxiolytic-like effect. The potential anxiolytic effect of MTEP (1 mg/kg) was inhibited by a nonselective 5-HT receptor antagonist metergoline (2 mg/kg i.p.) and 5-HT2A/2C receptor antagonist ritanserin (0.5 mg/kg i.p.), but not by a 5-HT1A receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl)cyclohexane-carboxamide (WAY 100635) (0.1 mg/kg i.p). The anxiolytic effect of MTEP (6 mg/kg) was attenuated by ritanserin (1 mg/kg i.p.). Moreover, MTEP-induced a dose-dependent release of serotonin in the frontal cortex. The obtained results suggest that the potential anxiolytic effect of the mGlu5 receptor antagonist MTEP is due to the increased serotonin release with subsequent activation of 5-HT2A/2C receptors, most probably located postsynaptically, but not by the 5-HT1A receptors.     

The anxiolytic effect of the novel antipsychotic ziprasidone compared with diazepam in subjects anxious before dental surgery

The novel atypical antipsychotic ziprasidone has a pharmacologic profile notable for potent agonism of serotonin (5-HT)1A receptors, antagonism at 5-HT1D receptors, and reuptake inhibition of norepinephrine. 5-HT1A receptor agonism, in particular, suggests anxiolytic activity, and ziprasidone has shown preliminary efficacy in treating the symptoms of anxiety associated with psychotic disorders. In this study, the anxiolytic efficacy of ziprasidone was evaluated in nonpsychotic subjects who were anxious before undergoing minor dental surgery. We compared a single oral dose of 20 mg ziprasidone (N = 30) with that of 10 mg diazepam (N = 30) and placebo (N = 30) in a randomized, parallel-group, double-blind study. The peak anxiolytic effect of ziprasidone compared with that of placebo was similar to that of diazepam but had a later onset. At 3 hours postdose, the anxiolytic effect of ziprasidone was significantly greater than that of placebo (p < 0.05) and somewhat greater than that of diazepam. Diazepam showed a significantly greater anxiolytic effect than placebo at 1 hour (p < 0.05) but not at 3 hours. The sedative effect of ziprasidone was never greater than that of placebo, whereas that of diazepam was significantly greater than that of placebo 1 to 1.5 hours postdose. Ziprasidone was generally well tolerated. Only one patient reported treatment-related adverse events (nausea and vomiting) and, unlike diazepam, ziprasidone did not cause reductions in blood pressure. Dystonia, extrapyramidal syndrome, akathisia, and postural hypotension were not seen with ziprasidone. Thus, ziprasidone may possess anxiolytic effects in addition to its antipsychotic properties.     

Early onset anxiolytic efficacy after a single dose of pregabalin: double-blind, placebo- and active-comparator controlled evaluation using a dental anxiety model

To evaluate acute onset of anxiolytic activity using a dental anxiety model, 89 patients were randomised to double-blind single dose pregabalin 150 mg, alprazolam 0.5 mg or placebo 4 h before a scheduled dental procedure. A Dental Anxiety Total score >12 (moderate-to-severe) without meeting Diagnostic and Statistical Manual of Mental Disorders (Fourth edition) (DSM-IV) anxiety disorder criteria was required. Efficacy and safety, assessed 2, 2.5, 3, 3.5 and 4 h postdose, included 100 mm Visual Analogue Scale for Anxiety (VAS-Anxiety; primary outcome), 100 mm VAS-Sedation and Time-to-Onset of Action Scale (TOAS), a patient-rated anti-anxiety drug-benefit scale (no [0] to full benefit [10]). Mixed model analysis found significantly greater VAS-A improvement slopes for pregabalin (t = -2.47; P = 0.014) and alprazolam (t = -2.39; P = 0.018). There was a significant improvement versus placebo in the TOAS from 2 h through endpoint in alprazolam patients and from 3 h onward in pregabalin patients. Pregabalin produced significantly greater increases in VAS-Sedation versus placebo from 2.5 h through 4 h (2 h onward for alprazolam). Notably, there was a higher correlation between TOAS and VAS-Sedation (r = +0.58) than VAS-Anxiety (r = -0.50) on Spearman's analysis. The majority of Adverse Effects (AEs) were mild, and the most frequent for pregabalin, alprazolam, and placebo, respectively, were fatigue (N = 7, 7, 3), dizziness (N = 6, 3, 3), attention disturbance (N = 3, 1, 0), somnolence (N = 3, 0, 0), feeling abnormal (N = 0, 2, 0) and balance disorder (N = 0, 2, 0). These results suggest that onset of clinically meaningful anxiolytic effect after single-dose pregabalin occurs within the first 3-4 h. Additional research is needed to determine whether anxiolytic effect occurs in generalized anxiety disorder populations by day 1 or within 3-4 h post-first dose.     

ELB139 an agonist at the benzodiazepine binding site increases 5-HT in the striatum and prefrontal cortex of rats: a microdialysis study

Benzodiazepines induce an immediate anxiolytic activity at the expense of side effects such as sedation, tolerance and withdrawal. In contrast, selective serotonin receptor uptake inhibitors (SSRIs) are known to offer long-term symptom improvement without inducing tolerance and withdrawal, but with a delayed onset of the anxiolytic effect. ELB139 is a novel agonist at the benzodiazepine binding site with pronounced anxiolytic and anticonvulsant activity without inducing tolerance to both effects after chronic administration. ELB139 shows a selectivity for alpha-3-subunit containing GABA(A) receptors. In the present study the effect of the compound on monoaminergic neurotransmitter levels were investigated by microdialysis. ELB139 induced a significant increase of extracellular 5-HT in the striatum and the medial prefrontal cortex of rats without affecting dopamine levels in these areas. The increase of 5-HT in the striatum was reversed by systemic and by local administration of the benzodiazepine antagonist flumazenil in the dorsal raphe nucleus by a microdialysis probe, suggesting that the increase in 5-HT was mediated by the activity of ELB139 at the benzodiazepine binding site. As the dorsal raphe nucleus is rich in alpha-3 subunits, this effect of ELB139 may be mediated by its subtype selectivity. Thus, ELB139 seems to combine effects seen with benzodiazepine agonists and SSRIs in one compound.     

Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro

Using radioligand binding techniques and human frontal cortex, we determined the equilibrium dissociation constants (KDs) of 25 antidepressants at the serotonin S1 (probably the S1A subtype) and serotonin S2 receptors using [3H]WB4101 and [3H]ketanserin, respectively. At the serotonin S1 receptor, the most and least potent antidepressants were trazodone (KD = 60 nM) and bupropion (KD = 170 microM), respectively. At the serotonin S2 receptor, the most and least potent antidepressants were amoxapine (KD = 0.6 nM) and bupropion (KD = 90 microM), respectively. Analysis of the data revealed a relationship between structure and serotonin S1 affinity for some tricyclic antidepressants. Buspirone, a new anxiolytic agent, possessed high affinity for the serotonin S1 receptor (KD = 3.8 nM).     

Effects of the putative anxiolytic SM-3997 on central monoaminergic systems

The effects of SM-3997 on central monoaminergic systems were evaluated by ex vivo measurement of monoamines and their metabolite levels in rat brain after intraperitoneal treatment of drugs and by in vitro measurement of monoamine uptake into rat brain slices. The effects of SM-3997 were also compared with those of other new nonbenzodiazepine anxiolytic compounds. SM-3997, buspirone, gepirone and ipsapirone showed no effects on serotonin uptake and dopamine uptake, and a weak inhibition of norepinephrine uptake at the concentration of 100 microM. SM-3997 decreased the serotonin metabolite (5-hydroxyindole-3-acetic acid) level without changing the serotonin level in hippocampus and increased dopamine metabolite (3,4-dihydroxyphenylacetic acid, homovanillic acid) level with no effect on the dopamine level in striatum. SM-3997 also produced an increase in the norepinephrine metabolite (3-methoxy-4-hydroxyphenylglycol) level with a decrease in the norepinephrine levels in hippocampus. Similar effects on serotonin metabolites and norepinephrine metabolites were observed in several other regions. Although the serotonergic effect of SM-3997 was similar to that of buspirone, gepirone and ipsapirone, the dopaminergic effect of SM-3997 was much weaker than that of buspirone.     

Antidepressant and anxiolytic effects of selective 5-HT6 receptor agonists in rats

Rationale

Although selective serotonin reuptake inhibitors (SSRIs) produce clinical therapeutic effects on depression and anxiety through augmentation of serotonergic neurotransmission, there is little known about the potential contributions of the 5-HT₆ receptor in the treatment of mood disorders.

Objectives

The aim of this study was to test the potential antidepressant-like and anxiolytic-like effects of the 5-HT₆ receptor agonists WAY-208466 and WAY-181187 using established behavioral tests in rats.

Methods

In order to determine if the 5-HT₆ receptor agonists possess antidepressant-like activity, rats were treated with WAY-208466 or WAY-181187 and tested in the modified rat forced swim test (FST). Also, the potential anxiolytic-like effects of WAY-208466 and WAY-181187 were measured using the defensive burying (DB) test and novelty-induced hypophagia (NIH) test.

Results

WAY-208466 and WAY-181187 produced both antidepressant-like and anxiolytic-like effects. Both compounds decreased immobility and increased swimming behavior in the FST. The effects of the 5-HT₆ receptor agonists were similar to those seen after treatment with the SSRI fluoxetine. Both 5-HT₆ receptor agonists also decreased burying duration in the DB test, indicative of anxiolytic activity in the test. The anxiolytic effects of WAY-208466 were reproduced in the NIH test. Assessment of the anxiolytic effects of WAY-181187 in the NIH was confounded by alterations in home cage feeding behavior.

Conclusions

These findings suggest that 5-HT₆ receptor agonists may represent a new class of potential antidepressant and anxiolytic compounds and could possess a number of advantages over currently available treatments, including rapid onset of anxiolytic efficacy.     

Effects of acute and chronic treatment with fluoxetine on stress-induced hyperthermia in telemetered rats and mice

Preclinical and clinical evidence suggests that anxiolytic effects are observed after chronic administration of the selective serotonin reuptake inhibitor fluoxetine. In contrast, acute treatment may increase signs of anxiety. The present study examined the effects of acute and chronic administration of fluoxetine on a physiological measure of anxiety, stress-induced hyperthermia, in rats and mice using radiotelemetry to record core temperature and locomotor activity and ethologically relevant stressors to evoke the hyperthermic response. In both species, the benzodiazepine agonist chlordiazepoxide reduced stress-induced hyperthermia at doses (5 mg/kg i.p. rat, 10 mg/kg p.o. mouse) that had no significant effect on locomotor activity. Similarly, in both species, chronic (21 days) treatment with fluoxetine attenuated the hyperthermic response without significantly affecting locomotor activity. However, acute fluoxetine elicited species-specific effects. Thus in mice, stress-induced hyperthermia and activity were unaffected by fluoxetine (20 mg/kg p.o.) consistent with a lack of anxiolytic or anxiogenic activity. In contrast, in rats, fluoxetine (10 mg/kg i.p.) caused a significant baseline hypothermia in the absence of stress, confounding further interpretation. In conclusion, stress-induced hyperthermia in mice was unaffected by acute treatment and significantly reduced by chronic treatment with fluoxetine. However, in rats chronic administration of fluoxetine significantly reduced stress-induced hyperthermia while the effects of acute treatment were confounded by a decrease in body temperature in the absence of stress. Together, these observations support the view that chronic administration of fluoxetine is anxiolytic; however, the stress-induced hyperthermia assay does not reveal anxiogenic effects of acute administration of fluoxetine in rats or mice.     

Inhibition of serotonin release in the mouse brain via presynaptic cannabinoid CB1 receptors

We studied whether serotonin release in the CNS is inhibited via cannabinoid receptors. In mouse brain cortex slices preincubated with [3H]serotonin and superfused with medium containing indalpine and metitepine, tritium overflow was evoked either electrically (3 Hz) or by introduction of Ca2+ (1.3 mM) into Ca2+-free K+-rich (25 mM) medium containing tetrodotoxin. The effects of cannabinoid receptor ligands on the electrically evoked tritium overflow from mouse brain cortex slices preincubated with [3H]choline and on the binding of [3H]WIN 55,212-2 and [35S]GTPgammaS to mouse brain cortex membranes were examined as well. In superfused mouse cortex membranes preincubated with [3H]serotonin, the electrically evoked tritium overflow was inhibited by the cannabinoid receptor agonist WIN 55,212-2 (maximum effect of 20%, obtained at 1 microM; pEC50=7.11) and this effect was counteracted by the CB1 receptor antagonist SR 141716 (apparent pA2=8.02), which did not affect the evoked tritium overflow by itself. The effect of WIN 55,212-2 was not shared by its enantiomer WIN 55,212-3 but was mimicked by another cannabinoid receptor agonist, CP-55,940. WIN 55,212-2 also inhibited the Ca2+-evoked tritium overflow and this effect was antagonized by SR 141716. Concentrations of histamine, prostaglandin E2 and neuropeptide Y, causing the maximum effect at their respective receptors, inhibited the electrically evoked tritium overflow by 33, 69 and 73%, respectively. WIN 55,212-2 (1 microM) inhibited the electrically evoked tritium overflow from mouse brain cortex slices preincubated with [3H]choline by 49%. [3H]WIN 55,212-2 binding to mouse cortex membranes was inhibited by CP-55,940, SR 141716 and WIN 55,212-2 (pKi=9.30, 8.70 and 8.19, respectively) but not by the auxiliary drugs indalpine, metitepine and tetrodotoxin (pKi<4.5). [35S]GTPgammaS binding was increased by WIN 55,212-2 (maximum effect of 80%, pEC50=6.94) but not affected by WIN 55,212-3. In conclusion, serotonin release in the mouse brain cortex is inhibited via CB1 receptors, which may be located presynaptically and are not activated by endogenous cannabinoids. The extent of inhibition is smaller than that obtained (1) via another three presynaptic receptors on serotoninergic neurones and (2) via CB1 receptors on cholinergic neurones in the same tissue.     

Assessment of sodium-potassium ATPase activity in human erythrocytes in vitro

The red cell Na+,K+-ATPase pump activity was measured either by the ouabain-sensitive 86Rb-uptake in the presence or absence of 4 mM potassium in the external medium or by the ouabain-sensitive Na+-efflux in normal male subjects without any medication (n = 14) and during short-term treatment with the serotonin-antagonist, ketanserin. The ouabain-sensitive 86Rb-uptake in a medium containing 4 mM K+ was related to the 86Rb-uptake in a K+-free medium (r = 0.82; p less than 0.001) and to the Na+ efflux (r = 0.74; p less than 0.01). The intra-erythrocyte sodium concentration was negatively related to the ouabain-sensitive 86Rb-uptake (K+-free medium r = 0.59, p less than 0.05: 4 mM K+ in medium r = -0.85; p less than 0.01) and to the ouabain-sensitive Na+ efflux (r = -0.53; p less than 0.05). During serotonin antagonism with ketanserin no changes were found in the ouabain-sensitive 86Rb-uptake or Na+-efflux.     

R-citalopram attenuates anxiolytic effects of escitalopram in a rat ultrasonic vocalisation model

Escitalopram mediates the serotonin reuptake inhibitory effect of citalopram. To investigate the potential interactive effects between escitalopram and R-citalopram, they were studied at standard and elevated serotonin levels in a model predictive of anxiolytic activity (inhibition of footshock-induced ultrasonic vocalisation in adult rats). At standard levels, citalopram partially inhibited (64%) and escitalopram abolished (97%) vocalisation. Co-treatment with L-5-hydroxytryptophan resulted in complete inhibition with citalopram and a substantially enhanced response to escitalopram, while R-citalopram increased the vocalisation significantly. Furthermore, R-citalopram attenuated the effect of escitalopram. These findings may be relevant to the enhanced clinical efficacy seen with escitalopram compared to citalopram.